# Patent

## Title
Multicellular metabolic models and methods

## Abstract

The invention provides a computer readable medium or media, having: (a) a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (d) a constraint set for said plurality of reactions for said first, second and third data structures, and (e) commands for determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells. The first, second and third data structures also can include a plurality of data structures. Additionally provided is a method for predicting a physiological function of a multicellular organism. The method includes: (a) providing a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) providing a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) providing a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (d) providing a constraint set for said plurality of reactions for said first, second and third data structures; (e) providing an objective function, and (f) determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells.

## Background
This application claims benefit of the filing date of U.S. Provisional Application No. 60/368,588, filed Mar. 29, 2002, and which is incorporated herein by reference.
This application is a continuation-in-part application of U.S. Ser. No. 10/402,854, filed Mar. 27, 2003, and which is incorporated herein by reference in its entirety.


BACKGROUND OF THE INVENTION
This invention relates generally to analysis of the activity of chemical reaction networks and, more specifically, to computational methods for simulating and predicting the activity of multiple interacting reaction networks.
Therapeutic agents, including drugs and gene-based agents, are being rapidly developed by the pharmaceutical industry with the goal of preventing or treating human disease. Dietary supplements, including herbal products, vitamins and amino acids, are also being developed and marketed by the nutraceutical industry. Because of the complexity of the biochemical reaction networks in and between human cells, even relatively minor perturbations caused by a therapeutic agent or a dietary component in the abundance or activity of a particular target, such as a metabolite, gene or protein, can affect hundreds of biochemical reactions. These perturbations can lead to desirable therapeutic effects, such as cell stasis or cell death in the case of cancer cells or other pathologically hyperproliferative cells. However, these perturbations can also lead to undesirable side effects, such as production of toxic byproducts, if the systemic effects of the perturbations are not taken into account.
Current approaches to drug and nutraceutical development do not take into account the effect of a perturbation in a molecular target on systemic cellular behavior. In order to design effective methods of repairing, engineering or disabling cellular activities, it is essential to understand human cellular behavior from an integrated perspective.
Cellular metabolism, which is an example of a process involving a highly integrated network of biochemical reactions, is fundamental to all normal cellular or physiological processes, including homeostatis, proliferation, differentiation, programmed cell death (apoptosis) and motility. Alterations in cellular metabolism characterize a vast number of human diseases. For example, tissue injury is often characterized by increased catabolism of glucose, fatty acids and amino acids, which, if persistent, can lead to organ dysfunction. Conditions of low oxygen supply (hypoxia) and nutrient supply, such as occur in solid tumors, result in a myriad of adaptive metabolic changes including activation of glycolysis and neovascularization. Metabolic dysfunctions also contribute to neurodegenerative diseases, cardiovascular disease, neuromuscular diseases, obesity and diabetes. Currently, despite the importance of cellular metabolism to normal and pathological processes, a detailed systemic understanding of cellular metabolism in human cells is currently lacking.
Thus, there exists a need for models that describe interacting reaction networks within and between cells, including core metabolic reaction networks and metabolic reaction networks in specialized cell types, which can be used to simulate different aspects of multicellular behavior under physiological, pathological and therapeutic conditions. The present invention satisfies this need, and provides related advantages as well.
SUMMARY OF THE INVENTION
The invention provides a computer readable medium or media, having: (a) a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (d) a constraint set for said plurality of reactions for said first, second and third data structures, and (e) commands for determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells. The first, second and third data structures also can include a plurality of data structures. Additionally provided is a method for predicting a physiological function of a multicellular organism. The method includes: (a) providing a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) providing a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) providing a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (d) providing a constraint set for said plurality of reactions for said first, second and third data structures; (e) providing an objective function, and (f) determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a schematic representation of a hypothetical metabolic network.
FIG. 2 shows mass balance constraints and flux constraints (reversibility constraints) that can be placed on the hypothetical metabolic network shown in FIG. 1.
FIG. 3 shows the stoichiometric matrix (S) for the hypothetical metabolic network shown in FIG. 1.
FIG. 4 shows, in Panel A, an exemplary biochemical reaction network and in Panel B, an exemplary regulatory control structure for the reaction network in panel A.
FIG. 5 shows a metabolic network of central human metabolism.
FIG. 6 shows an example of a gene-protein-reaction association for trios-phosphate isomerase.
FIG. 7 shows a metabolic network of adipocyte metabolism.
FIG. 8 shows muscle contraction in a myocyte metabolic model.
FIG. 9 shows a metabolic network of myocyte metabolism.
FIG. 10 shows a metabolic network of coupled adipoctye-myocyte metabolism.
FIG. 11 shows triacylglycerol degradation in an adipocyte model.
FIG. 12 shows the impairment of muscle contraction as a result of lactate accumulation during anaerobic exercise. Time is in arbitrary unit. Concentration and yield of lactate (YLac) production are in mol/mol glucose.
FIG. 13 shows glycogen utilization versus (highlighted on the left) glucose utilization (highlighted on the right) in myocyte.



DETAILED DESCRIPTION OF THE INVENTION
The present invention provides in silico models that describe the interconnections between genes in the Homo sapiens genome and their associated reactions and reactants. The invention also provides in silico models that describe interconnections between different biochemical networks within a cell as well as between cells. The interconnections among different biochemical networks between cells can describe interactions between, for example, groups of cells including cells within different locations, tissues, organs or between cells carrying out different functions of a multicellular organism. Therefore, the models can be used to simulate different aspects of the cellular behavior of a cell derived from a multicellular organism, including a human cell, as well as be used to simulate different aspects of cellular behavioral interactions of groups of cells. Such groups of cells include, for example, eukaryotic cells, such as those of the same tissue type or colonies of prokaryotic cells, or different types of eukaryotic cells derived from the same or different tissue types from a multicellular organism. The different aspects of cellular behavior, including cellular behavioral interactions, can be simulated under different normal, pathological and therapeutic conditions, thereby providing valuable information for therapeutic, diagnostic and research applications. One advantage of the models of the invention is that they provide a holistic approach to simulating and predicting the activity of multicellular organisms, cellular interactions and individual cells, including the activity of Homo sapiens cells. Therefore, the models and methods can be used to simulate the activity of multiple interacting cells, including organs, physiological systems and whole body metabolism for practical diagnostic and therapeutic purposes.
In one embodiment, the invention is exemplified by reference to a metabolic model of a Homo sapien cell. This in silico model of an eukaryotic cell describes the cellular behavior resulting from two or more interacting networks because it can contain metabolic, regulatory and other network interactions, as described below. The models and methods of the invention applicable to the production and use of a cellular model containing two or more interacting networks also are applicable to the production and use of a multi-network model where the two or more networks are separated between compartments such as cells or tissues of a multicellular organism. Therefore, a Homo sapien or other eukaryotic cell model of the invention exemplifies application of the models and methods of the invention to models that describe the interaction of multiple biochemical networks between and among cells of a tissue, organ, physiological system or whole organism.
In another embodiment, the Homo sapiens metabolic models of the invention can be used to determine the effects of changes from aerobic to anaerobic conditions, such as occurs in skeletal muscles during exercise or in tumors, or to determine the effect of various dietary changes. The Homo sapiens metabolic models can also be used to determine the consequences of genetic defects, such as deficiencies in metabolic enzymes such as phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase and adenosine deaminase.
In a further embodiment, the invention provides a model of multicellular interactions that includes the network reconstruction, characteristics and simulation performance of an integrated two cell model of human adipocyte and myocyte cells. This multicellular model also included an intra-system biochemical network for extracellular physiological systems. The model was generated by reconstructing each of the component biochemical networks within the cells and combining them together with the addition of the intra-system biochemical network and achieved accurate predictive performance of the two cell types under different physiological conditions. Such multicellular metabolic models can be employed for the same determinations as described above for the Homo sapiens metabolic models. The determinations can be performed at the cellular, tissue, physiological system or organism level.
The multicellular and Homo sapiens metabolic models also can be used to choose appropriate targets for drug design. Such targets include genes, proteins or reactants, which when modulated positively or negatively in a simulation produce a desired therapeutic result. The models and methods of the invention can also be used to predict the effects of a therapeutic agent or dietary supplement on a cellular function of interest. Likewise, the models and methods can be used to predict both desirable and undesirable side effects of the therapeutic agent on an interrelated cellular function in the target cell, as well as the desirable and undesirable effects that may occur in other cell types. Thus, the models and methods of the invention can make the drug development process more rapid and cost effective than is currently possible.
The multicellular and Homo sapiens metabolic models also can be used to predict or validate the assignment of particular biochemical reactions to the enzyme-encoding genes found in the genome, and to identify the presence of reactions or pathways not indicated by current genomic data. Thus, the models can be used to guide the research and discovery process, potentially leading to the identification of new enzymes, medicines or metabolites of clinical importance.
The models of the invention are based on a data structure relating a plurality of reactants to a plurality of reactions, wherein each of the reactions includes a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product. The reactions included in the data structure can be those that are common to all or most cells or to a particular type or species of cell, including Homo sapiens cells, such as core metabolic reactions, or reactions specific for one or more given cell type.
As used herein, the term “reaction” is intended to mean a conversion that consumes a substrate or forms a product that occurs in or by a cell. The term can include a conversion that occurs due to the activity of one or more enzymes that are genetically encoded by a genome of the cell. The term can also include a conversion that occurs spontaneously in a cell. When used in reference to a Homo sapiens reaction, the term is intended to mean a conversion that consumes a substrate or forms a product that occurs in or by a Homo sapiens cell. Conversions included in the term include, for example, changes in chemical composition such as those due to nucleophilic or electrophilic addition, nucleophilic or electrophilic substitution, elimination, isomerization, deamination, phosphorylation, methylation, reduction, oxidation or changes in location such as those that occur due to a transport reaction that moves a reactant from one cellular compartment to another. In the case of a transport reaction, the substrate and product of the reaction can be chemically the same and the substrate and product can be differentiated according to location in a particular cellular compartment. Thus, a reaction that transports a chemically unchanged reactant from a first compartment to a second compartment has as its substrate the reactant in the first compartment and as its product the reactant in the second compartment. It will be understood that when used in reference to an in silico model or data structure, a reaction is intended to be a representation of a chemical conversion that consumes a substrate or produces a product.
As used herein, the term “reactant” is intended to mean a chemical that is a substrate or a product of a reaction that occurs in or by a cell. The term can include substrates or products of reactions performed by one or more enzymes encoded by a genome, reactions occurring in cells or organisms that are performed by one or more non-genetically encoded macromolecule, protein or enzyme, or reactions that occur spontaneously in a cell. When used in reference to a Homo sapiens reactant, the term is intended to mean a chemical that is a substrate or product of a reaction that occurs in or by a Homo sapiens cell. Metabolites are understood to be reactants within the meaning of the term. It will be understood that when used in reference to an in silico model or data structure, a reactant is intended to be a representation of a chemical that is a substrate or a product of a reaction that occurs in or by a cell.
As used herein the term “substrate” is intended to mean a reactant that can be converted to one or more products by a reaction. The term can include, for example, a reactant that is to be chemically changed due to nucleophilic or electrophilic addition, nucleophilic or electrophilic substitution, elimination, isomerization, deamination, phosphorylation, methylation, reduction, oxidation or that is to change location such as by being transported across a membrane or to a different compartment.
As used herein, the term “product” is intended to mean a reactant that results from a reaction with one or more substrates. The term can include, for example, a reactant that has been chemically changed due to nucleophilic or electrophilic addition, nucleophilic or electrophilic substitution, elimination, isomerization, deamination, phosphorylation, methylation, reduction or oxidation or that has changed location such as by being transported across a membrane or to a different compartment.
As used herein, the term “stoichiometric coefficient” is intended to mean a numerical constant correlating the number of one or more reactants and the number of one or more products in a chemical reaction. Typically, the numbers are integers as they denote the number of molecules of each reactant in an elementally balanced chemical equation that describes the corresponding conversion. However, in some cases the numbers can take on non-integer values, for example, when used in a lumped reaction or to reflect empirical data.
As used herein, the term “plurality,” when used in reference to reactions or reactants including Homo sapiens reactions or reactants, is intended to mean at least 2 reactions or reactants. The term can include any number of reactions or reactants in the range from 2 to the number of naturally occurring reactants or reactions for a particular of cell or cells. Thus, the term can include, for example, at least 10, 20, 30, 50, 100, 150, 200, 300, 400, 500, 600 or more reactions or reactants. The number of reactions or reactants can be expressed as a portion of the total number of naturally occurring reactions for a particular cell or cells including a Homo sapiens cell or cells, such as at least 20%, 30%, 50%, 60%, 75%, 90%, 95% or 98% of the total number of naturally occurring reactions that occur in a particular Homo sapiens cell.
Similarly, the term “plurality,” when used in reference to data structures, is intended to mean at least 2 data structures. The term can include any number of data structures in the range from 2 to the number of naturally occurring biochemical networks for a particular subsystem, system, intracellular system, cellular compartment, organelle, extra-cellular space, cytosol, mitochondrion, nucleus, endoplasmic reticulum, group of cells, tissue, organ or organism. Therefore, the term can include, for example, at least about 3, 4, 5, 6, 7, 8, 9, 10, 25, 20, 25, 50, 100 or more biochemical networks. The term also can be expressed as a portion of the total number of naturally occurring networks for any of the particular categories above occurring in prokaryotic or eukaryotic cells including Homo sapiens. 
As used herein, the term “data structure” is intended to mean a physical or logical relationship among data elements, designed to support specific data manipulation functions. The term can include, for example, a list of data elements that can be added combined or otherwise manipulated such as a list of representations for reactions from which reactants can be related in a matrix or network. The term can also include a matrix that correlates data elements from two or more lists of information such as a matrix that correlates reactants to reactions. Information included in the term can represent, for example, a substrate or product of a chemical reaction, a chemical reaction relating one or more substrates to one or more products, a constraint placed on a reaction, or a stoichiometric coefficient.
As used herein, the term “constraint” is intended to mean an upper or lower boundary for a reaction. A boundary can specify a minimum or maximum flow of mass, electrons or energy through a reaction. A boundary can further specify directionality of a reaction. A boundary can be a constant value such as zero, infinity, or a numerical value such as an integer. Alternatively, a boundary can be a variable boundary value as set forth below.
As used herein, the term “variable,” when used in reference to a constraint is intended to mean capable of assuming any of a set of values in response to being acted upon by a constraint function. The term “function,” when used in the context of a constraint, is intended to be consistent with the meaning of the term as it is understood in the computer and mathematical arts. A function can be binary such that changes correspond to a reaction being off or on. Alternatively, continuous functions can be used such that changes in boundary values correspond to increases or decreases in activity. Such increases or decreases can also be binned or effectively digitized by a function capable of converting sets of values to discreet integer values. A function included in the term can correlate a boundary value with the presence, absence or amount of a biochemical reaction network participant such as a reactant, reaction, enzyme or gene. A function included in the term can correlate a boundary value with an outcome of at least one reaction in a reaction network that includes the reaction that is constrained by the boundary limit. A function included in the term can also correlate a boundary value with an environmental condition such as time, pH, temperature or redox potential.
As used herein, the term “activity,” when used in reference to a reaction, is intended to mean the amount of product produced by the reaction, the amount of substrate consumed by the reaction or the rate at which a product is produced or a substrate is consumed. The amount of product produced by the reaction, the amount of substrate consumed by the reaction or the rate at which a product is produced or a substrate is consumed can also be referred to as the flux for the reaction.
As used herein, the term “activity,” when used in reference to a Homo sapiens cell or a multicellular interaction, is intended to mean the magnitude or rate of a change from an initial state to a final state. The term can include, for example, the amount of a chemical consumed or produced by a cell, the rate at which a chemical is consumed or produced by a cell, the amount or rate of growth of a cell or the amount of or rate at which energy, mass or electrons flow through a particular subset of reactions.
The invention provides a computer readable medium, having a data structure relating a plurality of Homo sapiens reactants to a plurality of Homo sapiens reactions, wherein each of the Homo sapiens reactions includes a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product.
Also provided is a computer readable medium or media, having: (a) a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) a constraint set for said plurality of reactions for said first, second and third data structures, and (d) commands for determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells.
Depending on the application, the plurality of reactions for any of a multicellular, multi-network or single cell model or method of the invention, including a Homo sapiens cell model or method, can include reactions selected from core metabolic reactions or peripheral metabolic reactions. As used herein, the term “core,” when used in reference to a metabolic pathway, is intended to mean a metabolic pathway selected from glycolysis/gluconeogenesis, the pentose phosphate pathway (PPP), the tricarboxylic acid (TCA) cycle, glycogen storage, electron transfer system (ETS), the malate/aspartate shuttle, the glycerol phosphate shuttle, and plasma and mitochondrial membrane transporters. As used herein, the term “peripheral,” when used in reference to a metabolic pathway, is intended to mean a metabolic pathway that includes one or more reactions that are not a part of a core metabolic pathway.
A plurality of reactants can be related to a plurality of reactions in any data structure that represents, for each reactant, the reactions by which it is consumed or produced. Thus, the data structure, which is referred to herein as a “reaction network data structure,” serves as a representation of a biological reaction network or system. An example of a reaction network that can be represented in a reaction network data structure of the invention is the collection of reactions that constitute the core metabolic reactions of Homo sapiens, or the metabolic reactions of a skeletal muscle cell, as shown in the Examples. Further examples of reaction networks that can be represented in a reaction network data structure of the invention are the collection of reactions that constitute the core metabolic reactions and the triacylglycerol (TAG) biosynthetic pathways of an adipocyte cell; the core metabolic reactions and the energy and contractile reactions of a myocyte cell, and the intra-system reactions that supply buffering functions of the kidney.
The choice of reactions to include in a particular reaction network data structure, from among all the possible reactions that can occur in multicellular organisms or among multicellular interactions, including human cells, depends on the cell type or types and the physiological, pathological or therapeutic condition being modeled, and can be determined experimentally or from the literature, as described further below.
The reactions to be included in a particular network data structure of a multicellular interaction can be determined experimentally using, for example, gene or protein expression profiles, where the molecular characteristics of the cell can be correlated to the expression levels. The expression or lack of expression of genes or proteins in a cell type can be used in determining whether a reaction is included in the model by association to the expressed gene(s) and or protein(s). Thus, it is possible to use experimental technologies to determine which genes and/or proteins are expressed in a specific cell type, and to further use this information to determine which reactions are present in the cell type of interest. In this way a subset of reactions from all of those reactions that can occur in human cells are selected to comprise the set of reactions that represent a specific cell type. cDNA expression profiles have been demonstrated to be useful, for example, for classification of breast cancer cells (Sorlie et al., Proc. Natl. Acad. Sci. U.S.A. 98(19):10869-10874 (2001)).
The methods and models of the invention can be applied to any multicellular interaction as well as to any Homo sapiens cell type at any stage of differentiation, including, for example, embryonic stem cells, hematopoietic stem cells, differentiated hematopoietic cells, skeletal muscle cells, cardiac muscle cells, smooth muscle cells, skin cells, nerve cells, kidney cells, pulmonary cells, liver cells, adipocytes and endocrine cells (e.g. beta islet cells of the pancreas, mammary gland cells, adrenal cells, and other specialized hormone secreting cells). Similarly, the methods and models of the invention can be applied to any interaction between any of these cell types, including two or more of the same cell type or two or more different cell types. Described below in Example IV is an example of the interactions that occur between myocyte cells and adipocyte cells during different physiological conditions.
The methods and models of the invention can be applied to normal cells, pathological cells as well as to combinations of interactions between normal cells, interactions between pathological cells or interactions between normal and pathological cells. Normal cells that exhibit a variety of physiological activities of interest, including homeostasis, proliferation, differentiation, apoptosis, contraction and motility, can be modeled. Pathological cells can also be modeled, including cells that reflect genetic or developmental abnormalities, nutritional deficiencies, environmental assaults, infection (such as by bacteria, viral, protozoan or fungal agents), neoplasia, aging, altered immune or endocrine function, tissue damage, or any combination of these factors. The pathological cells can be representative of any type of pathology, such as a human pathology, including, for example, various metabolic disorders of carbohydrate, lipid or protein metabolism, obesity, diabetes, cardiovascular disease, fibrosis, various cancers, kidney failure, immune pathologies, neurodegenerative diseases, and various monogenetic metabolic diseases described in the Online Mendelian Inheritance in Man database (Center for Medical Genetics, Johns Hopkins University (Baltimore, Md.) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, Md.)).
The methods and models of the invention can also be applied to cells or organisms undergoing therapeutic perturbations, such as cells treated with drugs that target participants in a reaction network or cause an effect on an interactive reaction network, cells or tissues treated with gene-based therapeutics that increase or decrease expression of an encoded protein, and cells or tissues treated with radiation. As used herein, the term “drug” refers to a compound of any molecular nature with a known or proposed therapeutic function, including, for example, small molecule compounds, peptides and other macromolecules, peptidomimetics and antibodies, any of which can optionally be tagged with cytostatic, targeting or detectable moieties. The term “gene-based therapeutic” refers to nucleic acid therapeutics, including, for example, expressible genes with normal or altered protein activity, antisense compounds, ribozymes, DNAzymes, RNA interference compounds (RNAi) and the like. The therapeutics can target any reaction network participant, in any cellular location, including participants in extracellular, cell surface, cytoplasmic, mitochondrial and nuclear locations. Experimental data that are gathered on the response of cells, tissues, or interactions thereof, to therapeutic treatment, such as alterations in gene or protein expression profiles, can be used to tailor a network or a combination of networks for a pathological state of a particular cell type.
The methods and models of the invention can be applied to cells, tissues and physiological systems, including Homo sapiens cells, tissues and physiological systems, as they exist in any form, such as in primary cell isolates or in established cell lines, or in the whole body, in intact organs or in tissue explants. Accordingly, the methods and models can take into account intercellular communications and/or inter-organ communications, the effect of adhesion to a substrate or neighboring cells (such as a stem cell interacting with mesenchymal cells or a cancer cell interacting with its tissue microenvironment, or beta-islet cells without normal stroma), and other interactions relevant to multicellular systems.
The reactants to be used in a reaction network data structure of the invention can be obtained from or stored in a compound database. As used herein, the term “compound database” is intended to mean a computer readable medium or media containing a plurality of molecules that includes substrates and products of biological reactions. The plurality of molecules can include molecules found in multiple organisms, thereby constituting a universal compound database. Alternatively, the plurality of molecules can be limited to those that occur in a particular organism, thereby constituting an organism-specific compound database. Each reactant in a compound database can be identified according to the chemical species and the cellular compartment in which it is present. Thus, for example, a distinction can be made between glucose in the extracellular compartment versus glucose in the cytosol. Additionally each of the reactants can be specified as a metabolite of a primary or secondary metabolic pathway. Although identification of a reactant as a metabolite of a primary or secondary metabolic pathway does not indicate any chemical distinction between the reactants in a reaction, such a designation can assist in visual representations of large networks of reactions.
As used herein, the term “compartment” is intended to mean a subdivided region containing at least one reactant, such that the reactant is separated from at least one other reactant in a second region. A subdivided region included in the term can be correlated with a subdivided region of a cell. Thus, a subdivided region included in the term can be, for example, the intracellular space of a cell; the extracellular space around a cell; the periplasmic space, the interior space of an organelle such as a mitochondrium, endoplasmic reticulum, Golgi apparatus, vacuole or nucleus; or any subcellular space that is separated from another by a membrane or other physical barrier. For example, a mitochondrial compartment is a subdivided region of the intracellular space of a cell, which in turn, is a subdivided region of a cell or tissue. A subdivided region also can include, for example, different regions or systems of a tissue, organ or physiological system of an organism. Subdivided regions can also be made in order to create virtual boundaries in a reaction network that are not correlated with physical barriers. Virtual boundaries can be made for the purpose of segmenting the reactions in a network into different compartments or substructures.
As used herein, the term “substructure” is intended to mean a portion of the information in a data structure that is separated from other information in the data structure such that the portion of information can be separately manipulated or analyzed. The term can include portions subdivided according to a biological function including, for example, information relevant to a particular metabolic pathway such as an internal flux pathway, exchange flux pathway, central metabolic pathway, peripheral metabolic pathway, or secondary metabolic pathway. The term can include portions subdivided according to computational or mathematical principles that allow for a particular type of analysis or manipulation of the data structure.
The reactions included in a reaction network data structure can be obtained from a metabolic reaction database that includes the substrates, products, and stoichiometry of a plurality of metabolic reactions of Homo sapiens, other multicellular organisms or single cell organisms that exhibit biochemical or physiological interactions. The reactants in a reaction network data structure can be designated as either substrates or products of a particular reaction, each with a stoichiometric coefficient assigned to it to describe the chemical conversion taking place in the reaction. Each reaction is also described as occurring in either a reversible or irreversible direction. Reversible reactions can either be represented as one reaction that operates in both the forward and reverse direction or be decomposed into two irreversible reactions, one corresponding to the forward reaction and the other corresponding to the backward reaction.
Reactions included in a reaction network data structure can include intra-system or exchange reactions. Intra-system reactions are the chemically and electrically balanced interconversions of chemical species and transport processes, which serve to replenish or drain the relative amounts of certain metabolites. These intra-system reactions can be classified as either being transformations or translocations. A transformation is a reaction that contains distinct sets of compounds as substrates and products, while a translocation contains reactants located in different compartments. Thus a reaction that simply transports a metabolite from the extracellular environment to the cytosol, without changing its chemical composition is solely classified as a translocation, while a reaction that takes an extracellular substrate and converts it into a cytosolic product is both a translocation and a transformation. Further, intra-system reactions can include reactions representing one or more biochemical or physiological functions of an independent cell, tissue, organ or physiological system. For example, the buffering function of the kidneys for the hematopoietic system and intra-cellular environments can be represented as intra-system reactions and be included in a multicellular interaction model either as an independent reaction network or merged with one or more reaction networks of the constituent cells.
Exchange reactions are those which constitute sources and sinks, allowing the passage of metabolites into and out of a compartment or across a hypothetical system boundary. These reactions are included in a model for simulation purposes and represent the metabolic demands placed on Homo sapiens. While they may be chemically balanced in certain cases, they are typically not balanced and can often have only a single substrate or product. As a matter of convention the exchange reactions are further classified into demand exchange and input/output exchange reactions.
The metabolic demands placed on a multicellular or Homo sapiens metabolic reaction network can be readily determined from the dry weight composition of the cell, cells, tissue, organ or organism which is available in the published literature or which can be determined experimentally. The uptake rates and maintenance requirements for Homo sapiens cells can also be obtained from the published literature or determined experimentally.
Input/output exchange reactions are used to allow extracellular reactants to enter or exit the reaction network represented by a model of the invention. For each of the extracellular metabolites a corresponding input/output exchange reaction can be created. These reactions are always reversible with the metabolite indicated as a substrate with a stoichiometric coefficient of one and no products produced by the reaction. This particular convention is adopted to allow the reaction to take on a positive flux value (activity level) when the metabolite is being produced or removed from the reaction network and a negative flux value when the metabolite is being consumed or introduced into the reaction network. These reactions will be further constrained during the course of a simulation to specify exactly which metabolites are available to the cell and which can be excreted by the cell.
A demand exchange reaction is always specified as an irreversible reaction containing at least one substrate. These reactions are typically formulated to represent the production of an intracellular metabolite by the metabolic network or the aggregate production of many reactants in balanced ratios such as in the representation of a reaction that leads to biomass formation, also referred to as growth.
A demand exchange reactions can be introduced for any metabolite in a model of the invention. Most commonly these reactions are introduced for metabolites that are required to be produced by the cell for the purposes of creating a new cell such as amino acids, nucleotides, phospholipids, and other biomass constituents, or metabolites that are to be produced for alternative purposes. Once these metabolites are identified, a demand exchange reaction that is irreversible and specifies the metabolite as a substrate with a stoichiometric coefficient of unity can be created. With these specifications, if the reaction is active it leads to the net production of the metabolite by the system meeting potential production demands. Examples of processes that can be represented as a demand exchange reaction in a reaction network data structure and analyzed by the methods of the invention include, for example, production or secretion of an individual protein; production or secretion of an individual metabolite such as an amino acid, vitamin, nucleoside, antibiotic or surfactant; production of ATP for extraneous energy requiring processes such as locomotion or muscle contraction; or formation of biomass constituents.
In addition to these demand exchange reactions that are placed on individual metabolites, demand exchange reactions that utilize multiple metabolites in defined stoichiometric ratios can be introduced. These reactions are referred to as aggregate demand exchange reactions. An example of an aggregate demand reaction is a reaction used to simulate the concurrent growth demands or production requirements associated with cell growth that are placed on a cell, for example, by simulating the formation of multiple biomass constituents simultaneously at a particular cellular or organismic growth rate.
A specific reaction network is provided in FIG. 1 to exemplify the above-described reactions and their interactions. The reactions can be represented in the exemplary data structure shown in FIG. 3 as set forth below. The reaction network, shown in FIG. 1, includes intra-system reactions that occur entirely within the compartment indicated by the shaded oval such as reversible reaction R2 which acts on reactants B and G and reaction R3 which converts one equivalent of B to 2 equivalents of F. The reaction network shown in FIG. 1 also contains exchange reactions such as input/output exchange reactions Axt and Ext, and the demand exchange reaction, Vgrowth, which represents growth in response to the one equivalent of D and one equivalent of F. Other intra-system reactions include R1 which is a translocation and transformation reaction that translocates reactant A into the compartment and transforms it to reactant G and reaction R6 which is a transport reaction that translocates reactant E out of the compartment.
A reaction network can be represented as a set of linear algebraic equations which can be presented as a stoichiometric matrix S, with S being an m×n matrix where m corresponds to the number of reactants or metabolites and n corresponds to the number of reactions taking place in the network. An example of a stoichiometric matrix representing the reaction network of FIG. 1 is shown in FIG. 3. As shown in FIG. 3, each column in the matrix corresponds to a particular reaction n, each row corresponds to a particular reactant m, and each Smn element corresponds to the stoichiometric coefficient of the reactant m in the reaction denoted n. The stoichiometric matrix includes intra-system reactions such as R2 and R3 which are related to reactants that participate in the respective reactions according to a stoichiometric coefficient having a sign indicative of whether the reactant is a substrate or product of the reaction and a value correlated with the number of equivalents of the reactant consumed or produced by the reaction. Exchange reactions such as −Ext and −Axt are similarly correlated with a stoichiometric coefficient. As exemplified by reactant E, the same compound can be treated separately as an internal reactant (E) and an external reactant (Eexternal) such that an exchange reaction (R6) exporting the compound is correlated by stoichiometric coefficients of −1 and 1, respectively. However, because the compound is treated as a separate reactant by virtue of its compartmental location, a reaction, such as R5, which produces the internal reactant (E) but does not act on the external reactant (Eexternal) is correlated by stoichiometric coefficients of 1 and 0, respectively. Demand reactions such as Vgrowth can also be included in the stoichiometric matrix being correlated with substrates by an appropriate stoichiometric coefficient.
As set forth in further detail below, a stoichiometric matrix provides a convenient format for representing and analyzing a reaction network because it can be readily manipulated and used to compute network properties, for example, by using linear programming or general convex analysis. A reaction network data structure can take on a variety of formats so long as it is capable of relating reactants and reactions in the manner exemplified above for a stoichiometric matrix and in a manner that can be manipulated to determine an activity of one or more reactions using methods such as those exemplified below. Other examples of reaction network data structures that are useful in the invention include a connected graph, list of chemical reactions or a table of reaction equations.
A reaction network data structure can be constructed to include all reactions that are involved in metabolism occurring during the interaction of two or more cells, Homo sapiens cell metabolism or any portion thereof. A portion of an organisms metabolic reactions that can be included in a reaction network data structure of the invention includes, for example, a central metabolic pathway such as glycolysis, the TCA cycle, the PPP or ETS; or a peripheral metabolic pathway such as amino acid biosynthesis, amino acid degradation, purine biosynthesis, pyrimidine biosynthesis, lipid biosynthesis, fatty acid metabolism, vitamin or cofactor biosynthesis, transport processes and alternative carbon source catabolism. Examples of individual pathways within the peripheral pathways are set forth in Table 1. Other examples of portions of metabolic reactions that can be included in a reaction network data structure of the invention include, for example, TAG biosynthesis, muscle contraction requirements, bicarbonate buffer system and/or ammonia buffer system. Specific examples of these and other reactions are described further below and in the Examples.
Depending upon a particular application, a reaction network data structure can include a plurality of Homo sapiens reactions including any or all of the reactions listed in Table 1. Similarly, a reaction network data structure also can include the reaction set forth in Examples I-IV and include, for example, single reaction networks, multiple reaction networks that interact within a cell as well as multiple reaction networks that interact between cells or physiological systems.
For some applications, it can be advantageous to use a reaction network data structure that includes a minimal number of reactions to achieve a particular Homo sapiens activity or activity of a multicellular interaction under a particular set of environmental conditions. A reaction network data structure having a minimal number of reactions can be identified by performing the simulation methods described below in an iterative fashion where different reactions or sets of reactions are systematically removed and the effects observed. Accordingly, the invention provides a computer readable medium, containing a data structure relating a plurality of Homo sapiens reactants to a plurality of Homo sapiens reactions, wherein the plurality of Homo sapiens reactions contains at least 65 reactions. For example, the core metabolic reaction database shown in Tables 2 and 3 contains 65 reactions, and is sufficient to simulate aerobic and anaerobic metabolism on a number of carbon sources, including glucose. Similarly, the invention provides a computer readable medium containing a data structure relating a plurality of reactants of multicellular interactions to a plurality of reactions from multicellular interactions, wherein the reactions contain at least 430 for a two cell interaction. Such reactions between multicellular interactions are exemplified in Table 11, for example.
Depending upon the particular cell type or types, the physiological, pathological or therapeutic conditions being tested, the desired activity and the number of cellular interactions of a model or method of the invention, a reaction network data structure can contain smaller numbers of reactions such as at least 200, 150, 100 or 50 reactions. A reaction network data structure having relatively few reactions can provide the advantage of reducing computation time and resources required to perform a simulation. When desired, a reaction network data structure having a particular subset of reactions can be made or used in which reactions that are not relevant to the particular simulation are omitted. Alternatively, larger numbers of reactions can be included in order to increase the accuracy or molecular detail of the methods of the invention or to suit a particular application. Thus, a reaction network data structure can contain at least 300, 350, 400, 450, 500, 550, 600 or more reactions up to the number of reactions that occur in or by multicellular interactions, including Homo sapiens, or that are desired to simulate the activity of the full set of reactions occurring in multicellular interactions, including Homo sapiens. A reaction network data structure that is substantially complete with respect to the metabolic reactions of a multicellular organism, including Homo sapiens, provides an advantage of being relevant to a wide range of conditions to be simulated, whereas those with smaller numbers of metabolic reactions are specific to a particular subset of conditions to be simulated.
A Homo sapiens reaction network data structure can include one or more reactions that occur in or by Homo sapiens and that do not occur, either naturally or following manipulation, in or by another organism, such as Saccharomyces cerevisiae. It is understood that a Homo sapiens reaction network data structure of a particular cell type can also include one or more reactions that occur in another cell type. Addition of such heterologous reactions to a reaction network data structure of the invention can be used in methods to predict the consequences of heterologous gene transfer and protein expression, for example, when designing in vivo and ex vivo gene therapy approaches. Similarly, reaction networks for a multicellular interactions also can include one or more reactions that occur entirely within the species of origin of the cellular interactions or can contain one or more heterologous reactions from one or more different species.
The reactions included in a reaction network data structure of the invention can be metabolic reactions. A reaction network data structure can also be constructed to include other types of reactions such as regulatory reactions, signal transduction reactions, cell cycle reactions, reactions controlling developmental processes, reactions involved in apoptosis, reactions involved in responses to hypoxia, reactions involved in responses to cell-cell or cell-substrate interactions, reactions involved in protein synthesis and regulation thereof, reactions involved in gene transcription and translation, and regulation thereof, and reactions involved in assembly of a cell and its subcellular components.
A reaction network data structure or index of reactions used in the data structure such as that available in a metabolic reaction database, as described above, can be annotated to include information about a particular reaction. A reaction can be annotated to indicate, for example, assignment of the reaction to a protein, macromolecule or enzyme that performs the reaction, assignment of a gene(s) that codes for the protein, macromolecule or enzyme, the Enzyme Commission (EC) number of the particular metabolic reaction, a subset of reactions to which the reaction belongs, citations to references from which information was obtained, or a level of confidence with which a reaction is believed to occur in Homo sapiens or other organism. A computer readable medium or media of the invention can include a gene database containing annotated reactions. Such information can be obtained during the course of building a metabolic reaction database or model of the invention as described below.
As used herein, the term “gene database” is intended to mean a computer readable medium or media that contains at least one reaction that is annotated to assign a reaction to one or more macromolecules that perform the reaction or to assign one or more nucleic acid that encodes the one or more macromolecules that perform the reaction. A gene database can contain a plurality of reactions, some or all of which are annotated. An annotation can include, for example, a name for a macromolecule; assignment of a function to a macromolecule; assignment of an organism that contains the macromolecule or produces the macromolecule; assignment of a subcellular location for the macromolecule; assignment of conditions under which a macromolecule is regulated with respect to performing a reaction, being expressed or being degraded; assignment of a cellular component that regulates a macromolecule; an amino acid or nucleotide sequence for the macromolecule; a mRNA isoform, enzyme isoform, or any other desirable annotation or annotation found for a macromolecule in a genome database such as those that can be found in Genbank, a site maintained by the NCBI (ncbi.nlm.gov), the Kyoto Encyclopedia of Genes and Genomes (KEGG) (www.genome.ad.jp/kegg/), the protein database SWISS-PROT (ca.expasy.org/sprot/), the LocusLink database maintained by the NCBI (www.ncbi.nlm.nih.gov/LocusLink/), the Enzyme Nomenclature database maintained by G. P. Moss of Queen Mary and Westfield College in the United Kingdom (www.chem.qmw.ac.uk/iubmb/enzyme/).
A gene database of the invention can include a substantially complete collection of genes or open reading frames in a multicellular organism, including Homo sapiens, or a substantially complete collection of the macromolecules encoded by the organism's genome. Alternatively, a gene database can include a portion of genes or open reading frames in an organism or a portion of the macromolecules encoded by the organism's genome, such as the portion that includes substantially all metabolic genes or macromolecules. The portion can be at least 10%, 15%, 20%, 25%, 50%, 75%, 90% or 95% of the genes or open reading frames encoded by the organism's genome, or the macromolecules encoded therein. A gene database can also include macromolecules encoded by at least a portion of the nucleotide sequence for the organism's genome such as at least 10%, 15%, 20%, 25%, 50%, 75%, 90% or 95% of the organism's genome. Accordingly, a computer readable medium or media of the invention can include at least one reaction for each macromolecule encoded by a portion of an organism's genome, including a Homo sapiens genome.
An in silico model of multicellular interactions, including a Homo sapiens model, of the invention can be built by an iterative process which includes gathering information regarding particular reactions to be added to a model, representing the reactions in a reaction network data structure, and performing preliminary simulations wherein a set of constraints is placed on the reaction network and the output evaluated to identify errors in the network. Errors in the network such as gaps that lead to non-natural accumulation or consumption of a particular metabolite can be identified as described below and simulations repeated until a desired performance of the model is attained. An exemplary method for iterative model construction is provided in Example I. For multicellular interactions, an iterative process includes producing one or more component reaction networks followed by combining the components into a higher order multi-network system, as described in Example IV. For example, components can include the central metabolism reaction network and the cell specific reaction networks such as TAG biosynthesis for adipocytes or muscle contraction for myocytes. Combination of the central metabolism and the cell specific reaction networks into a single model produces, for example, a cell specific reaction network. Components also can include the individual cell types, tissues, physiological systems or intra-system reaction networks that are constituents of the larger multicellular system. Combining these components into a larger model produces, for example, a model describing the relationships and interactions of the multicellular system together with its various interactions.
Thus, the invention provides a method for making a data structure relating a plurality of reactants to a plurality of reactions in a computer readable medium or media. The method includes the steps of: (a) identifying a plurality of reactions and a plurality of reactants that are substrates and products of the reactions; (b) relating the plurality of reactants to the plurality of Homo sapiens reactions in a data structure, wherein each of the reactions includes a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product; (c) making a constraint set for the plurality of reactions; (d) providing an objective function; (e) determining at least one flux distribution that minimizes or maximizes the objective function when the constraint set is applied to the data structure, and (f) if the at least one flux distribution is not predictive of physiology, then adding a reaction to or deleting a reaction from the data structure and repeating step (e), if the at least one flux distribution is predictive of physiology, then storing the data structure in a computer readable medium or media. The method can be applied to multicellular interactions within or among single or multicullar organisms, including Homo sapiens. 
Information to be included in a data structure of the invention can be gathered from a variety of sources including, for example, annotated genome sequence information and biochemical literature.
Sources of annotated human genome sequence information include, for example, KEGG, SWISS-PROT, LocusLink, the Enzyme Nomenclature database, the International Human Genome Sequencing Consortium and commercial databases. KEGG contains a broad range of information, including a substantial amount of metabolic reconstruction. The genomes of 304 organisms can be accessed here, with gene products grouped by coordinated functions, often represented by a map (e.g., the enzymes involved in glycolysis would be grouped together). The maps are biochemical pathway templates which show enzymes connecting metabolites for various parts of metabolism. These general pathway templates are customized for a given organism by highlighting enzymes on a given template which have been identified in the genome of the organism. Enzymes and metabolites are active and yield useful information about stoichiometry, structure, alternative names and the like, when accessed.
SWISS-PROT contains detailed information about protein function. Accessible information includes alternate gene and gene product names, function, structure and sequence information, relevant literature references, and the like.
LocusLink contains general information about the locus where the gene is located and, of relevance, tissue specificity, cellular location, and implication of the gene product in various disease states.
The Enzyme Nomenclature database can be used to compare the gene products of two organisms. Often the gene names for genes with similar functions in two or more organisms are unrelated. When this is the case, the E.C. (Enzyme Commission) numbers can be used as unambiguous indicators of gene product function. The information in the Enzyme Nomenclature database is also published in Enzyme Nomenclature (Academic Press, San Diego, Calif., 1992) with 5 supplements to date, all found in the European Journal of Biochemistry (Blackwell Science, Malden, Mass.).
Sources of biochemical information include, for example, general resources relating to metabolism, resources relating specifically to human metabolism, and resources relating to the biochemistry, physiology and pathology of specific human cell types.
Sources of general information relating to metabolism, which were used to generate the human reaction databases and models described herein, were J. G. Salway, Metabolism at a Glance, 2nd ed., Blackwell Science, Malden, Mass. (1999) and T. M. Devlin, ed., Textbook of Biochemistry with Clinical Correlations, 4th ed., John Wiley and Sons, New York, N.Y. (1997). Human metabolism-specific resources included J. R. Bronk, Human Metabolism: Functional Diversity and Integration, Addison Wesley Longman, Essex, England (1999).
The literature used in conjunction with the skeletal muscle metabolic models and simulations described herein included R. Maughan et al., Biochemistrv of Exercise and Training, Oxford University Press, Oxford, England (1997), as well as references on muscle pathology such as S. Carpenter et al., Pathology of Skeletal Muscle, 2nd ed., Oxford University Press, Oxford, England (2001), and more specific articles on muscle metabolism as may be found in the Journal of Physiology (Cambridge University Press, Cambridge, England).
In the course of developing an in silico model of metabolism during or for multicellular interactions, the types of data that can be considered include, for example, biochemical information which is information related to the experimental characterization of a chemical reaction, often directly indicating a protein(s) associated with a reaction and the stoichiometry of the reaction or indirectly demonstrating the existence of a reaction occurring within a cellular extract; genetic information, which is information related to the experimental identification and genetic characterization of a gene(s) shown to code for a particular protein(s) implicated in carrying out a biochemical event; genomic information, which is information related to the identification of an open reading frame and functional assignment, through computational sequence analysis, that is then linked to a protein performing a biochemical event; physiological information, which is information related to overall cellular physiology, fitness characteristics, substrate utilization, and phenotyping results, which provide evidence of the assimilation or dissimilation of a compound used to infer the presence of specific biochemical event (in particular translocations); and modeling information, which is information generated through the course of simulating activity of cells, tissues or physiological systems using methods such as those described herein which lead to predictions regarding the status of a reaction such as whether or not the reaction is required to fulfill certain demands placed on a metabolic network. Additional information relevant to multicellular organisms that can be considered includes, for example, cell type-specific or condition-specific gene expression information, which can be determined experimentally, such as by gene array analysis or from expressed sequence tag (EST) analysis, or obtained from the biochemical and physiological literature.
The majority of the reactions occurring in a multicellular organism's reaction networks are catalyzed by enzymes/proteins, which are created through the transcription and translation of the genes found within the chromosome in the cell. The remaining reactions occur either spontaneously or through non-enzymatic processes. Furthermore, a reaction network data structure can contain reactions that add or delete steps to or from a particular reaction pathway. For example, reactions can be added to optimize or improve performance of a model for multicellular interactions in view of empirically observed activity. Alternatively, reactions can be deleted to remove intermediate steps in a pathway when the intermediate steps are not necessary to model flux through the pathway. For example, if a pathway contains 3 nonbranched steps, the reactions can be combined or added together to give a net reaction, thereby reducing memory required to store the reaction network data structure and the computational resources required for manipulation of the data structure.
The reactions that occur due to the activity of gene-encoded enzymes can be obtained from a genome database which lists genes identified from genome sequencing and subsequent genome annotation. Genome annotation consists of the locations of open reading frames and assignment of function from homology to other known genes or empirically determined activity. Such a genome database can be acquired through public or private databases containing annotated nucleic acid or protein sequences, including Homo sapiens sequences. If desired, a model developer can perform a network reconstruction and establish the model content associations between the genes, proteins, and reactions as described, for example, in Covert et al. Trends in Biochemical Sciences 26:179-186 (2001) and Palsson, WO 00/46405.
As reactions are added to a reaction network data structure or metabolic reaction database, those having known or putative associations to the proteins/enzymes which enable/catalyze the reaction and the associated genes that code for these proteins can be identified by annotation. Accordingly, the appropriate associations for all of the reactions to their related proteins or genes or both can be assigned. These associations can be used to capture the non-linear relationship between the genes and proteins as well as between proteins and reactions. In some cases one gene codes for one protein which then perform one reaction. However, often there are multiple genes which are required to create an active enzyme complex and often there are multiple reactions that can be carried out by one protein or multiple proteins that can carry out the same reaction. These associations capture the logic (i.e. AND or OR relationships) within the associations. Annotating a metabolic reaction database with these associations can allow the methods to be used to determine the effects of adding or eliminating a particular reaction not only at the reaction level, but at the genetic or protein level in the context of running a simulation or predicting a multicellular interaction activity, including Homo sapiens activity.
A reaction network data structure of the invention can be used to determine the activity of one or more reactions in a plurality of reactions occurring from multicellular interactions, including a plurality of Homo sapiens reactions, independent of any knowledge or annotation of the identity of the protein that performs the reaction or the gene encoding the protein. A model that is annotated with gene or protein identities can include reactions for which a protein or encoding gene is not assigned. While a large portion of the reactions in a cellular metabolic network are associated with genes in the organism's genome, there are also a substantial number of reactions included in a model for which there are no known genetic associations. Such reactions can be added to a reaction database based upon other information that is not necessarily related to genetics such as biochemical or cell based measurements or theoretical considerations based on observed biochemical or cellular activity. For example, there are many reactions that can either occur spontaneously or are not protein-enabled reactions. Furthermore, the occurrence of a particular reaction in a cell for which no associated proteins or genetics have been currently identified can be indicated during the course of model building by the iterative model building methods of the invention.
The reactions in a reaction network data structure or reaction database can be assigned to subsystems by annotation, if desired. The reactions can be subdivided according to biological criteria, such as according to traditionally identified metabolic pathways (glycolysis, amino acid metabolism and the like) or according to mathematical or computational criteria that facilitate manipulation of a model that incorporates or manipulates the reactions. Methods and criteria for subdviding a reaction database are described in further detail in Schilling et al., J Theor. Biol. 203:249-283 (2000), and in Schuster et al., Bioinformatics 18:351-361 (2002). The use of subsystems can be advantageous for a number of analysis methods, such as extreme pathway analysis, and can make the management of model content easier. Although assigning reactions to subsystems can be achieved without affecting the use of the entire model for simulation, assigning reactions to subsystems can allow a user to search for reactions in a particular subsystem which may be useful in performing various types of analyses. Therefore, a reaction network data structure can include any number of desired subsystems including, for example, 2 or more subsystems, 5 or more subsystems, 10 or more subsystems, 25 or more subsystems or 50 or more subsystems.
The reactions in a reaction network data structure or metabolic reaction database can be annotated with a value indicating the confidence with which the reaction is believed to occur in one or more cells of a multicellular interaction or in one or more reaction networks within a cell such as a Homo sapiens cell. The level of confidence can be, for example, a function of the amount and form of supporting data that is available. This data can come in various forms including published literature, documented experimental results, or results of computational analyses. Furthermore, the data can provide direct or indirect evidence for the existence of a chemical reaction in a cell based on genetic, biochemical, and/or physiological data.
The invention further provides a computer readable medium, containing (a) a data structure relating a plurality of Homo sapiens reactants to a plurality of Homo sapiens reactions, wherein each of the Homo sapiens reactions includes a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product, and (b) a constraint set for the plurality of Homo sapiens reactions. Similarly, the computer readable medium or media can relate a plurality of reactions to a plurality of reactions within first and second cells and for an intra-system between first and second interacting cells.
Constraints can be placed on the value of any of the fluxes in the metabolic network using a constraint set. These constraints can be representative of a minimum or maximum allowable flux through a given reaction, possibly resulting from a limited amount of an enzyme present. Additionally, the constraints can determine the direction or reversibility of any of the reactions or transport fluxes in the reaction network data structure. Based on the in vivo environment where multiple cells interact, such as in a human organism, the metabolic resources available to the cell for biosynthesis of essential molecules for can be determined. Allowing the corresponding transport fluxes to be active provides the in silico interaction between cells with inputs and outputs for substrates and by-products produced by the metabolic network.
Returning to the hypothetical reaction network shown in FIG. 1, constraints can be placed on each reaction in the exemplary format shown in FIG. 2, as follows. The constraints are provided in a format that can be used to constrain the reactions of the stoichiometric matrix shown in FIG. 3. The format for the constraints used for a matrix or in linear programming can be conveniently represented as a linear inequality such as

bj≦vj≦aj:j=1 . . . n   (Eq. 1)

where vj is the metabolic flux vector, bj is the minimum flux value and aj is the maximum flux value. Thus, aj can take on a finite value representing a maximum allowable flux through a given reaction or bj can take on a finite value representing minimum allowable flux through a given reaction. Additionally, if one chooses to leave certain reversible reactions or transport fluxes to operate in a forward and reverse manner the flux may remain unconstrained by setting bj to negative infinity and aj to positive infinity as shown for reaction R2 in FIG. 2. If reactions proceed only in the forward reaction bj is set to zero while aj is set to positive infinity as shown for reactions R1, R3, R4, R5, and R6 in FIG. 2. As an example, to simulate the event of a genetic deletion or non-expression of a particular protein, the flux through all of the corresponding metabolic reactions related to the gene or protein in question are reduced to zero by setting aj and bj to be zero. Furthermore, if one wishes to simulate the absence of a particular growth substrate one can simply constrain the corresponding transport fluxes that allow the metabolite to enter the cell to be zero by setting aj and bj to be zero. On the other hand if a substrate is only allowed to enter or exit the cell via transport mechanisms, the corresponding fluxes can be properly constrained to reflect this scenario.

The ability of a reaction to be actively occurring is dependent on a large number of additional factors beyond just the availability of substrates. These factors, which can be represented as variable constraints in the models and methods of the invention include, for example, the presence of cofactors necessary to stabilize the protein/enzyme, the presence or absence of enzymatic inhibition and activation factors, the active formation of the protein/enzyme through translation of the corresponding mRNA transcript, the transcription of the associated gene(s) or the presence of chemical signals and/or proteins that assist in controlling these processes that ultimately determine whether a chemical reaction is capable of being carried out within an organism. Of particular importance in the regulation of human cell types is the implementation of paracrine and endocrine signaling pathways to control cellular activities. In these cases a cell secretes signaling molecules that may be carried far afield to act on distant targets (endocrine signaling), or act as local mediators (paracrine signaling). Examples of endocrine signaling molecules include hormones such as insulin, while examples of paracrine signaling molecules include neurotransmitters such as acetylcholine. These molecules induce cellular responses through signaling cascades that affect the activity of biochemical reactions in the cell. Regulation can be represented in an in silico Homo sapiens model by providing a variable constraint as set forth below.
Thus, the invention provides a computer readable medium or media, including (a) a data structure relating a plurality of Homo sapiens reactants to a plurality of Homo sapiens reactions, wherein each of the reactions includes a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product, and wherein at least one of the reactions is a regulated reaction; and (b) a constraint set for the plurality of reactions, wherein the constraint set includes a variable constraint for the regulated reaction. Additionally, the invention provides a computer readable medium or media including data structures for two or more cells and for an intra-system and a constraint set for the plurality of reactions within the data structures that includes a variable constraint for a regulated reaction.
As used herein, the term “regulated,” when used in reference to a reaction in a data structure, is intended to mean a reaction that experiences an altered flux due to a change in the value of a constraint or a reaction that has a variable constraint.
As used herein, the term “regulatory reaction” is intended to mean a chemical conversion or interaction that alters the activity of a protein, macromolecule or enzyme. A chemical conversion or interaction can directly alter the activity of a protein, macromolecule or enzyme such as occurs when the protein, macromolecule or enzyme is post-translationally modified or can indirectly alter the activity of a protein, macromolecule or enzyme such as occurs when a chemical conversion or binding event leads to altered expression of the protein, macromolecule or enzyme. Thus, transcriptional or translational regulatory pathways can indirectly alter a protein, macromolecule or enzyme or an associated reaction. Similarly, indirect regulatory reactions can include reactions that occur due to downstream components or participants in a regulatory reaction network. When used in reference to a data structure or in silico Homo sapiens model, for example, the term is intended to mean a first reaction that is related to a second reaction by a function that alters the flux through the second reaction by changing the value of a constraint on the second reaction.
As used herein, the term “regulatory data structure” is intended to mean a representation of an event, reaction or network of reactions that activate or inhibit a reaction, the representation being in a format that can be manipulated or analyzed. An event that activates a reaction can be an event that initiates the reaction or an event that increases the rate or level of activity for the reaction. An event that inhibits a reaction can be an event that stops the reaction or an event that decreases the rate or level of activity for the reaction. Reactions that can be represented in a regulatory data structure include, for example, reactions that control expression of a macromolecule that in turn, performs a reaction such as transcription and translation reactions, reactions that lead to post translational modification of a protein or enzyme such as phophorylation, dephosphorylation, prenylation, methylation, oxidation or covalent modification, reactions that process a protein or enzyme such as removal of a pre- or pro-sequence, reactions that degrade a protein or enzyme or reactions that lead to assembly of a protein or enzyme.
As used herein, the term “regulatory event” is intended to mean a modifier of the flux through a reaction that is independent of the amount of reactants available to the reaction. A modification included in the term can be a change in the presence, absence, or amount of an enzyme that performs a reaction. A modifier included in the term can be a regulatory reaction such as a signal transduction reaction or an environmental condition such as a change in pH, temperature, redox potential or time. It will be understood that when used in reference to an in silico Homo sapiens model. or data structure, or when used in reference to a model or data structure for a multicellular interaction, a regulatory event is intended to be a representation of a modifier of the flux through a Homo sapiens reaction or reaction occurring in one or more cells in a multicellular interaction that is independent of the amount of reactants available to the reaction.
The effects of regulation on one or more reactions that occur in Homo sapiens can be predicted using an in silico Homo sapiens model or multicellular model of the invention. Regulation can be taken into consideration in the context of a particular condition being examined by providing a variable constraint for the reaction in an in silico Homo sapiens model or multicellular model. Such constraints constitute condition-dependent constraints. A data structure can represent regulatory reactions as Boolean logic statements (Reg-reaction). The variable takes on a value of 1 when the reaction is available for use in the reaction network and will take on a value of 0 if the reaction is restrained due to some regulatory feature. A series of Boolean statements can then be introduced to mathematically represent the regulatory network as described for example in Covert et al. J. Theor. Biol. 213:73-88 (2001). For example, in the case of a transport reaction (A_in) that imports metabolite A, where metabolite A inhibits reaction R2 as shown in FIG. 4, a Boolean rule can state that:

Reg-R2=IF NOT(A—in).   (Eq. 2)

This statement indicates that reaction R2 can occur if reaction A_in is not occurring (i.e. if metabolite A is not present). Similarly, it is possible to assign the regulation to a variable A which would indicate an amount of A above or below a threshold that leads to the inhibition of reaction R2. Any function that provides values for variables corresponding to each of the reactions in the biochemical reaction network can be used to represent a regulatory reaction or set of regulatory reactions in a regulatory data structure. Such functions can include, for example, fuzzy logic, heuristic rule-based descriptions, differential equations or kinetic equations detailing system dynamics.

A reaction constraint placed on a reaction can be incorporated into an in silico Homo sapiens model or mulicellular model of interacting cells using the following general equation:

(Reg-Reaction)*bj≦vj≦aj*(Reg-Reaction), ∀

j=1 . . . n   (Eq. 3)

For the example of reaction R2 this equation is written as follows:

(0)*Reg-R2≦R2≦(∞)*Reg-R2.   (Eq. 4)

Thus, during the course of a simulation, depending upon the presence or absence of metabolite A in the interior of the cell where reaction R2 occurs, the value for the upper boundary of flux for reaction R2 will change from 0 to infinity, respectively.
With the effects of a regulatory event or network taken into consideration by a constraint function and the condition-dependent constraints set to an initial relevant value, the behavior of the Homo sapiens reaction network or one or more reaction networks of a multicellular interaction can be simulated for the conditions considered as set forth below.
Although regulation has been exemplified above for the case where a variable constraint is dependent upon the outcome of a reaction in the data structure, a plurality of variable constraints can be included in an in silico Homo sapiens model or other model of multicellular interactions to represent regulation of a plurality of reactions. Furthermore, in the exemplary case set forth above, the regulatory structure includes a general control stating that a reaction is inhibited by a particular environmental condition. Using a general control of this type, it is possible to incorporate molecular mechanisms and additional detail into the regulatory structure that is responsible for determining the active nature of a particular chemical reaction within an organism.
Regulation can also be simulated by a model of the invention and used to predict a Homo sapiens physiological function without knowledge of the precise molecular mechanisms involved in the reaction network being modeled. Thus, the model can be used to predict, in silico, overall regulatory events or causal relationships that are not apparent from in vivo observation of any one reaction in a network or whose in vivo effects on a particular reaction are not known. Such overall regulatory effects can include those that result from overall environmental conditions such as changes in pH, temperature, redox potential, or the passage of time.
As described previously and further below, the models and method of the invention are applicable to a wide range of multicellular interactions. The multicellular interactions include, for example, interactions between prokaryotic cells such as colony growth and chemotaxis. The multicellular interactions include, for example, interactions between two or more eukaryotic cells such as the concerted action of two or more cells of the same or different cell type. A specific example of the concerted action of the same cell type includes the combined output of the contractile activity of myocytes. A specific example of the concerted action of different cell types includes the energy production of adipocyte cells and the contractile activity of myocyte cells based on the consumption of energy available from the adipocyte cells. Multicellular interactions also can include, for example, interactions between host cells and a pathogen, such as a bacteria, virus or worm, as well as symbiotic interactions between host cells and microbes, for example. A symbiotic microbe can include, for example, E. coli. Further examples of host and microbe interactions include bacterial communities that reside in the skin and mouth and the vagina flora, providing the host with a defense against infections. Moreover, the models and methods of the invention also can be used to reconstruction the reaction networks between a plurality of dynamic multicellular interactions including, for example, interactions between host cells or tissues, pathogen and symbiotic microbe.
Multicellular interactions also include, for example, interactions between cells of different tissues, different organs and/or physiological systems as well as interactions between some or all cells, tissues organs and/or physiological systems within a multicellular organism. Specific examples of such interactions include organismic homeostasis, signal transduction, the endocrine system, the exocrine system, sensory transduction, secretion, the hematopoietic system, the immune system, cell migration, cell adherence, cell invasion and neuronal and synaptic transduction. Numerous other multicellular interactions are well known in the art and can similarly be reconstructed and simulated to predict an activity thereof using the models and methods of the invention.
Given the teachings and guidance provided herein with respect to the construction and use of multiple reaction networks including, for example, the regulated and metabolic reaction networks of a Homo sapiens cell, those skilled in the art will know how to employ the models and methods of the invention for the construction and use of any multicellular interaction. Specific examples of such multicellular interactions are described above. Other examples of multicellular interactions include, for example, all interactions occurring between two or more cells such as those cells set forth in Table 5 below. Such multicellular interactions can occur between cells within the same or different physiological category or functional characterization. Similarly, such multicellular interactions also can occur between cells within the same and between different physiological categories or functional characterizations. The number and types of different cellular interactions will be determined by the multicellular model being produced using the methods of the invention.
Models of multicellular interactions also can include, for example, interactions between cells of one or more tissues and organs. The models and methods of the invention are applicable to predict the activity of interactions between some or all cell types of a tissue or organ. The models and methods of the invention also can include reaction networks that include interactions between some or all cell types of two or more tissues or organs. Specific examples of tissues or organs and their respective cell types and functions are shown below in Table 6. The models and methods of the invention can include, for example, some or all of these interactions to predict their respective activities. Similarly, Table 7 exemplifies the cell types of a liver. Given the teachings and guidance provided herein, the models and methods of the invention can be used to construct an in silico reconstruction of the reaction networks for some or all of these cell types to predict some or all of the activities of the liver. Further, an in silico reconstruction of reaction networks for some or all multicellular interactions exemplified in Tables 5-7, including those within and between tissues and organs, can be produced that can be used to predict some or all activities of one or more tissues or of an organism. Therefore, the invention provides for the in silico reconstruction of whole organisms, including human organisms, tissues, cells and physical or physiological functions performed by such cellular systems.
The invention also provides for the in silico reconstruction of a plurality of reaction networks that interact to perform the same or different activity. The plurality can be a small, medium or large plurality and can reside within the same cell, different cells or in different tissues or organisms. Specific examples of such pluralities residing within the same cell include the reaction networks exemplified below in Example IV for a myocyte or for an adipocyte. Specific examples of such pluralities residing in different cells or tissues include the reaction networks exemplified below in Example IV for coupled adipocyte-myocyte metabolism. Another example of interactions between different reaction networks within different networks includes interactions between pathogen and host cells.
Briefly, and as described previously, a computer readable medium or media can be produced that includes a plurality of data structures each relating a plurality of reactants to a plurality of reactions from each cell within the multicellular interaction. The reactions include a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating the substrate and said product In a two cell interaction, including populations of two cell types, the plurality of data structures can include a first data structure and a second data structure corresponding to the reactions within the two cells or populations of two cell types. The data structures will describe the reaction networks for each cell.
For optimization of the multicellular interaction containing two cells, a third data structure is particularly useful for relating a plurality of intra-system reactants to a plurality of intra-system reactions between the first and second cells. Each of the intra-system reactions includes a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating the substrate and said product. The inta-system data structure can be included in the reconstruction as an independent data structure or as a component of one or more data structures for either or both cells within such a two cell interaction model. A specific example of intra-system reactions represented by a third data structure is shown in FIG. 10 for the bicarbonate and ammonia buffer systems employed in the two cell model describing adipocyte and myocyte interactions.
As with the models and methods of the invention described above and below, a computer readable medium or media describing a multicellular interaction also will contain a constraint set for the plurality of reactions for each of the first, second and third data structures as well as commands for determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures. The objective function can be, for example, those objective functions exemplified previously, those exemplified below or in the Examples as well as various other object functions well known to those skilled in the art given the teachings and guidance provided herein. Solving the optimization problem by determining one or more flux distribution will predict a physiological function of occurring as a result of the interaction between the first and second cells of the model.
Each of the first, second or third data structures can include one or more reaction networks. For example, and with reference to FIGS. 5-10, a reaction network for each of the cells exemplified therein can be defined as the different networks within each cell such as central metabolism and the cell specific reactions. Applying this view, the adipocyte and myocyte cells each contain at least two reaction networks. When combined together with the intra-cellular reaction network and the exchange reactions, the interactions of the two cells exemplified in FIG. 6 can be described by at least five different reaction networks. The interactions of this two cell model can therefore be described using at least five data structures. Alternatively, a reaction network can be defined as all the networks within each cell. When combined together with the intra-cellular reaction network and the exchange reactions, the interactions of the exemplified adipocyte and myocyte cells can be described by at least three different reaction networks. One reaction network for each cell and one reaction network for the intra-system reactions. Therefore, each of the first, second or third data structures can consist of a plurality of two or more reaction networks including, for example, 2, 3, 4, 5, 10, 20 or 25 or more as well as all integer numbers between and above these exemplary numbers. Similarly, given the teachings and guidance provided herein, the models and methods of the invention can be generated and used to predict an activity and/or physiological function of the intercellular network interactions or the intracellular network interaction. The latter interactions, for example, also predict an activity and/or a physiological function of the interactions between two or more cells including cells of different tissues, organs of a multicellular organism or of a whole organism.
As with the number of reaction networks within a data structure, the models and methods of the invention also can employ greater than three data structures as exemplified above. For example, the models and method of the invention can comprise one or more fourth data structures having one or more fourth constraint sets where each fourth data structure relates a plurality of reactants to a plurality of reactions from a cell already included in the model or from one or more third cells within the multicellular interaction. Use of one or more fourth data structures is particularly useful when reconstructing a interactions between three or more interacting cells including a large plurality of cells such as the cells within a tissue, organ, physiological system or organism. Each of the reactions within such fourth data structures include a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating the substrate and said product.
The number of fourth data structures can correspond to the number of cells greater than the first and second cells of the multicellular interaction and include, for example, a plurality of data structures. As with the specific embodiment of a two cell interaction, the plurality of data structures for three or more interacting cells can correspond to different cells within the cellular interaction as well as correspond to different cell types within the cellular interaction. The number of cells can include, for example, at least 4 cells, 5 cells, 6 cells, 7 cells, 8 cells, 9 cells, 10 cells, 100 cells, 1000 cells, 5000 cells, 10,000 cells or more. Therefore, the number of cells within a multicellular interaction model or used in a method of predicting a behavior of such multicellular interactions can include some or all cells which constitute a group of interacting cells, a tissue, organ, physiological system or whole organism. The multicellular interaction models and methods of the invention also can include some or all cells which constitute a group of interacting cells of different types or from different tissues, organs, physiological systems or organisms. The organism can be single cell prokaryotic or eukaryotic organism or multicellular eukaryotic organisms. Specific examples of different cell types include a mammary gland cell, hepatocyte, white fat cell, brown fat cell, liver lipocyte, red skeletal muscle cell, white skeletal muscle cell, intermediate skeletal muscle cell, smooth muscle cell, red blood cell, adipocyte, monocyte, reticulocyte, fibroblast, neuronal cell epithelial cell or one or more cells set forth in Table 5. Specific examples of physiological functions resulting from multicellular interactions that can be predicted include metabolite yield, ATP yield, biomass demand, growth, triacylglycerol storage, muscle contraction, milk secretion and oxygen transport capacity.
Intra-system reactions of a multicellular interaction model or method of the invention has been exemplified above and below with reference to the extracellular in vivo environment and, in particular, with reference to buffering this environment by supplying functions of the renal system. Given the teachings and guidance provided herein, those skilled in the art will understand that any extracellular reaction, plurality of reactions, function of the extracellular space or function supplied into the extracellular space by another cell, tissue or physiological system can be employed as an intra-system reaction network. Such reactions or activities can represent normal or pathological conditions or both conditions occurring within this intra-system environment. Specific examples of intra-system reactions include one or more reactions performed in the hematopoietic system, urine, connective tissue, contractile tissue or cells, lymphatic system, respiratory system or renal system. Reactions or reactants included in one or more intra-system data structures can be, for example, bicarbonate buffer system, an ammonia buffer system, a hormone, a signaling molecule, a vitamin, a mineral or a combination thereof.
The in silico models of multicellular or multi-network interactions, including Homo sapiens model and methods, described herein can be implemented on any conventional host computer system, such as those based on Intel® microprocessors and running Microsoft Windows operating systems. Other systems, such as those using the UNIX or LINUX operating system and based on IBM®, DEC® or Motorola® microprocessors are also contemplated. The systems and methods described herein can also be implemented to run on client-server systems and wide-area networks, such as the Internet.
Software to implement a method or model of the invention can be written in any well-known computer language, such as Java, C, C++, Visual Basic, FORTRAN or COBOL and compiled using any well-known compatible compiler. The software of the invention normally runs from instructions stored in a memory on a host computer system. A memory or computer readable medium can be a hard disk, floppy disc, compact disc, magneto-optical disc, Random Access Memory, Read Only Memory or Flash Memory. The memory or computer readable medium used in the invention can be contained within a single computer or distributed in a network. A network can be any of a number of conventional network systems known in the art such as a local area network (LAN) or a wide area network (WAN). Client-server environments, database servers and networks that can be used in the invention are well known in the art. For example, the database server can run on an operating system such as UNIX, running a relational database management system, a World Wide Web application and a World Wide Web server. Other types of memories and computer readable media are also contemplated to function within the scope of the invention.
A database or data structure of the invention can be represented in a markup language format including, for example, Standard Generalized Markup Language (SGML), Hypertext markup language (HTML) or Extensible Markup language (XML). Markup languages can be used to tag the information stored in a database or data structure of the invention, thereby providing convenient annotation and transfer of data between databases and data structures. In particular, an XML format can be useful for structuring the data representation of reactions, reactants and their annotations; for exchanging database contents, for example, over a network or internet; for updating individual elements using the document object model; or for providing differential access to multiple users for different information content of a data base or data structure of the invention. XML programming methods and editors for writing XML code are known in the art as described, for example, in Ray, “Learning XML” O'Reilly and Associates, Sebastopol, Calif. (2001).
A set of constraints can be applied to a reaction network data structure to simulate the flux of mass through the reaction network under a particular set of environmental conditions specified by a constraints set. Because the time constants characterizing metabolic transients and/or metabolic reactions are typically very rapid, on the order of milli-seconds to seconds, compared to the time constants of cell growth on the order of hours to days, the transient mass balances can be simplified to only consider the steady state behavior. Referring now to an example where the reaction network data structure is a stoichiometric matrix, the steady state mass balances can be applied using the following system of linear equations

S·v=0   (Eq. 5)

where S is the stoichiometric matrix as defined above and v is the flux vector. This equation defines the mass, energy, and redox potential constraints placed on the metabolic network as a result of stoichiometry. Together Equations 1 and 5 representing the reaction constraints and mass balances, respectively, effectively define the capabilities and constraints of the metabolic genotype and the organism's metabolic potential. All vectors, v, that satisfy Equation 5 are said to occur in the mathematical nullspace of S. Thus, the null space defines steady-state metabolic flux distributions that do not violate the mass, energy, or redox balance constraints. Typically, the number of fluxes is greater than the number of mass balance constraints, thus a plurality of flux distributions satisfy the mass balance constraints and occupy the null space. The null space, which defines the feasible set of metabolic flux distributions, is further reduced in size by applying the reaction constraints set forth in Equation 1 leading to a defined solution space. A point in this space represents a flux distribution and hence a metabolic phenotype for the network. An optimal solution within the set of all solutions can be determined using mathematical optimization methods when provided with a stated objective and a constraint set. The calculation of any solution constitutes a simulation of the model.

Objectives for activity of a human cell can be chosen. While the overall objective of a multi-cellular organism may be growth or reproduction, individual human cell types generally have much more complex objectives, even to the seemingly extreme objective of apoptosis (programmed cell death), which may benefit the organism but certainly not the individual cell. For example, certain cell types may have the objective of maximizing energy production, while others have the objective of maximizing the production of a particular hormone, extracellular matrix component, or a mechanical property such as contractile force. In cases where cell reproduction is slow, such as human skeletal muscle, growth and its effects need not be taken into account. In other cases, biomass composition and growth rate could be incorporated into a “maintenance” type of flux, where rather than optimizing for growth, production of precursors is set at a level consistent with experimental knowledge and a different objective is optimized.
Certain cell types, including cancer cells, can be viewed as having an objective of maximizing cell growth. Growth can be defined in terms of biosynthetic requirements based on literature values of biomass composition or experimentally determined values such as those obtained as described above. Thus, biomass generation can be defined as an exchange reaction that removes intermediate metabolites in the appropriate ratios and represented as an objective function. In addition to draining intermediate metabolites this reaction flux can be formed to utilize energy molecules such as ATP, NADH and NADPH so as to incorporate any maintenance requirement that must be met. This new reaction flux then becomes another constraint/balance equation that the system must satisfy as the objective function. Using the stoichiometric matrix of FIG. 3 as an example, adding such a constraint is analogous to adding the additional column Vgrowth to the stoichiometric matrix to represent fluxes to describe the production demands placed on the metabolic system. Setting this new flux as the objective function and asking the system to maximize the value of this flux for a given set of constraints on all the other fluxes is then a method to simulate the growth of the organism.
Continuing with the example of the stoichiometric matrix applying a constraint set to a reaction network data structure can be illustrated as follows. The solution to equation 5 can be formulated as an optimization problem, in which the flux distribution that minimizes a particular objective is found. Mathematically, this optimization problem can be stated as:

Minimize Z   (Eq. 6)

where z=Σci·vi   (Eq. 7)

where Z is the objective which is represented as a linear combination of metabolic fluxes vi using the weights ci in this linear combination. The optimization problem can also be stated as the equivalent maximization problem; i.e. by changing the sign on Z. Any commands for solving the optimazation problem can be used including, for example, linear programming commands.

A computer system of the invention can further include a user interface capable of receiving a representation of one or more reactions. A user interface of the invention can also be capable of sending at least one command for modifying the data structure, the constraint set or the commands for applying the constraint set to the data representation, or a combination thereof. The interface can be a graphic user interface having graphical means for making selections such as menus or dialog boxes. The interface can be arranged with layered screens accessible by making selections from a main screen. The user interface can provide access to other databases useful in the invention such as a metabolic reaction database or links to other databases having information relevant to the reactions or reactants in the reaction network data structure or to a multicellular organism's physiology, including Homo sapiens physiology. Also, the user interface can display a graphical representation of a reaction network or the results of a simulation using a model of the invention.
Once an initial reaction network data structure and set of constraints has been created, this model can be tested by preliminary simulation. During preliminary simulation, gaps in the network or “dead-ends” in which a metabolite can be produced but not consumed or where a metabolite can be consumed but not produced can be identified. Based on the results of preliminary simulations areas of the metabolic reconstruction that require an additional reaction can be identified. The determination of these gaps can be readily calculated through appropriate queries of the reaction network data structure and need not require the use of simulation strategies, however, simulation would be an alternative approach to locating such gaps.
In the preliminary simulation testing and model content refinement stage the existing model is subjected to a series of functional tests to determine if it can perform basic requirements such as the ability to produce the required biomass constituents and generate predictions concerning the basic physiological characteristics of the particular cell type being modeled. The more preliminary testing that is conducted the higher the quality of the model that will be generated. Typically, the majority of the simulations used in this stage of development will be single optimizations. A single optimization can be used to calculate a single flux distribution demonstrating how metabolic resources are routed determined from the solution to one optimization problem. An optimization problem can be solved using linear programming as demonstrated in the Examples below. The result can be viewed as a display of a flux distribution on a reaction map. Temporary reactions can be added to the network to determine if they should be included into the model based on modeling/simulation requirements.
Once a model of the invention is sufficiently complete with respect to the content of the reaction network data structure according to the criteria set forth above, the model can be used to simulate activity of one or more reactions in a reaction network. The results of a simulation can be displayed in a variety of formats including, for example, a table, graph, reaction network, flux distribution map or a phenotypic phase plane graph.
Thus, the invention provides a method for predicting a Homo sapiens physiological function. The method includes the steps of (a) providing a data structure relating a plurality of Homo sapiens reactants to a plurality of Homo sapiens reactions, wherein each of the Homo sapiens reactions includes a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) providing a constraint set for the plurality of Homo sapiens reactions; (c) providing an objective function, and (d) determining at least one flux distribution that minimizes or maximizes the objective function when the constraint set is applied to the data structure, thereby predicting a Homo sapiens physiological function.
A method for predicting a Homo sapiens physiological function can include the steps of (a) providing a data structure relating a plurality of Homo sapiens reactants to a plurality of Homo sapiens reactions, wherein each of the Homo sapiens reactions includes a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product, and wherein at least one of the reactions is a regulated reaction; (b) providing a constraint set for the plurality of reactions, wherein the constraint set includes a variable constraint for the regulated reaction; (c) providing a condition-dependent value to the variable constraint; (d) providing an objective function, and (e) determining at least one flux distribution that minimizes or maximizes the objective function when the constraint set is applied to the data structure, thereby predicting a Homo sapiens physiological function.
Further, a method for predicting a physiological function of a multicellular organism also is provided. The method includes: (a) providing a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) providing a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) providing a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (d) providing a constraint set for said plurality of reactions for said first, second and third data structures; (e) providing an objective function, and (f) determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells.
As used herein, the term “physiological function,” when used in reference to Homo Sapiens, is intended to mean an activity of an organism as a whole, including a multicellular organism and/or a Homo sapiens organism or cell as a whole. An activity included in the term can be the magnitude or rate of a change from an initial state of, for example, two or more interacting cells or a Homo sapiens cell to a final state of the two or more interacting cells or the Homo sapiens cell. An activity included in the term can be, for example, growth, energy production, redox equivalent production, biomass production, development, or consumption of carbon nitrogen, sulfur, phosphate, hydrogen or oxygen. An activity can also be an output of a particular reaction that is determined or predicted in the context of substantially all of the reactions that affect the particular reaction in two or more interacting cells or a Homo sapiens cell, for example, or substantially all of the reactions that occur in a plurality of interacting cells such as a tissue, organ or organism, or substantially all of the reactions that occur in a Homo sapiens cell (e.g. muscle contraction). Examples of a particular reaction included in the term are production of biomass precursors, production of a protein, production of an amino acid, production of a purine, production of a pyrimidine, production of a lipid, production of a fatty acid, production of a cofactor or transport of a metabolite. A physiological function can include an emergent property which emerges from the whole but not from the sum of parts where the parts are observed in isolation (see for example, Palsson, Nat. Biotech 18:1147-1150 (2000)).
A physiological function of reactions within two or more interacting cells, including Homo sapiens reactions, can be determined using phase plane analysis of flux distributions. Phase planes are representations of the feasible set which can be presented in two or three dimensions. As an example, two parameters that describe the growth conditions such as substrate and oxygen uptake rates can be defined as two axes of a two-dimensional space. The optimal flux distribution can be calculated from a reaction network data structure and a set of constraints as set forth above for all points in this plane by repeatedly solving the linear programming problem while adjusting the exchange fluxes defining the two-dimensional space. A finite number of qualitatively different metabolic pathway utilization patterns can be identified in such a plane, and lines can be drawn to demarcate these regions. The demarcations defining the regions can be determined using shadow prices of linear optimization as described, for example in Chvatal, Linear Programming New York, W. H. Freeman and Co. (1983). The regions are referred to as regions of constant shadow price structure. The shadow prices define the intrinsic value of each reactant toward the objective function as a number that is either negative, zero, or positive and are graphed according to the uptake rates represented by the x and y axes. When the shadow prices become zero as the value of the uptake rates are changed there is a qualitative shift in the optimal reaction network.
One demarcation line in the phenotype phase plane is defined as the line of optimality (LO). This line represents the optimal relation between respective metabolic fluxes. The LO can be identified by varying the x-axis flux and calculating the optimal y-axis flux with the objective function defined as the growth flux. From the phenotype phase plane analysis the conditions under which a desired activity is optimal can be determined. The maximal uptake rates lead to the definition of a finite area of the plot that is the predicted outcome of a reaction network within the environmental conditions represented by the constraint set. Similar analyses can be performed in multiple dimensions where each dimension on the plot corresponds to a different uptake rate. These and other methods for using phase plane analysis, such as those described in Edwards et al., Biotech Bioeng. 77:27-36(2002), can be used to analyze the results of a simulation using an in silico Homo sapiens model of the invention.
A physiological function of Homo sapiens can also be determined using a reaction map to display a flux distribution. A reaction map of Homo sapiens can be used to view reaction networks at a variety of levels. In the case of a cellular metabolic reaction network a reaction map can contain the entire reaction complement representing a global perspective. Alternatively, a reaction map can focus on a particular region of metabolism such as a region corresponding to a reaction subsystem described above or even on an individual pathway or reaction.
Thus, the invention provides an apparatus that produces a representation of a Homo sapiens physiological function, wherein the representation is produced by a process including the steps of: (a) providing a data structure relating a plurality of Homo sapiens reactants to a plurality of Homo sapiens reactions, wherein each of the Homo sapiens reactions includes a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) providing a constraint set for the plurality of Homo sapiens reactions; (c) providing an objective function; (d) determining at least one flux distribution that minimizes or maximizes the objective function when the constraint set is applied to the data structure, thereby predicting a Homo sapiens physiological function, and (e) producing a representation of the activity of the one or more Homo sapiens reactions. Similarly, the invention provides an apparatus that produces a representation of two or more interacting cells, including a tissue, organ, physiological system or whole organism wherein data structures are provided relating a plurality of reactants to a plurality of reactions for each type of interacting cell and for one or more intra-system functions. A constraint set is provided for the plurality of reactions for the plurality of data structures as well as an objective function that minimizes or maximizes an objective function when the constraint set is applied to predict a physiological function of the two or more interacting cells. The apparatus produces a representation of the activity of one more reactions of the two or more interacting cells.
The methods of the invention can be used to determine the activity of a plurality of Homo sapiens reactions including, for example, biosynthesis of an amino acid, degradation of an amino acid, biosynthesis of a purine, biosynthesis of a pyrimidine, biosynthesis of a lipid, metabolism of a fatty acid, biosynthesis of a cofactor, transport of a metabolite and metabolism of an alternative carbon source. In addition, the methods can be used to determine the activity of one or more of the reactions described above or listed in Table 1.
The methods of the invention can be used to determine a phenotype of a Homo sapiens mutant or aberrant cellular interaction between two or more cells. The activity of one or more reactions can be determined using the methods described above, wherein the reaction network data structure lacks one or more gene-associated reactions that occur in Homo sapiens or in a multicellular organism or multicellular interaction. Alternatively, the methods can be used to determine the activity of one or more reactions when a reaction that does not naturally occur in the model of multicellular interactions or in Homo sapiens, for example, is added to the reaction network data structure. Deletion of a gene can also be represented in a model of the invention by constraining the flux through the reaction to zero, thereby allowing the reaction to remain within the data structure. Thus, simulations can be made to predict the effects of adding or removing genes to or from one or more cells within a multicellular interaction, including Homo sapiens and/or a Homo sapiens cell. The methods can be particularly useful for determining the effects of adding or deleting a gene that encodes for a gene product that performs a reaction in a peripheral metabolic pathway.
A drug target or target for any other agent that affects a function of a multicellular interaction, including a Homo sapiens function can be predicted using the methods of the invention. Such predictions can be made by removing a reaction to simulate total inhibition or prevention by a drug or agent. Alternatively, partial inhibition or reduction in the activity a particular reaction can be predicted by performing the methods with altered constraints. For example, reduced activity can be introduced into a model of the invention by altering the aj or bj values for the metabolic flux vector of a target reaction to reflect a finite maximum or minimum flux value corresponding to the level of inhibition. Similarly, the effects of activating a reaction, by initiating or increasing the activity of the reaction, can be predicted by performing the methods with a reaction network data structure lacking a particular reaction or by altering the aj or bj values for the metabolic flux vector of a target reaction to reflect a maximum or minimum flux value corresponding to the level of activation. The methods can be particularly useful for identifying a target in a peripheral metabolic pathway.
Once a reaction has been identified for which activation or inhibition produces a desired effect on a function of a multicellular interaction, including a Homo sapiens function, an enzyme or macromolecule that performs the reaction in the multicellular system or a gene that expresses the enzyme or macromolecule can be identified as a target for a drug or other agent. A candidate compound for a target identified by the methods of the invention can be isolated or synthesized using known methods. Such methods for isolating or synthesizing compounds can include, for example, rational design based on known properties of the target (see, for example, DeCamp et al., Protein Engineering Principles and Practice, Ed. Cleland and Craik, Wiley-Liss, New York, pp. 467-506 (1996)), screening the target against combinatorial libraries of compounds (see for example, Houghten et al., Nature, 354, 84-86 (1991); Dooley et al., Science, 266, 2019-2022 (1994), which describe an iterative approach, or R. Houghten et al. PCT/US91/08694 and U.S. Pat. No. 5,556,762 which describe the positional-scanning approach), or a combination of both to obtain focused libraries. Those skilled in the art will know or will be able to routinely determine assay conditions to be used in a screen based on properties of the target or activity assays known in the art.
A candidate drug or agent, whether identified by the methods described above or by other methods known in the art, can be validated using an in silico model or method of multicellular interactions, including a Homo sapiens model or method of the invention. The effect of a candidate drug or agent on physiological function can be predicted based on the activity for a target in the presence of the candidate drug or agent measured in vitro or in vivo. This activity can be represented in an in silico model of the multicellular system by adding a reaction to the model, removing a reaction from the model or adjusting a constraint for a reaction in the model to reflect the measured effect of the candidate drug or agent on the activity of the reaction. By running a simulation under these conditions the holistic effect of the candidate drug or agent on the physiological function of the multicellular system, including Homo sapiens physiological function can be predicted.
The methods of the invention can be used to determine the effects of one or more environmental components or conditions on an activity of, for example, a multicellular interaction, a tissue, organ, physiological function or a Homo sapiens cell. As set forth above an exchange reaction can be added to a reaction network data structure corresponding to uptake of an environmental component, release of a component to the environment, or other environmental demand. The effect of the environmental component or condition can be further investigated by running simulations with adjusted aj or bj values for the metabolic flux vector of the exchange reaction target reaction to reflect a finite maximum or minimum flux value corresponding to the effect of the environmental component or condition. The environmental component can be, for example an alternative carbon source or a metabolite that when added to the environment of a multicellular system, organism or Homo sapiens cell can be taken up and metabolized. The environmental component can also be a combination of components present for example in a minimal medium composition. Thus, the methods can be used to determine an optimal or minimal medium composition that is capable of supporting a particular activity of a multicellular interaction or system, including a particular activity of Homo sapiens. 
The invention further provides a method for determining a set of environmental components to achieve a desired activity for Homo sapiens. The method includes the steps of (a) providing a data structure relating a plurality of Homo sapiens reactants to a plurality of Homo sapiens reactions, wherein each of the Homo sapiens reactions includes a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product; (b) providing a constraint set for the plurality of Homo sapiens reactions; (c) applying the constraint set to the data representation, thereby determining the activity of one or more Homo sapiens reactions (d) determining the activity of one or more Homo sapiens reactions according to steps (a) through (c), wherein the constraint set includes an upper or lower bound on the amount of an environmental component and (e) repeating steps (a) through (c) with a changed constraint set, wherein the activity determined in step (e) is improved compared to the activity determined in step (d). Similarly, a method for determining a set of environmental components to achieve a desired activity for a multicellular interaction also is provided. The method includes providing a plurality of data structures relating a plurality of reactants to a plurality of reactions for each type of interacting cell and for one or more intra-system functions; providing a constraint set for the plurality of reactions for the plurality of data structures as well as providing an objective function that minimizes or maximizes an objective function when the constraint set is applied to predict a physiological function of the two or more interacting cells; determining the activity of one or more reactions within two or more interacting cells using a constraint set having an upper or lower bound on the amount of an environmental component and repeating these steps until the activity is improved.
It is understood that modifications which do not substantially affect the activity of the various embodiments of this invention are also included within the definition of the invention provided herein. Accordingly, the following examples are intended to illustrate but not limit the present invention.
EXAMPLE I
This example shows the construction of a universal Homo sapiens metabolic reaction database, a Homo sapiens core metabolic reaction database and a Homo sapiens muscle cell metabolic reaction database. This example also shows the iterative model building process used to generate a Homo sapiens core metabolic model and a Homo sapiens muscle cell metabolic model.
A universal Homo sapiens reaction database was prepared from the genome databases and biochemical literature. The reaction database shown in Table 1 contains the following information:
Locus ID—the locus number of the gene found in the LocusLink website.
Gene Ab.—various abbreviations which are used for the gene.
Reaction Stoichiometry—includes all metabolites and direction of the reaction, as well as reversibility.
E.C.—The Enzyme Commission number.
Additional information included in the universal reaction database, although not shown in Table 1, included the chapter of Salway, surra (1999), where relevant reactions were found; the cellular location, if the reaction primarily occurs in a given compartment; the SWISS PROT identifier, which can be used to locate the gene record in SWISS PROT; the full name of the gene at the given locus; the chromosomal location of the gene; the Mendelian Inheritance in Man (MIM) data associated with the gene; and the tissue type, if the gene is primarily expressed in a certain tissue. Overall, 1130 metabolic enzyme- or transporter-encoding genes were included in the universal reaction database.
Fifty-nine reactions in the universal reaction database were identified and included based on biological data as found in Salway supra (1999), currently without genome annotation. Ten additional reactions, not described in the biochemical literature or genome annotation, were subsequently included in the reaction database following preliminary simulation testing and model content refinement. These 69 reactions are shown at the end of Table 1.
From the universal Homo sapiens reaction database shown in Table 1, a core metabolic reaction database was established, which included core metabolic reactions as well as some amino acid and fatty acid metabolic reactions, as described in Chapters 1, 3, 4, 7, 9, 10, 13, 17, 18 and 44 of J. G. Salway, Metabolism at a Glance, 2nd ed., Blackwell Science, Malden, Mass. (1999). The core metabolic reaction database included 211 unique reactions, accounting for 737 genes in the Homo sapiens genome. The core metabolic reaction database was used, although not in its entirety, to create the core metabolic model described in Example II.
To allow for the modeling of muscle cells, the core reaction database was expanded to include 446 unique reactions, accounting for 889 genes in the Homo sapiens genome. This skeletal muscle metabolic reaction database was used to create the skeletal muscle metabolic model described in Example II.
Once the core and muscle cell metabolic reaction databases were compiled, the reactions were represented as a metabolic network data structure, or “stoichiometric input file.” For example, the core metabolic network data structure shown in Table 2 contains 33 reversible reactions, 31 non-reversible reactions, 97 matrix columns and 52 unique enzymes. Each reaction in Table 2 is represented so as to indicate the substrate or substrates (a negative number) and the product or products (a positive number); the stoichiometry; the name of each reaction (the term following the zero); and whether the reaction is reversible (an R following the reaction name). A metabolite that appears in the mitochondria is indicated by an “m,” and a metabolite that appears in the extracellular space is indicated by an “ex.”
To perform a preliminary simulation or to simulate a physiological condition, a set of inputs and outputs has to be defined and the network objective function specified. To calculate the maximum ATP production of the Homo sapiens core metabolic network using glucose as a carbon source, a non-zero uptake value for glucose was assigned and ATP production was maximized as the objective function, using the representation shown in Table 2. The network's performance was examined by optimizing for the given objective function and the set of constraints defined in the input file, using flux balance analysis methods. The model was refined in an iterative manner by examining the results of the simulation and implementing the appropriate changes.
Using this iterative procedure, two metabolic reaction networks were generated, representing human core metabolism and human skeletal muscle cell metabolism.
EXAMPLE II
This example shows how human metabolism can be accurately simulated using a Homo sapiens core metabolic model.
The human core metabolic reaction database shown in Table 3 was used in simulations of human core metabolism. This reaction database contains a total of 65 reactions, covering the classic biochemical pathways of glycolysis, the pentose phosphate pathway, the tricitric acid cycle, oxidative phosphorylation, glycogen storage, the malate/aspartate shuttle, the glycerol phosphate shuttle, and plasma and mitochondrial membrane transporters. The reaction network was divided into three compartments: the cytosol, mitochondria, and the extracellular space. The total number of metabolites in the network is 50, of which 35 also appear in the mitochondria. This core metabolic network accounts for 250 human genes.
To perform simulations using the core metabolic network, network properties such as the P/O ratio were specified using Salway, supra (1999) as a reference. Oxidation of NADH through the Electron Transport System (ETS) was set to generate 2.5 ATP molecules (i.e. a P/O ratio of 2.5 for NADH), and that of FADH2 was set to 1.5 ATP molecules (i.e. a P/O ratio of 1.5 for FADH2).
Using the core metabolic network, aerobic and anaerobic metabolisms were simulated in silico. Secretion of metabolic by-products was in agreement with the known physiological parameters. Maximum yield of all 12 precursor-metabolites (glucose-6-phosphate, fructose-6-phosphate, ribose-5-phosphate, erythrose-4-phosphate, triose phosphate, 3-phosphoglycerate, phosphoenolpyruvate, pyruvate, acetyl CoA, α-ketoglutarate, succinyl CoA, and oxaloacetate) was examined and none found to exceed the values of its theoretical yield.
Maximum ATP yield was also examined in the cytosol and mitochondria. Salway, supra (1999) reports that in the absence of membrane proton-coupled transport systems, the energy yield is 38 ATP molecules per molecule of glucose and otherwise 31 ATP molecules per molecule of glucose. The core metabolic model demonstrated the same values as described by Salway supra (1999). Energy yield in the mitochondria was determined to be 38 molecules of ATP per glucose molecule. This is equivalent to production of energy in the absence of proton-couple transporters across mitochondrial membrane since all the protons were utilized only in oxidative phosphorylation. In the cytosol, energy yield was calculated to be 30.5 molecules of ATP per glucose molecule. This value reflects the cost of metabolite exchange across the mitochondrial membrane as described by Salway, supra (1999).
EXAMPLE III
This example shows how human muscle cell metabolism can be accurately simulated under various physiological and pathological conditions using a Homo sapiens muscle cell metabolic model.
As described in Example I, the core metabolic model was extended to also include all the major reactions occurring in the skeletal muscle cell, adding new functions to the classical metabolic pathways found in the core model, such as fatty acid synthesis and β-oxidation, triacylglycerol and phospholipid formation, and amino acid metabolism. Simulations were performed using the muscle cell reaction database shown in Table 4. The biochemical reactions were again compartmentalized into cytosolic and mitochondrial compartments.
To simulate physiological behavior of human skeletal muscle cells, an objective function had to be defined. Growth of muscle cells occurs in time scales of several hours to days. The time scale of interest in the simulation, however, was in the order of several to tens of minutes, reflecting the time period of metabolic changes during exercise. Thus, contraction (defined as, and related to energy production) was chosen to be the objective function, and no additional constraints were imposed to represent growth demands in the cell.
To study and test the behavior of the network, twelve physiological cases (Table 8) and five disease cases (Table 9) were examined. The input and output of metabolites were specified as indicated in Table 8, and maximum energy production and metabolite secretions were calculated and taken into account.



















TABLE 8





Metabolite














Exchange
1
2
3
4
5
6
7
8
9
10
11
12







Glucose
I
I
—
—
I
I
—
—
—
—
—
—


O2
I
—
I
—
I
—
I
—
I
—
I
—


Palmitate
I
I
—
—
—
—
—
—
I
I
—
—


Glycogen
I
I
I
I
—
—
—
—
—
—
—
—


Phospho-
I
I
—
—
—
—
—
—
—
—
I
I


creatine


Triacylglycerol
I
I
—
—
—
—
I
I
—
—
—
—


Isoleucine
I
I
—
—
—
—
—
—
—
—
—
—


Valine
I
I
—
—
—
—
—
—
—
—
—
—


Hydroxy-
—
—
—
—
—
—
—
—
—
—
—
—


butyrate


Pyruvate
◯
◯
◯
◯
◯
◯
◯
◯
◯
◯
◯
◯


Lactate
◯
◯
◯
◯
◯
◯
◯
◯
◯
◯
◯
◯


Albumin
◯
◯
◯
◯
◯
◯
◯
◯
◯
◯
◯
◯


















TABLE 9







Reaction


Disease
Enzyme Deficiency
Constrained







McArdle's disease
phosphorylase
GBE1


Tarui's disease
phosphofructokianse
PFKL


Phosphoglycerate kinase
phosphoglycerate
PGK1R


deficiency
kinase


Phosphoglycerate mutase
phosphoglycerate
PGAM3R


deficiency
mutase


Lactate dehydrogenase deficiency
Lactate dehyrogenase
LDHAR









The skeletal muscle model was tested for utilization of various carbon sources available during various stages of exercise and food starvation (Table 8). The by-product secretion of the network in an aerobic to anaerobic shift was qualitatively compared to physiological outcome of exercise and found to exhibit the same general features such as secretion of fermentative by-products and lowered energy yield.
The network behavior was also examined for five disease cases (Table 9). The test cases were chosen based on their physiological relevance to the model's predictive capabilities. In brief, McArdle's disease is marked by the impairment of glycogen breakdown. Tarui's disease is characterized by a deficiency in phosphofructokinase. The remaining diseases examined are marked by a deficiency of metabolic enzymes phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase. In each case, the changes in flux and by-product secretion of metabolites were examined for an aerobic to anaerobic metabolic shift with glycogen and phosphocreatine as the sole carbon sources to the network and pyruvate, lactate, and albumin as the only metabolic by-products allowed to leave the system. To simulate the disease cases, the corresponding deficient enzyme was constrained to zero. In all cases, a severe reduction in energy production was demonstrated during exercise, representing the state of the disease as seen in clinical cases.
EXAMPLE IV
This Example shows the construction and simulation of a multi-cellular model demonstrating the interactions between human adipocytes and monocytes.
The specific examples described above demonstrate the use a constraint-based approach in modeling metabolism in microbial organisms including prokaryotes such as E. coli and eukaryotes such as S. cerevisiae as well as for complex multicellular organisms requiring regulatory interactions such as humans. Described below is the modeling procedure, network content, and simulation results including network characteristics and metabolic performance of an integrated two-cell model of human adipocyte (fatty cell) and myocyte (muscle cell) using the compositions and methods of the invention. Simulations were performed to exemplify the coupled function of the two cell types during distinct physiological conditions corresponding to the coupled function of adipocyes and myocytes during sprint and marathon physiological conditions.
A human metabolic network model was reconstructed using biochemical, physiological, and genomic data as described previously. Briefly, the central metabolic network was used as a template for the construction of cell-specific models by adding biochemical reactions known to occur in specific cell-types of interest based on genomic, biochemical, and/or physiological information. Other methods for reconstructing the cell-specific models included reconstructing all the biochemical pathways and biochemical reactions that occur in the human metabolism regardless of their tissue specificity and location within the cell in a database and then reconstructing cell-, tissue-, organ-specific models by separating reactions that occur in specified cells, tissues, and/or organs based on genomic, physiological, biochemical, and/or high throughput data such as gene expression, proteomics, metabolomics, and other types of “omic” data. In this latter approach, in addition to the cell-, tissue-, and/or organ-specific reactions, reactions can be added to balance metabolites and represent the biochemistry, physiology, and genetics of the cells, tissues, organs, and/or whole human body. In the approach described below, the initial reconstruction of a central metabolic network followed by development of cell-specific models, the reconstruction of a generic central metabolic network is not a necessary step in reconstructing and modeling human metabolism. Rather, it is performed to accelerate the reconstruction process.
Implementation of the multi-cellular adipocyte-myocyte model is described below with reference to the reconstruction of the constituent components. In this regard, the reconstruction of a central human metabolic network is described first followed by the reconstruction procedures for fatty cell and muscle cell specific networks. The reconstruction procedure by which the two cell-specific models were combined to generate a multi-cellular model for human metabolism is then described.
Metabolic Network of Central Human Metabolism
The metabolic network of the central human metabolism was constructed as a template and a starting point for reconstructing more specific cell models. To construct a central metabolic network for human metabolism, a compendium of 1557 annotated human genes obtained from Kyoto Encyclopedia of Genes and Genomes KEGG, National Center for Biotechnology Information or NCBI, and the Universal Protein Resource or UniProt databases was used. In addition to the genomic and proteomic data, several primary textbooks and publications on the biochemistry of human metabolism also were used and includedthe Human Metabolism: Functional Diversity and Integration, Ed. by J. R. Bronk, Harlow, Addison, Wesley, Longman (1999); Textbook of Biochemistry with Clinical Correlations, Ed. by Thomas M. Devlin, New York, Wiley-Liss (2002), and Metabolism at a Glance, Ed. by J. G. Salway, Oxford, Malden, Mass., Blackwell Science (1999). The network reconstruction of human central metabolism included metabolic pathways for glycolysis, gluconeogenesis, citrate cycle (TCA cycle), pentose phosphate pathway, galactose, malonyl-CoA, lactate, and pyruvate metabolism. The methods described previously were similarly used for this reconstruction as well as those described below. Metabolic reactions were compartmentalized into extra-cellular space, cytosol, mitochondrion, and endoplasmic reticulum. In addition to the biochemical pathways, exchange reactions were included based on biochemical literature and physiological evidence to provide the transport of metabolites across different organelles and cytosolic membrane.
The completed central metabolic network for human metabolism is shown in FIG. 5 where dashed lines indicate organelle, cell, or system boundary. The large dashed rectangle (black) represents the cytosolic membrane. The large dashed circle (red) represents the mitochondrial membrane and small dashed circle (green) represents the endoplasmic reticulum membrane. The human central metabolic network contains 80 reactions of which 25 are transporters and 60 unique metabolites 5. A representative example of a gene-protein-reaction association is shown in FIG. 6 where the open reading frame or ORF (7167) is associated to an mRNA transcript (TPI1). The transcript is then associated to a translated protein (TPi1) that catalyzes a corresponding reaction (TPI).
Adipocyte Metabolic Network
Adipocytes are specialized cells for synthesizing and storing triacylglycerol. Triacylglycerols (TAG's) are synthesized from dihydroxyacetone phosphate and fatty acids in white adipose tissue. Triacylglycerol synthesized in adipocytes can be hydrolyzed (or degraded) into fatty acids and glycerol via specialized pathways in the fat cells. The fatty acids that are released from triacylglycerol leave the cell and are transported to other cell types such as myocytes for energy production. The fatty acid composition of triacylglycerol in human mammary adipose tissue has been experimentally measured (Raclot et al., 324:911-5 (1997)) and includes essential, non-essential, saturated, unsaturated, even-, and odd-chain fatty acids (Table 10).







TABLE 10







Fatty acid composition of fat cell TAG in human, NEFA released by these


cells in vitro, and relative mobilization (% NEFA/% TAG) of fatty acids.











TAG
NEFA
Relative


Fatty acid
(weight %)
(weight %)
mobilization





C12:0
0.50 ± 0.07
0.45 ± 0.06
0.88 ± 0.02


C14:0
3.08 ± 0.13
2.94 ± 0.15
0.94 ± 0.01


C14:1,n-7
0.03 ± 0.00
0.03 ± 0.00
1.07 ± 0.14


C14:1,n-5
0.20 ± 0.01
0.19 ± 0.02
0.96 ± 0.03


C15:0
0.33 ± 0.02
0.35 ± 0.02
1.05 ± 0.02


C16:0
22.79 ± 0.56 
23.51 ± 0.74 
1.02 ± 0.01


C16:1,n-9
0.54 ± 0.01
  0.42 ± 0.02***
0.77 ± 0.01


C16:1,n-7
2.77 ± 0.21
 3.69 ± 0.34*
1.31 ± 0.02


C17:1,n-8
0.29 ± 0.02
 0.36 ± 0.02*
1.21 ± 0.03


C18:0
6.67 ± 0.35
6.41 ± 1.39
0.95 ± 0.06


C18:1,n-9
40.79 ± 0.52 
39.77 ± 0.57 
0.96 ± 0.01


C18:1,n-7
1.90 ± 0.05
2.12 ± 0.10
1.10 ± 0.03


C18:1,n-5
0.27 ± 0.01
0.31 ± 0.03
1.12 ± 0.04


C18:2,n-6
16.23 ± 0.86 
16.21 ± 0.62 
0.99 ± 0.01


C18:3,n-6
0.04 ± 0.00
0.05 ± 0.01
1.27 ± 0.07


C18:3,n-3
0.51 ± 0.02
  0.75 ± 0.03***
1.43 ± 0.03


C20:0
0.21 ± 0.02
  0.10 ± 0.01***
0.47 ± 0.04


C20:1,n-11
0.17 ± 0.01
  0.11 ± 0.01***
0.66 ± 0.03


C20:1,n-9
0.84 ± 0.02
  0.53 ± 0.02***
0.62 ± 0.01


C20:1,n-7
0.03 ± 0.00
 0.02 ± 0.00*
0.67 ± 0.03


C20:2,n-9
0.04 ± 0.00
 0.02 ± 0.00**
0.63 ± 0.06


C20:2,n-6
0.31 ± 0.02
 0.26 ± 0.01*
0.82 ± 0.04


C20:3,n-6
0.26 ± 0.03
0.24 ± 0.03
0.90 ± 0.05


C20:3,n-3
0.03 ± 0.00
0.03 ± 0.00
0.90 ± 0.06


C20:4,n-6
0.35 ± 0.03
  0.57 ± 0.04***
1.60 ± 0.04


C20:4,n-3
0.03 ± 0.01
0.04 ± 0.01
1.13 ± 0.16


C20:5,n-3
0.04 ± 0.01
  0.10 ± 0.01***
2.25 ± 0.08


C22:0
0.04 ± 0.01
 0.02 ± 0.01*
0.42 ± 0.05


C22:1,n-11
0.03 ± 0.01
 0.01 ± 0.00*
0.37 ± 0.02


C22:1,n-9
0.07 ± 0.01
 0.03 ± 0.00**
0.45 ± 0.03


C22:4,n-6
0.17 ± 0.02
 0.10 ± 0.01**
0.58 ± 0.03


C22:5,n-6
0.02 ± 0.01
0.01 ± 0.00
0.59 ± 0.05


C22:5,n-3
0.20 ± 0.03
 0.11 ± 0.01**
0.55 ± 0.02


C22:6,n-3
0.21 ± 0.04
 0.14 ± 0.02*
0.65 ± 0.04





*P < 0.05;


** P < 0.01;


***P < 0.001






The adipocyte metabolic model was constructed by adding the non-essential saturated, unsaturated, even- and odd-chain fatty acid biosynthetic pathways to the central metabolic network for 21 of the fatty acids listed in Table 10. The remaining 13 essential fatty acids were supplied to the cell via the extra-cellular space, representing the nutritional intake from the environment. Pathway for biosynthesis of triacylglycerol (TAG) from all 34 fatty acids was included to account for the formation and storage of TAG in adipocytes. Reactions for hydrolysis of TAG into fatty acids were also included to represent TAG degradation. In addition to fatty acid synthesis and TAG biosynthesis and degradation, transport reactions were included to allow for the release of fatty acids from intra-cellular space to the environment.
The metabolic model of an adipocyte cell contains a total of 198 reactions of which 63 are transporters. The adipocyte cell model is shown in FIG. 7 where dashed lines indicate organelle, cell, or system boundary. The large dashed rectangle (yellow) represents the adipocyte cytosolic membrane. The two large dashed circles (red) represent the mitochondrial membrane and the small dashed circle at the top (green) represents the endoplasmic reticulum membrane. As shown, metabolic reactions were compartmentalized into extra-cellular, cytosolic, mitochondrial, and endoplasmic reticulum. As described above, the extra-cellular space represents the environment outside the cell, which can include the space outside the body, connective tissues, and interstitial space between cells.
Myocyte Metabolic Network
The energy required for muscle contraction is generally supplied by glucose, stored glycogen, phosphocreatine, and fatty acids. The myocyte model was constructed by adding phosphocreatine kinase reaction, myosin-actin activation mechanism, and β-oxidation pathway to the central metabolic network. Muscle contraction was represented by a sequential conversion of myoactin to myosin-ATP, myosin-ATP to myosin-ADP-P, myosin-ADP-P to myosin-actin-ADP-P complex, myosin-actin-ADP-P to myoactin, and subsequently the formation of muscle contraction as shown in FIG. 8.
The conversion of myoactin to myosin-actin-ADP-P complex and muscle contraction results in a net conversion of ATP and H2O to ADP, H+, and Pi.
The complete reconstructed metabolic model for myocyte cell metabolism is shown in FIG. 9 where dashed lines indicate organelle, cell, or system boundary. The large dashed rectangle (brown) represents the myocyte cytosolic membrane. The two large dashed circles (red) represent the mitochondrial membrane. The medium sized dashed circle (purple) represents the peroxisomal membrane and the small dashed circle (green) represents the endoplasmic reticulum membrane. The myocyte network contains a total of 205 reactions of which 46 are transport reactions. Reactions for utilizing phosphcreatine as well as selected pathways for β-oxidation of saturated, unsaturated, even- and odd-chain fatty acids and their intermediates were also included in the model and are shown in FIG. 9. As with the previous network models, metabolic reactions were compartmentalized into extra-cellular, cytosolic, mitochondrial, peroxisomal, and endoplasmic reticulum.
Multi-Cellular Adipocyte-Myocyte Reconstruction
To generate a multi-cellular model for human metabolism, the metabolic function of the two models of adipocyte and myocyte were integrated by reconstructing a model that includes all the metabolic reactions in the two individual cell types. The interaction of the two cell types were then represented within an “intra-system” space, which represents the connective tissues such as blood, urine, and interstitial space, and an outside environment or “extra-system” space. To represent the uptake of metabolites and essential fatty acids from the environment, appropriate transport reactions were added to exchange metabolites across the extra-system boundary. Additional reactions also were added to balance metabolites in the intra-system space by including the bicarbonate and ammonia buffer systems as they function in the kidneys. These reactions were initially omitted but were added to improve the model once the requirement for the integrated system to buffer extracellular protons in the interstitial space became apparent once simulation testing began. The combined adipocyte-myocyte model contains 430 reactions and 240 unique metabolites. The complete reconstruction is shown in FIG. 10 and a summary of the reactions is set forth in Table 11. A substantially complete listing of all the reactions set forth in FIG. 10 is set forth below in Table 15.







TABLE 11







Network properties of central metabolic network, adipocyte,


myocyte, and multi-cell adipocyte-myocyte models.












Model
Reactions
Transporters
Compounds
















Central
80
25
60



Metabolism



Adipocyte
198
63
150



Myocyte
205
46
167



Adipocyte-
430
135
240



Myocyte










In FIG. 10, dashed lines again indicate organelle, cell, or system boundaries. The outer most large dashed rectangle (black) separates the environment inside and outside the human body. The two interior dashed rectangles represents the adipocyte cytosolic membrane (top, yellow) and the myocyte cytosolic membrane (bottom, brown). The pair of larger dashed circles within the adipocyte and myocyte cytosol (red) represent the mitochondrial membrane. The medium sized dashed circle in the myocyte cytosol (purple) represents the peroxisomal membrane and small dashed circle within the adipocyte and myocyte cytosol (green) represent the endoplasmic reticulum membrane.
Metabolic Simulations
The computational and infrastructure requirements for producing the integrated multi-cellular model were assessed by examining the network properties of first, the cell-specific models, and then the integrated multi-cellular reconstruction.
Metabolic Model of Central Human Metabolism
The metabolic capabilities of the central human model was determined through computation of maximum yield of the 12 precursor metabolites per glucose. The results are shown in Table 12. In all cases, the network's yield was less or equal to the maximum theoretical values except for succinyl-CoA. In the case of succinyl-CoA, a higher yield was possible by incorporating CO2 via pyruvate carboxylase reaction, PCm. In addition to precursor metabolite yields, the maximum ATP yield per mole of glucose was computed in the network. The maximum ATP yield for the central human metabolism was computed to be 31.5 mol ATP/mol glucose, which is consistent with previously calculated values (Vo et al., J. Biol. Chem. 279:39532-40. (2004)).







TABLE 12







Maximum theoretical and central human metabolic network yields


for the precursor metabolites per glucose. Units are in mol/mol glucose.













Central



Precursor Metabolites
Theoretical
Metabolism















Glucose 6-P
1
0.94



Fructose 6-P
1
0.94



Ribose 5-P
1.2
1.115



Erythrose 4-P
1.5
1.37



Glyceraldehyde 3-P
2
1.775



3-P Glycerate
2
2



Phosphoenolpyruvate
2
2



Pyruvate
2
2



Oxaloacetate,
2
1.969



mitochondrial



Acetyl-CoA,
2
2



mitochondrial



aKeto-glutarate,
1
1



mitochondrial



Succinyl-CoA,
1
1.595



mitochondrial










The biomass demand in living cells is a requirement for the production of biosynthetic components such as amino acids, lipids and other molecules that are needed to provide cell integrity, maintenance, and growth. All the biosynthetic components were made from the 12 precursor metabolites in the central metabolism shown in Table 12. The rate of growth and biomass maintenance in mammalian cells however is typically much lower than the rate of metabolic activities. Thus to represent the cells' biosynthetic requirement, a small flux demand was imposed for the production of the 12 precursor metabolites while maximizing for ATP. In the absence of experimental measurements, the capability of the network to meet the biosynthetic requirements was examined by constructing a reaction in which all the precursor metabolites were made simultaneously with stoichiometric coefficients of one as set forth in the reaction below:

Precursor Demand: 3pg[c]+accoa[m]+akg[m]+e4p[c]+f6p[c]+g3p[c]+g6p[c]+oaa[m]+pep[c]+pyr[c]+r5p[c]+succoa[m]→(2) coa[m]

In the absence of quantitative measurement, the above reaction serves to demonstrate the ability of the network to meet both biomass and energy requirements in the cell simultaneously. The maximum ATP yield for the central metabolism with a demand of 0.01 mmol/gDW of precursor metabolites was computed to be 29.0, demonstrating that the energy and carbon requirements for precursor metabolite generation, as expected, reduce the maximum energy production in the cell and this amount can be quantified using the reconstructed model.
Triacylglycerol Storage and Utilization in Adipocyte Tissue
As described previously, a main function of adipocyte is to synthesize, store, and hydrolyze triacylglycerols. The stored TAG can be used to generate ATP during starvation or under high-energy demand conditions. TAG hydrolysis results in the formation of fatty acids and glycerol in adipocyte. Fatty acids are transported to other tissues such as the muscle tissue where they can be utilized to generate energy. Glycerol is utilized further by the liver and other tissues where it is converted into glycerol phosphate and enters glycolytic pathway.
To simulate the storage of triacylglycerol from glucose in adipocyte, TAG synthesis was simulated by maximizing an internal demand for cytosolic triacylglycerol. The maximum yield of triacylglycerol per glucose was computed to be 0.06 mol TAG/mol glucose, without any biomass demand. To demonstrate how the stored TAG can be reutilized to produce fatty acids, the influx of all other carbon sources including glucose was constrained to zero and glycerol secretion, which is assumed to be taken up by the liver, was maximized. When 2 mol of cytosolic proton was allowed to leave the system, a glycerol yield of 1 mol glycerol/mol TAG or 100% was computed. The excess two protons were formed in TAG degradation pathway. As shown in FIG. 11, degradation of TAG was performed in the following three steps: (1) TRIGH_ac_HS_ub; (2) 12DGRH_ac_HS_ub, and (3) MGLYCH_ac_HS_ub). Glycerol generated as an end product of this pathway was transported out of the cell via a proton-coupled symport mechanism. TAG was hydrolyzed completely to fatty acids and glycerol in three steps and in each step one proton is released. Glycerol transport was coupled to one proton. Thus, a net amount of two protons were generated per mol TAG degraded.
To balance protons, an ATPase reaction across the cytosolic membrane was used. However, since the β-oxidative pathways were not included in this adipocyte model, this network is unable to use membrane bound ATPase to balance the internal protons. When β-oxidative pathways are added to the adipocyte model, the model can completely balance protons.
In addition to triacylglycerol synthesis and hydrolysis, the maximum ATP yield on glucose (YATP/glucose) was computed in the adipocyte model. As for the central human metabolic network, YATP/glucose was 31.5 mol ATP/mol glucose.
Muscle Contraction During Aerobic and Anaerobic Exercise
The required energy in muscle tissue is generally supplied by glucose, stored glycogen, and phosphocreatine. During anaerobic exercise such as a sprint, for example, the blood vessels in the muscle tissue are compressed and the cells are isolated from the rest of the body (Devlin, supra). This compression restricts the oxygen supply to the tissue and enforces anaerobic energy metabolism in the cell. As a result, lactate is generated to balance the redox potential and must be secreted out of the cell. In the liver, lactate is converted into glucose. However, rapid muscle contraction and decreased blood flow to the muscle tissue cause lactate accumulation during anaerobic exercise and quickly impairs muscle contraction. During starvation or under high-energy demands, the glucose and glycogen storage of the muscle tissue quickly depletes and the energy storage in triacylglycerol molecules supplied by fatty cells is used to generate ATP.
To simulate the muscle physiology at steady state, phosphocreatine kinase reaction, myosin-actin activation mechanism, and β-oxidation pathway were included in the central metabolic network. The physiological function of muscle tissue was simulated by determining the maximum amount of contraction that is generated from the energy supplied by glucose, stored glycogen, phosphocreatine, and supplied fatty acids.
The metabolic capabilities of the myocyte model were assessed by first computing the maximum ATP yield on glucose. As for the central human metabolic network, YATP/glucose was 31.5 mol ATP/mol glucose. The muscle contraction was also examined with glucose as the sole carbon source. Maximum muscle contraction with glucose was computed to be 31.5 mol/mol glucose in aerobic and 2 mol/mol glucose in anaerobic condition. Lactate was secreted as a byproduct during anaerobic contraction (Yieldlactate/glucose=2 mol/mol).
As lactate accumulates during anaerobic metabolism, its secretion rate quickly fails to meet the demand to release lactate into the blood. To simulation the impairment of muscle contraction in anaerobic exercise, the maximum lactate secretion rate was constrained to 75%, 50%, 25%, and 0% of its maximum value under anaerobic condition. The results using these different constraints are shown in FIG. 12 where the time is shown as an arbitrary unit, rate of contraction and lactate secretion are in mols per cell mass per unit time, r corresponds to rate and lac corresponds to lactate. The results show that as more lactate accumulates in anaerobic metabolism, the maximum allowable lactate secretion decreases and maximum muscle contraction decreased proportionally.
The muscle contraction was simulated also with stored glycogen and phosphocreatine as the energy source. The maximum contraction for glycogen was computed to be 32.5 mol/mol glycogen in aerobic and 3 mol/mol glycogen in anaerobic condition. The observed difference between the maximum contraction generated by glycogen in comparison to glucose arises from the absence of the phosphorylation or glucokinase step in the first step of glycolysis. The results of glycogen versus glucose utilization are illustrated in FIG. 13 where the glycogen utilization pathway is shown as the thick bent arrow on the left (red) and the glucose utilization pathway is shown as the thick straight arrow on the right (blue). The dashed circle (green) represents the endoplasmic reticulum membrane. The maximum contraction from phosphocreatine under both aerobic and anaerobic conditions was computed to be 1 mol/mol phosphocreatine. The energy generated from phosphocreatine is independent of the energy produced through oxidative phosphorylation and thus was computed to be the same in both aerobic and anaerobic conditions.
In addition, β-oxidative pathways in the myocyte tissue were examined by supplying the network with eicosanoate (n-C20:0), octadecenoate (C18:1, n-9), and pentadecanoate (C15:0) as examples of fatty acid oxidation of odd- and even-chain, and saturated and unsaturated fatty acids. The results are shown in Table 13 and demonstrate that maximum contraction in the myocyte model was 134 mol/mol for eicosanoate, 118.5 mol/mol for octadecenoate, and 98.5 mol/mol for pentadecanoate. The results also show that on a carbon-mole basis, all the fatty acids yielded approximately the same contraction, which was equivalent to ATP yield. Contraction was observed to be larger in terms of carbon yield than that generated from glucose (i.e.  ̃6.6 mol ATP/C-mol fatty acid in comparison to 5.3 mol ATP/C-mol glucose). The maximum ATP yield for palmitate (C16:0) was also computed to be 106 mol ATP/mol palmitate, which was consistent with the previously calculated values (Vo et al, supra). One mol of cytosolic protons per mol of fatty acid was supplied to the network for fatty acid oxidation.







TABLE 13







Maximum contraction in the myocyte model given different fatty acids












Maximum
Maximum




Contraction (mol/mol
Contraction


Fatty Acid
Abbreviation*
fatty acid)
(mol/C-mol)













Eicosanoate
C20:0
134
6.7


Octadecenoate
C18:1, n-9
118.5
6.6


Palmitate
C16:0
106
6.6


Pentadecanoate
C15:0
98.5
6.6





*Abbreviation indicates: number of carbons in the fatty acid, number of double bonds, carbon number where the 1st double bond appears if the fatty acid is unsaturated.






A unit of proton per fatty acid is required in the network to balance fatty acyl CoA formation in the cell as illustrated in the following reaction:













Fatty Acid CoA Ligase:
Fatty Acid + ATP + CoA → Fatty



Acyl-CoA + AMP + PPi


Adenylate Kinase:
AMP + ATP   (2) ADP


Inorganic Diphosphatase:
PPi + H2O → H+ + (2) Pi


Net:
Fatty Acid + CoA + (2) ATP + H2O → Fatty



Acyl-CoA + (2)O ADP + (2) Pi + H+









With respect to ATP balance (i.e. ATP+H2O→ADP+Pi+H+), the net reaction has one mol less H2O and H+. Water can freely diffuse through the membrane. However, cell membrane is impermeable to free protons and thus protons were balanced in all compartments. The proton requirement in the cell can be fulfilled with a proton-coupled fatty acid transporter. It has been observed that the proton electrochemical gradient across the inner membrane plays a crucial role in energizing the long-chain fatty acid transport apparatus in E. coli and the proton electrochemical gradient across the inner membrane is required for optimal fatty acid transport (DiRusso et al., Mol. Cell. Biochem. 192:41-52 (1999)). Fatty acid transporters in S. cerevisiae have also been studied, however, no evidence is currently available on the mechanism of transport. When a proton coupled fatty acid transporter was used in the model, the requirement for supplying a mol of proton to the system was eliminated.
Adipocyte-Myoctye Coupled Functions
Muscle cells largely rely on their stored glycogen and phosphocreatine content. During aerobic exercise, however, glucose, glycogen, and phosphcreatine storage of muscle cells are depleted and energy generation in myocytes is achieved by fatty acid oxidation. Lipolysis or lipid degradation proceeds in muscle cells following the transfer of fatty acids from adipocytes to myocytes via blood.
Modeling of multi-cellular metabolism was performed using a constraint-based approach as described herein where the metabolic networks of adipocyte and myocyte were combined into a multi-cellular metabolic model as shown in FIG. 10. The integrated model was assessed by computing the network energy requirements during anaerobic exercise such as that corresponding to a sprint and aerobic exercise such as that corresponding to a marathon. From a purely additive perspective, combining all of the reactions from the adipocyte model with those from the myocyte model was initially performed as a sufficient indicator for the combined network to compute integrated physiological results. However, with the two models strictly combined in this manner they were deficient at computing integrated functions such as those described below and, in particular, the results described in the “Muscle Contraction in a Marathon” section below. Addition of buffer systems for bicarbonate and ammonia allowed the combined model to function more efficiently and predictably. In retrospect, the inclusion of intra-system reactions is consistent with the role that, for example, the kidney plays in integrated metabolic physiology.
Simulation of an Integrated Model for Muscle Contraction During a Sprint: The energy requirements of myocytes in a sprint are extremely high and supplied primarily from the fuel present in the muscle. In addition, oxygen cannot be transported to the cells fast enough to trigger an aerobic metabolism. It has been estimated that only 5% of the energy in a sprint is supplied via oxidative phosphorylation and the remaining ATP is generated from anaerobic metabolism from stored glycogen and phosphocreatine (Biochemical and Physiological Aspects of Human Nutrition, Philadelphia, Ed. by M. H. Stipanuk, W. B. Saunders, (2000)).
To simulate the metabolic activity of the muscle in a sprint, the maximum muscle contraction in an aerobic condition was computed by supplying the multi-cellular model with glucose, glycogen, and phosphocreatine as shown in Table 14. In addition, muscle contraction was simulated under anaerobic condition by constraining the oxygen supply to zero. Maximum contraction was computed to be the same as in the isolated myocyte model, as expected, demonstrating that the integrated model retains the functionalities observed in the single-cell model.







TABLE 14







Simulation results in the adipocyte-myocyte integrated model.1











Objective (Cell
Aerobic
Anaerobic


Carbon Source
Type)
mol/mol
carbon source





Glucose
Contraction (M)
31.5
2


Glycogen
Contraction (M)
32.5
3


Phosphocreatine
Contraction (M)
1 
1


Glucose
ATP synthesis (A)
32.5
—


Glucose
TAG synthesis (A)
 0.06
—


TAG
Glycerol (I)
 1*
—


TAG supplying C12:0,
Contraction (M)
253.9 
—


C14:0, C15:0, C16:0,


C18:0, C18:1 n-9,


and C20:0





*Two protons were allowed to leave the cytosol (see section “Triacylglycerol Storage and Utilization in Adipocyte Tissue”)


— Not relevant


1M, myocyte; A, adipocyte; I, intra-system; TAG, triacylglycerol; C12:0, dodecanoate; C14:0, tetradecanoate; C15:0, pentadecanoate; C16:0, palmitate, C18:0, octadecanoate; C18:1 n-9, octadecenoate; C20:0, eicosanoate






Simulation of an Integrated Model for Muscle Contraction During a Marathon: The total energy expenditure in a marathon is about 12,000 kJ or 2868 kcal, which is equivalent to burning about 750 g of carbohydrate or 330 g of fat (Stipanuk, supra). Since the total stored carbohydrate in the body is only about 400 to 900 g, the mobilized fatty acids from adipose tissue provide an important part of the supplied energy to the muscle cells in an aerobic metabolism and especially in a marathon.
To simulate the aerobic oxidation of fatty acid in the muscle cells, the integrated model was first demonstrated to be able to synthesize and store triacylglycerol in the adipocyte compartment when supplied by glucose. As for the single cell model, the integrated adipocyte-myocyte network was able to store TAG in adipocyte compartment. The results are shown in Table 14. In addition, TAG degradation and fatty acid mobilization to the blood was simulated by maximizing glycerol secretion in the intra-system space generated from the stored TAG in adipocyte. As with the single cell model, TAG hydrolysis was simulated with the integrated adipocyte-myocyte model and maximum glycerol secretion rate was shown to be the same.
To demonstrate the coupled function of the two cell types, muscle contraction in an aerobic exercise was simulated by constraining all other alternative carbon sources including glucose, stored glycogen, and phosphocreatine to zero and supplying adipocyte with stored triacylglycerol as an energy source. Exchange fluxes were included to ensure the proper transfer of fatty acids between the two models. The maximum muscle contraction in the network that contains β-oxidative pathways for fatty acids C12:0, C14:0, C15:0, C16:0, C18:0, C18:1 n-9, and C20:0 was simulated and computed to be 253.9 mol/mol TAG. The total contraction in this simulation is the sum of maximum contraction that is generated if the model was supplied with each fatty acid individually. The results from using the integrated model demonstrated that energy generated in the muscle cell from triacylglycerol is produced in an additive fashion and metabolite balance in the two cell types does not reduce the energy production in the cell.
These studies further demonstrate the the application of a constraint-based approach to modeling multi-cellular integrated metabolic models. The results also indicate that modeling multi-cellular networks can be optimized by incorporating intra-system reactions such as the bicarbonate and ammonia buffer systems into the integrated adipocyte-myocyte model. The reconstructed models and simulation results also demonstrated that metabolic functions of various cell types can be studied, understood and reproduced using the methods of the invention. Furthermore, coupling of the functions of multiple cell types in a system was demonstrated through the transport of various metabolites and the coupled function of different cell types were studied by imposing biologically appropriate objective function. Finally, the ability to predict further network modifications, such as the transport mechanism of fatty acids into myocyte, using the reconstructed models also was demonstrated. These results also indicate that multi-cellular modeling can be extended to the modeling of more than two cells and which correspond to various cell types including the same specie or among multiple different species, tissues, organs, and whole body by including additional genomic, biochemical, physiological, and high throughput datasets.
Throughout this application various publications have been referenced within parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains.
Although the invention has been described with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific examples and studies detailed above are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.










TABLE 1





Locus ID
Gene Ab.
Reaction Stoichiometry
E.C.















1. Carbohydrate Metabolism


1.1 Glycolysis/Gluconeogenesis [PATH:hsa00010]










3098
HK1
GLC + ATP -> G6P + ADP
2.7.1.1


3099
HK2
GLC + ATP -> G6P + ADP
2.7.1.1


3101
HK3
GLC + ATP -> G6P + ADP
2.7.1.1


2645
GCK, HK4, MODY2, NIDDM
GLC + ATP -> G6P + ADP
2.7.1.2


2538
G6PC, G6PT
G6P + H2O -> GLC + PI
3.1.3.9


2821
GPI
G6P <-> F6P
5.3.1.9


5211
PFKL
F6P + ATP -> FDP + ADP
2.7.1.11


5213
PFKM
F6P + ATP -> FDP + ADP
2.7.1.11


5214
PFKP, PFK-C
F6P + ATP -> FDP + ADP
2.7.1.11


5215
PFKX
F6P + ATP -> FDP + ADP
2.7.1.11


2203
FBP1, FBP
FDP + H2O -> F6P + PI
3.1.3.11


8789
FBP2
FDP + H2O -> F6P + PI
3.1.3.11


226
ALDOA
FDP <-> T3P2 + T3P1
4.1.2.13


229
ALDOB
FDP <-> T3P2 + T3P1
4.1.2.13


230
ALDOC
FDP <-> T3P2 + T3P1
4.1.2.13


7167
TPI1
T3P2 <-> T3P1
5.3.1.1


2597
GAPD, GAPDH
T3P1 + PI + NAD <-> NADH + 13PDG
1.2.1.12


26330
GAPDS, GAPDH-2
T3P1 + PI + NAD <-> NADH + 13PDG
1.2.1.12


5230
PGK1, PGKA
13PDG + ADP <-> 3PG + ATP
2.7.2.3


5233
PGK2
13PDG + ADP <-> 3PG + ATP
2.7.2.3


5223
PGAM1, PGAMA
13PDG -> 23PDG
5.4.2.4




23PDG + H2O -> 3PG + PI
3.1.3.13




3PG <-> 2PG
5.4.2.1


5224
PGAM2, PGAMM
13PDG <-> 23PDG
5.4.2.4




23PDG + H2O -> 3PG + PI
3.1.3.13




3PG <-> 2PG
5.4.2.1


669
BPGM
13PDG <-> 23PDG
5.4.2.4




23PDG + H2O <-> 3PG + PI
3.1.3.13




3PG <-> 2PG
5.4.2.1


2023
ENO1, PPH, ENO1L1
2PG <-> PEP + H2O
4.2.1.11


2026
ENO2
2PG <-> PEP + H2O
4.2.1.11


2027
ENO3
2PG <-> PEP + H2O
4.2.1.11


26237
ENO1B
2PG <-> PEP + H2O
4.2.1.11


5313
PKLR, PK1
PEP + ADP -> PYR + ATP
2.7.1.40


5315
PKM2, PK3, THBP1, OIP3
PEP + ADP -> PYR + ATP
2.7.1.40


5160
PDHA1, PHE1A, PDHA
PYRm + COAm + NADm -> + NADHm + CO2m + ACCOAm
1.2.4.1


5161
PDHA2, PDHAL
PYRm + COAm + NADm -> + NADHm + CO2m + ACCOAm
1.2.4.1


5162
PDHB
PYRm + COAm + NADm -> + NADHm + CO2m + ACCOAm
1.2.4.1


1737
DLAT, DLTA, PDC-E2
PYRm + COAm + NADm -> + NADHm + CO2m + ACCOAm
2.3.1.12


8050
PDX1, E3BP
PYRm + COAm + NADm -> + NADHm + CO2m + ACCOAm
2.3.1.12


3939
LDHA, LDH1
NAD + LAC <-> PYR + NADH
1.1.1.27


3945
LDHB
NAD + LAC <-> PYR + NADH
1.1.1.27


3948
LDHC, LDH3
NAD + LAC <-> PYR + NADH
1.1.1.27


5236
PGM1
G1P <-> G6P
5.4.2.2


5237
PGM2
G1P <-> G6P
5.4.2.2


5238
PGM3
G1P <-> G6P
5.4.2.2


1738
DLD, LAD, PHE3, DLDH, E3
DLIPOm + FADm <-> LIPOm + FADH2m
1.8.1.4


124
ADH1
ETH + NAD <-> ACAL + NADH
1.1.1.1


125
ADH2
ETH + NAD <-> ACAL + NADH
1.1.1.1


126
ADH3
ETH + NAD <-> ACAL + NADH
1.1.1.1


127
ADH4
ETH + NAD <-> ACAL + NADH
1.1.1.1


128
ADH5
FALD + RGT + NAD <-> FGT + NADH
1.2.1.1




ETH + NAD <-> ACAL + NADH
1.1.1.1


130
ADH6
ETH + NAD <-> ACAL + NADH
1.1.1.1


131
ADH7
ETH + NAD <-> ACAL + NADH
1.1.1.1


10327
AKR1A1, ALR, ALDR1

1.1.1.2


97
ACYP1

3.6.1.7


98
ACYP2

3.6.1.7







1.2 Citrate cycle (TCA cycle) PATH:hsa00020










1431
CS
ACCOAm + OAm + H2Om -> COAm + CITm
4.1.3.7


48
ACO1, IREB1, IRP1
CIT <-> ICIT
4.2.1.3


50
ACO2
CITm <-> ICITm
4.2.1.3


3417
IDH1
ICIT + NADP -> NADPH + CO2 + AKG
1.1.1.42


3418
IDH2
ICITm + NADPm -> NADPHm + CO2m + AKGm
1.1.1.42


3419
IDH3A
ICITm + NADm -> CO2m + NADHm + AKGm
1.1.1.41


3420
IDH3B
ICITm + NADm -> CO2m + NADHm + AKGm
1.1.1.41


3421
IDH3G
ICITm + NADm -> CO2m + NADHm + AKGm
1.1.1.41


4967
OGDH
AKGm + NADm + COAm -> CO2m + NADHm + SUCCOAm
1.2.4.2


1743
DLST, DLTS
AKGm + NADm + COAm -> CO2m + NADHm + SUCCOAm
2.3.1.61


8802
SUCLG1, SUCLA1
GTPm + SUCCm + COAm <-> GDPm + PIm + SUCCOAm
6.2.1.4


8803
SUCLA2
ATPm + SUCCm + COAm <-> ADPm + PIm + SUCCOAm
6.2.1.4


2271
FH
FUMm + H2Om <-> MALm
4.2.1.2


4190
MDH1
MAL + NAD <-> NADH + OA
1.1.1.37


4191
MDH2
MALm + NADm <-> NADHm + OAm
1.1.1.37


5091
PC, PCB
PYRm + ATPm + CO2m -> ADPm + OAm + PIm
6.4.1.1


47
ACLY, ATPCL, CLATP
ATP + CIT + COA + H2O -> ADP + PI + ACCOA + OA
4.1.3.8


3657


5105
PCK1
OA + GTP -> PEP + GDP + CO2
4.1.1.32


5106
PCK2, PEPCK
OAm + GTPm -> PEPm + GDPm + CO2m
4.1.1.32







1.3 Pentose phosphate cycle PATH:hsa00030










2539
G6PD, G6PD1
G6P + NADP <-> D6PGL + NADPH
1.1.1.49


9563
H6PD

1.1.1.47




D6PGL + H2O -> D6PGC
3.1.1.31


25796
PGLS, 6PGL
D6PGL + H2O -> D6PGC
3.1.1.31


5226
PGD
D6PGC + NADP -> NADPH + CO2 + RL5P
1.1.1.44


6120
RPE
RL5P <-> X5P
5.1.3.1


7086
TKT
R5P + X5P <-> T3P1 + S7P
2.2.1.1




X5P + E4P <-> F6P + T3P1


8277
TKTL1, TKR, TKT2
R5P + X5P <-> T3P1 + S7P
2.2.1.1




X5P + E4P <-> F6P + T3P1


6888
TALDO1
T3P1 + S7P <-> E4P + F6P
2.2.1.2


5631
PRPS1, PRS I, PRS, I
R5P + ATP <-> PRPP + AMP
2.7.6.1


5634
PRPS2, PRS II, PRS, II
R5P + ATP <-> PRPP + AMP
2.7.6.1


2663
GDH

1.1.1.47







1.4 Pentose and glucuronate interconversions PATH:hsa00040










231
AKR1B1, AR, ALDR1, ADR

1.1.1.21


7359
UGP1
G1P + UTP -> UDPG + PPI
2.7.7.9


7360
UGP2, UGPP2
G1P + UTP -> UDPG + PPI
2.7.7.9


7358
UGDH, UDPGDH

1.1.1.22


10720
UGT2B11

2.4.1.17


54658
UGT1A1, UGT1A, GNT1, UGT1

2.4.1.17


7361
UGT1A, UGT1, UGT1A

2.4.1.17


7362
UGT2B, UGT2, UGT2B

2.4.1.17


7363
UGT2B4, UGT2B11

2.4.1.17


7364
UGT2B7, UGT2B9

2.4.1.17


7365
UGT2B10

2.4.1.17


7366
UGT2B15, UGT2B8

2.4.1.17


7367
UGT2B17

2.4.1.17


13
AADAC, DAC

3.1.1.—


3991
LIPE, LHS, HSL

3.1.1.—







1.5 Fructose and mannose metabolism PATH:hsa00051










4351
MPI, PMI1
MAN6P <-> F6P
5.3.1.8


5372
PMM1
MAN6P <-> MAN1P
5.4.2.8


5373
PMM2, CDG1, CDGS
MAN6P <-> MAN1P
5.4.2.8


2762
GMDS

4.2.1.47


8790
FPGT, GFPP

2.7.7.30


5207
PFKFB1, PFRX
ATP + F6P -> ADP + F26P
2.7.1.105




F26P -> F6P + PI
3.1.3.46


5208
PFKFB2
ATP + F6P -> ADP + F26P
2.7.1.105




F26P -> F6P + PI
3.1.3.46


5209
PFKFB3
ATP + F6P -> ADP + F26P
2.7.1.105




F26P -> F6P + PI
3.1.3.46


5210
PFKFB4
ATP + F6P -> ADP + F26P
2.7.1.105




F26P -> F6P + PI
3.1.3.46


3795
KHK

2.7.1.3


6652
SORD
DSOT + NAD -> FRU + NADH
1.1.1.14


2526
FUT4, FCT3A, FUC-TIV

2.4.1.—


2529
FUT7

2.4.1.—


3036
HAS1, HAS

2.4.1.—


3037
HAS2

2.4.1.—


8473
OGT, O-GLCNAC

2.4.1.—


51144
LOC51144

1.1.1.—







1.6 Galactose metabolism PATH:hsa00052










2584
GALK1, GALK
GLAC + ATP -> GAL1P + ADP
2.7.1.6


2585
GALK2, GK2
GLAC + ATP -> GAL1P + ADP
2.7.1.6


2592
GALT
UTP + GAL1P <-> PPI + UDPGAL
2.7.7.10


2582
GALE
UDPGAL <-> UDPG
5.1.3.2


2720
GLB1

3.2.1.23


3938
LCT, LAC

3.2.1.62





3.2.1.108


2683
B4GALT1, GGTB2, BETA4GAL-T1,

2.4.1.90



GT1, GTB

2.4.1.38





2.4.1.22


3906
LALBA

2.4.1.22


2717
GLA, GALA
MELI -> GLC + GLAC
3.2.1.22


2548
GAA
MLT-> 2 GLC
3.2.1.20




6DGLC -> GLAC + GLC


2594
GANAB
MLT -> 2 GLC
3.2.1.20




6DGLC -> GLAC + GLC


2595
GANC
MLT -> 2 GLC
3.2.1.20




6DGLC -> GLAC + GLC


8972
MGAM, MG, MGA
MLT -> 2 GLC
3.2.1.20




6DGLC -> GLAC + GLC





3.2.1.3







1.7 Ascorbate and aldarate metabolism PATH:hsa00053










216
ALDH1, PUMB1
ACAL + NAD -> NADH + AC
1.2.1.3


217
ALDH2
ACALm + NADm -> NADHm + ACm
1.2.1.3


219
ALDH5, ALDHX

1.2.1.3


223
ALDH9, E3

1.2.1.3





1.2.1.19


224
ALDH10, FALDH, SLS

1.2.1.3


8854
RALDH2

1.2.1.3


1591
CYP24

1.14.—.—


1592
CYP26A1, P450RAI

1.14.—.—


1593
CYP27A1, CTX, CYP27

1.14.—.—


1594
CYP27B1, PDDR, VDD1, VDR, CYP1,

1.14.—.—



VDDR, I, P450C1







1.8 Pyruvate metabolism PATH:hsa00620










54988
FLJ20581
ATP + AC + COA -> AMP + PPI + ACCOA
6.2.1.1


31
ACACA, ACAC, ACC
ACCOA + ATP + CO2 <-> MALCOA + ADP + PI + H
6.4.1.2





6.3.4.14


32
ACACB, ACCB, HACC275, ACC2
ACCOA + ATP + CO2 <-> MALCOA + ADP + PI + H
6.4.1.2





6.3.4.14


2739
GLO1, GLYI
RGT + MTHGXL <-> LGT
4.4.1.5


3029
HAGH, GLO2
LGT -> RGT + LAC
3.1.2.6


2223
FDH
FALD + RGT + NAD <-> FGT + NADH
1.2.1.1


9380
GRHPR, GLXR

1.1.1.79


4200
ME2
MALm + NADm -> CO2m + NADHm + PYRm
1.1.1.38


10873
ME3
MALm + NADPm -> CO2m + NADPHm + PYRm
1.1.1.40


29897
HUMNDME
MAL + NADP -> CO2 + NADPH + PYR
1.1.1.40


4199
ME1
MAL + NADP -> CO2 + NADPH + PYR
1.1.1.40


38
ACAT1, ACAT, T2, THIL, MAT
2 ACCOAm <-> COAm + AACCOAm
2.3.1.9


39
ACAT2
2 ACCOAm <-> COAm + AACCOAm
2.3.1.9







1.9 Glyoxylate and dicarboxylate metabolism PATH:hsa00630










5240
PGP

3.1.3.18


2758
GLYD
3HPm + NADHm -> NADm + GLYAm
1.1.1.29


10797
MTHFD2, NMDMC
METHF <-> FTHF
3.5.4.9




METTHF + NAD -> METHF + NADH
1.5.1.15


4522
MTHFD1
METTHF + NADP <-> METHF + NADPH
1.5.1.15




METHF <-> FTHF
3.5.4.9




THF + FOR + ATP -> ADP + PI + FTHF
6.3.4.3







1.10 Propanoate metabolism PATH:hsa00640










34
ACADM, MCAD
MBCOAm + FADm -> MCCOAm + FADH2m
1.3.99.3




IBCOAm + FADm -> MACOAm + FADH2m




IVCOAm + FADm -> MCRCOAm + FADH2m


36
ACADSB
MBCOAm + FADm -> MCCOAm + FADH2m
1.3.99.3




IBCOAm + FADm -> MACOAm + FADH2m




IVCOAm + FADm -> MCRCOAm + FADH2m


1892
ECHS1, SCEH
MACOAm + H2Om -> HIBCOAm
4.2.1.17




MCCOAm + H2Om -> MHVCOAm


1962
EHHADH
MHVCOAm + NADm -> MAACOAm + NADHm
1.1.1.35




HIBm + NADm -> MMAm + NADHm




MACOAm + H2Om -> HIBCOAm
4.2.1.17




MCCOAm + H2Om -> MHVCOAm


3030
HADHA, MTPA, GBP
MHVCOAm + NADm -> MAACOAm + NADHm
1.1.1.35




HIBm + NADm -> MMAm + NADHm




MACOAm + H2Om -> HIBCOAm
4.2.1.17




MCCOAm + H2Om -> MHVCOAm




C160CARm + COAm + FADm + NADm -> FADH2m +
1.1.1.35




NADHm + C140COAm + ACCOAm
4.2.1.17


23417
MLYCD, MCD

4.1.1.9


18
ABAT, GABAT
GABA + AKG -> SUCCSAL + GLU
2.6.1.19


5095
PCCA
PROPCOAm + CO2m + ATPm -> ADPm + PIm + DMMCOAm
6.4.1.3


5096
PCCB
PROPCOAm + CO2m + ATPm -> ADPm + PIm + DMMCOAm
6.4.1.3


4594
MUT, MCM
LMMCOAm -> SUCCOAm
5.4.99.2


4329
MMSDH
MMAm + COAm + NADm -> NADHm + CO2m + PROPCOAm
1.2.1.27


8523
FACVL1, VLCS, VLACS

6.2.1.—







1.11 Butanoate metabolism PATH:hsa00650










3028
HADH2, ERAB
C140COAm + 7 COAm + 7 FADm + 7 NADm -> 7 FADH2m + 7
1.1.1.35




NADHm + 7 ACCOAm


3033
HADHSC, SCHAD

1.1.1.35


35
ACADS, SCAD
MBCOAm + FADm -> MCCOAm + FADH2m
1.3.99.2




IBCOAm + FADm -> MACOAm + FADH2m


7915
ALDH5A1, SSADH, SSDH

1.2.1.24


2571
GAD1, GAD, GAD67, GAD25
GLU -> GABA + CO2
4.1.1.15


2572
GAD2
GLU -> GABA + CO2
4.1.1.15


2573
GAD3
GLU -> GABA + CO2
4.1.1.15


3157
HMGCS1, HMGCS
H3MCOA + COA <-> ACCOA + AACCOA
4.1.3.5


3158
HMGCS2
H3MCOA + COA <-> ACCOA + AACCOA
4.1.3.5


3155
HMGCL, HL
H3MCOAm -> ACCOAm + ACTACm
4.1.3.4


5019
OXCT

2.8.3.5


622
BDH
3HBm + NADm -> NADHm + Hm + ACTACm
1.1.1.30


1629
DBT, BCATE2
OMVALm + COAm + NADm -> MBCOAm + NADHm + CO2m
2.3.1.—




OIVALm + COAm + NADm -> IBCOAm + NADHm + CO2m




OICAPm + COAm + NADHm -> IVCOAm + NADHm + CO2m







1.13 Inositol metabolism PATH:hsa00031


2. Energy Metabolism


2.1 Oxidative phosphorylation PATH:hsa00190










4535
MTND1
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4536
MTND2
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4537
MTND3
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4538
MTND4
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4539
MTND4L
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4540
MTND5
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4541
MTND6
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4694
NDUFA1, MWFE
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4695
NDUFA2, B8
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4696
NDUFA3, B9
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4697
NDUFA4, MLRQ
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4698
NDUFA5, UQOR13, B13
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4700
NDUFA6, B14
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4701
NDUFA7, B14.5a, B14.5A
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4702
NDUFA8, PGIV
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4704
NDUFA9, NDUFS2L
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4705
NDUFA10
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4706
NDUFAB1, SDAP
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4707
NDUFB1, MNLL, CI-SGDH
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4708
NDUFB2, AGGG
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4709
NDUFB3, B12
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4710
NDUFB4, B15
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4711
NDUFB5, SGDH
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4712
NDUFB6, B17
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4713
NDUFB7, B18
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4714
NDUFB8, ASHI
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4715
NDUFB9, UQOR22, B22
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4716
NDUFB10, PDSW
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4717
NDUFC1, KFYI
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4718
NDUFC2, B14.5b, B14.5B
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4724
NDUFS4, AQDQ
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4725
NDUFS5
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4726
NDUFS6
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4731
NDUFV3
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4727
NDUFS7, PSST
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4722
NDUFS3
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4720
NDUFS2
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4729
NDUFV2
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4723
NDUFV1, UQOR1
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


4719
NDUFS1, PRO1304
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3


4728
NDUFS8
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.5.3




NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
1.6.99.3


6391
SDHC
SUCCm + FADm <-> FUMm + FADH2m
1.3.5.1




FADH2m + Qm <-> FADm + QH2m


6392
SDHD, CBT1, PGL, PGL1
SUCCm + FADm <-> FUMm + FADH2m
1.3.5.1




FADH2m + Qm <-> FADm + QH2m


6389
SDHA, SDH2, SDHF, FP
SUCCm + FADm <-> FUMm + FADH2m
1.3.5.1




FADH2m + Qm <-> FADm + QH2m


6390
SDHB, SDH1, IP, SDH
SUCCm + FADm <-> FUMm + FADH2m
1.3.5.1




FADH2m + Qm <-> FADm + QH2m


7386
UQCRFS1, RIS1
O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
1.10.2.2


4519
MTCYB
O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
1.10.2.2


1537
CYC1
O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
1.10.2.2


7384
UQCRC1, D3S3191
O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
1.10.2.2


7385
UQCRC2
O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
1.10.2.2


7388
UQCRH
O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
1.10.2.2


7381
UQCRB, QPC, UQBP, QP-C
O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
1.10.2.2


27089
QP-C
O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
1.10.2.2


10975
UQCR
O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
1.10.2.2


1333
COX5BL4
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


4514
MTCO3
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


4512
MTCO1
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


4513
MTCO2
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1329
COX5B
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1327
COX4
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1337
COX6A1, COX6A
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1339
COX6A2
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1340
COX6B
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1345
COX6C
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


9377
COX5A, COX, VA, COX-VA
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1346
COX7A1, COX7AM, COX7A
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1347
COX7A2, COX VIIa-L
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1348
COX7A3
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1349
COX7B
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


9167
COX7A2L, COX7RP, EB1
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1350
COX7C
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


1351
COX8, COX VIII
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
1.9.3.1


4508
MTATP6
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


4509
MTATP8
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


499
ATP5A2
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


507
ATP5BL1, ATPSBL1
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


508
ATP5BL2, ATPSBL2
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


519
ATP5H
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


537
ATP6S1, ORF, VATPS1, XAP-3
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


514
ATP5E
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


513
ATP5D
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


506
ATP5B, ATPSB
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


509
ATP5C1, ATP5C
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


498
ATP5A1, ATP5A, ATPM, OMR, HATP1
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


539
ATP5O, ATPO, OSCP
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


516
ATP5G1, ATP5G
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


517
ATP5G2
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


518
ATP5G3
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


515
ATP5F1
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


521
ATP5I
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


522
ATP5J, ATP5A, ATPM, ATP5
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


9551
ATP5J2, ATP5JL, F1FO-ATPASE
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


10476
ATP5JD
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


10632
ATP5JG
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


9296
ATP6S14
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


528
ATP6D
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


523
ATP6A1, VPP2
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


524
ATP6A2, VPP2
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


525
ATP6B1, VPP3, VATB
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


526
ATP6B2, VPP3
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


529
ATP6E
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


527
ATP6C, ATPL
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


533
ATP6F
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


10312
TCIRG1, TIRC7, OC-116, OC-116 kDa,
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34



OC-116 KDA, ATP6N1C


23545
TJ6
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


50617
ATP6N1B
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


535
ATP6N1
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


51382
VATD
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


8992
ATP6H
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


9550
ATP6J
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


51606
LOC51606
ADPm + Pim + 3 H -> ATPm + 3 Hm + H2Om
3.6.1.34


495
ATP4A, ATP6A
ATP + H + Kxt + H2O <-> ADP + PI + Hext + K
3.6.1.36


496
ATP4B, ATP6B
ATP + H + Kxt + H2O <-> ADP + PI + Hext + K
3.6.1.36


476
ATP1A1
ATP + 3 NA + 2 Kxt + H2O <-> ADP + 3 NAxt + 2 K + PI
3.6.1.37


477
ATP1A2
ATP + 3 NA + 2 Kxt + H2O <-> ADP + 3 NAxt + 2 K + PI
3.6.1.37


478
ATP1A3
ATP + 3 NA + 2 Kxt + H2O <-> ADP + 3 NAxt + 2 K + PI
3.6.1.37


479
ATP1AL1
ATP + 3 NA + 2 Kxt + H2O <-> ADP + 3 NAxt + 2 K + PI
3.6.1.37


23439
ATP1B4
ATP + 3 NA + 2 Kxt + H2O <-> ADP + 3 NAxt + 2 K + PI
3.6.1.37


481
ATP1B1, ATP1B
ATP + 3 NA + 2 Kxt + H2O <-> ADP + 3 NAxt + 2 K + PI
3.6.1.37


482
ATP1B2, AMOG
ATP + 3 NA + 2 Kxt + H2O <-> ADP + 3 NAxt + 2 K + PI
3.6.1.37


483
ATP1B3
ATP + 3 NA + 2 Kxt + H2O <-> ADP + 3 NAxt + 2 K + PI
3.6.1.37


27032
ATP2C1, ATP2C1A, PMR1
ATP + 2 CA + H2O <-> ADP + PI + 2 CAxt
3.6.1.38


487
ATP2A1, SERCA1, ATP2A
ATP + 2 CA + H2O <-> ADP + PI + 2 CAxt
3.6.1.38


488
ATP2A2, ATP2B, SERCA2, DAR, DD
ATP + 2 CA + H2O <-> ADP + PI + 2 CAxt
3.6.1.38


489
ATP2A3, SERCA3
ATP + 2 CA + H2O <-> ADP + PI + 2 CAxt
3.6.1.38


490
ATP2B1, PMCA1
ATP + 2 CA + H2O <-> ADP + PI + 2 CAxt
3.6.1.38


491
ATP2B2, PMCA2
ATP + 2 CA + H2O <-> ADP + PI + 2 CAxt
3.6.1.38


492
ATP2B3, PMCA3
ATP + 2 CA + H2O <-> ADP + PI + 2 CAxt
3.6.1.38


493
ATP2B4, ATP2B2, PMCA4
ATP + 2 CA + H2O <-> ADP + PI + 2 CAxt
3.6.1.38


538
ATP7A, MK, MNK, OHS
ATP + H2O + Cu2 -> ADP + PI + Cu2xt
3.6.3.4


540
ATP7B, WND
ATP + H2O + Cu2 -> ADP + PI + Cu2xt
3.6.3.4


5464
PP, SID6-8061
PPI -> 2 PI
3.6.1.1







2.2 Photosynthesis PATH:hsa00195


2.3 Carbon fixation PATH:hsa00710










2805
GOT1
OAm + GLUm <-> ASPm + AKGm
2.6.1.1


2806
GOT2
OA + GLU <-> ASP + AKG
2.6.1.1


2875
GPT
PYR + GLU <-> AKG + ALA
2.6.1.2







2.4 Reductive carboxylate cycle (CO2 fixation) PATH:hsa00720


2.5 Methane metabolism PATH:hsa00680










847
CAT
2 H2O2 -> O2
1.11.1.6


4025
LPO, SPO

1.11.1.7


4353
MPO

1.11.1.7


8288
EPX, EPX-PEN, EPO, EPP

1.11.1.7


9588
KIAA0106, AOP2

1.11.1.7


6470
SHMT1, CSHMT
THF + SER <-> GLY + METTHF
2.1.2.1


6472
SHMT2, GLYA, SHMT
THFm + SERm <-> GLYm + METTHFm
2.1.2.1


51004
LOC51004
2OPMPm + O2m -> 2OPMBm
1.14.13.—




2OPMMBm + O2m -> 2OMHMBm


9420
CYP7B1
2OPMPm + O2m -> 2OPMBm
1.14.13.—




2OPMMBm + O2m -> 2OMHMBm







2.6 Nitrogen metabolism PATH:hsa00910










11238
CA5B

4.2.1.1


23632
CA14

4.2.1.1


759
CA1

4.2.1.1


760
CA2

4.2.1.1


761
CA3, CAIII

4.2.1.1


762
CA4, CAIV

4.2.1.1


763
CA5A, CA5, CAV, CAVA

4.2.1.1


765
CA6

4.2.1.1


766
CA7

4.2.1.1


767
CA8, CALS, CARP

4.2.1.1


768
CA9, MN

4.2.1.1


770
CA11, CARP2

4.2.1.1


771
CA12

4.2.1.1


1373
CPS1
GLUm + CO2m + 2 ATPm -> 2 ADPm + 2 PIm + CAPm
6.3.4.16


275
AMT
GLYm + THFm + NADm <-> METTHFm + NADHm + CO2m + NH3m
2.1.2.10


3034
HAL, HSTD, HIS
HIS -> NH3 + URO
4.3.1.3


2746
GLUD1, GLUD
AKGm + NADHm + NH3m <-> NADm + H2Om + GLUm
1.4.1.3




AKGm + NADPHm + NH3m <-> NADPm + H2Om + GLUm


8307
GLUD2
AKGm + NADHm + NH3m <-> NADm + H2Om + GLUm
1.4.1.3




AKGm + NADPHm + NH3m <-> NADPm + H2Om + GLUm


2752
GLUL, GLNS
GLUm + NH3m + ATPm -> GLNm + ADPm + Pim
6.3.1.2


22842
KIAA0838
GLN -> GLU + NH3
3.5.1.2


27165
GA
GLN -> GLU + NH3
3.5.1.2


2744
GLS
GLNm -> GLUm + NH3m
3.5.1.2


440
ASNS
ASPm + ATPm + GLNm -> GLUm + ASNm + AMPm + PPIm
6.3.5.4


1491
CTH
LLCT + H2O -> CYS + HSER
4.4.1.1




OBUT + NH3 <-> HSER
4.4.1.1







2.7 Sulfur metabolism PATH:hsa00920










9060
PAPSS2, ATPSK2, SK2
APS + ATP -> ADP + PAPS
2.7.1.25




SLF + ATP -> PPI + APS
2.7.7.4


9061
PAPSS1, ATPSK1, SK1
APS + ATP -> ADP + PAPS
2.7.1.25




SLF + ATP -> PPI + APS
2.7.7.4


10380
BPNT1
PAP -> AMP + PI
3.1.3.7


6799
SULT1A2

2.8.2.1


6817
SULT1A1, STP1

2.8.2.1


6818
SULT1A3, STM

2.8.2.1


6822
SULT2A1, STD

2.8.2.2


6783
STE, EST

2.8.2.4


6821
SUOX

1.8.3.1







3. Lipid Metabolism


3.1 Fatty acid biosynthesis (path 1) PATH:hsa00061










2194
FASN

2.3.1.85







3.2 Fatty acid biosynthesis (path 2) PATH:hsa00062










10449
ACAA2, DSAEC
MAACOAm -> ACCOAm + PROPCOAm
2.3.1.16


30
ACAA1, ACAA
MAACOA -> ACCOA + PROPCOA
2.3.1.16


3032
HADHB
MAACOA -> ACCOA + PROPCOA
2.3.1.16







3.3 Fatty acid metabolism PATH:hsa00071










51
ACOX1, ACOX

1.3.3.6


33
ACADL, LCAD

1.3.99.13


2639
GCDH

1.3.99.7


2179
FACL1, LACS
ATP + LCCA + COA <-> AMP + PPI + ACOA
6.2.1.3


2180
FACL2, FACL1, LACS2
ATP + LCCA + COA <-> AMP + PPI + ACOA
6.2.1.3


2182
FACL4, ACS4
ATP + LCCA + COA <-> AMP + PPI + ACOA
6.2.1.3


1374
CPT1A, CPT1, CPT1-L

2.3.1.21


1375
CPT1B, CPT1-M

2.3.1.21


1376
CPT2, CPT1, CPTASE

2.3.1.21


1632
DCI

5.3.3.8


11283
CYP4F8

1.14.14.1


1543
CYP1A1, CYP1

1.14.14.1


1544
CYP1A2

1.14.14.1


1545
CYP1B1, GLC3A

1.14.14.1


1548
CYP2A6, CYP2A3

1.14.14.1


1549
CYP2A7

1.14.14.1


1551
CYP3A7

1.14.14.1


1553
CYP2A13

1.14.14.1


1554
CYP2B

1.14.14.1


1555
CYP2B6

1.14.14.1


1557
CYP2C19, CYP2C, P450IIC19

1.14.14.1


1558
CYP2C8

1.14.14.1


1559
CYP2C9, P450IIC9, CYP2C10

1.14.14.1


1562
CYP2C18, P450IIC17, CYP2C17

1.14.14.1


1565
CYP2D6

1.14.14.1


1571
CYP2E, CYP2E1, P450C2E

1.14.14.1


1572
CYP2F1, CYP2F

1.14.14.1


1573
CYP2J2

1.14.14.1


1575
CYP3A3

1.14.14.1


1576
CYP3A4

1.14.14.1


1577
CYP3A5, PCN3

1.14.14.1


1580
CYP4B1

1.14.14.1


1588
CYP19, ARO

1.14.14.1


1595
CYP51

1.14.14.1


194
AHHR, AHH

1.14.14.1







3.4 Synthesis and degradation of ketone bodies PATH:hsa00072


3.5 Sterol biosynthesis PATH:hsa00100










3156
HMGCR
MVL + COA + 2 NADP <-> H3MCOA + 2 NADPH
1.1.1.34


4598
MVK, MVLK
ATP + MVL -> ADP + PMVL
2.7.1.36




CTP + MVL -> CDP + PMVL




GTP + MVL -> GDP + PMVL




UTP + MVL -> UDP + PMVL


10654
PMVK, PMKASE, PMK, HUMPMKI
ATP + PMVL -> ADP + PPMVL
2.7.4.2


4597
MVD, MPD
ATP + PPMVL -> ADP + PI + IPPP + CO2
4.1.1.33


3422
IDI1
IPPP <-> DMPP
5.3.3.2


2224
FDPS
GPP + IPPP -> FPP + PPI
2.5.1.10




DMPP + IPPP -> GPP + PPI
2.5.1.1


9453
GGPS1, GGPPS
DMPP + IPPP -> GPP + PPI
2.5.1.1




GPP + IPPP -> FPP + PPI
2.5.1.10





2.5.1.29


2222
FDFT1, DGPT
2 FPP + NADPH -> NADP + SQL
2.5.1.21


6713
SQLE
SQL + O2 + NADP -> S23E + NADPH
1.14.99.7


4047
LSS, OSC
S23E -> LNST
5.4.99.7


1728
DIA4, NMOR1, NQO1, NMORI

1.6.99.2


4835
NMOR2, NQO2

1.6.99.2


37
ACADVL, VLCAD, LCACD

1.3.99.—







3.6 Bile acid biosynthesis PATH:hsa00120










1056
CEL, BSSL, BAL

3.1.1.3





3.1.1.13


3988
LIPA, LAL

3.1.1.13


6646
SOAT1, ACAT, STAT, SOAT, ACAT1,

2.3.1.26



ACACT


1581
CYP7A1, CYP7

1.14.13.17


6715
SRD5A1

1.3.99.5


6716
SRD5A2

1.3.99.5


6718
AKR1D1, SRD5B1, 3o5bred

1.3.99.6


570
BAAT, BAT

2.3.1.65







3.7 C21-Steroid hormone metabolism PATH:hsa00140










1583
CYP11A, P450SCC

1.14.15.6


3283
HSD3B1, HSD3B, HSDB3
IMZYMST -> IIMZYMST + CO2
5.3.3.1




IMZYMST -> IIZYMST + CO2
1.1.1.145


3284
HSD3B2
IMZYMST -> IIMZYMST + CO2
5.3.3.1




IMZYMST -> IIZYMST + CO2
1.1.1.145


1589
CYP21A2, CYP21, P450C21B,

1.14.99.10



CA21H, CYP21B, P450c21B


1586
CYP17, P450C17

1.14.99.9


1584
CYP11B1, P450C11, CYP11B

1.14.15.4


1585
CYP11B2, CYP11B

1.14.15.4


3290
HSD11B1, HSD11, HSD11L, HSD11B

1.1.1.146


3291
HSD11B2, HSD11K

1.1.1.146







3.8 Androgen and estrogen metabolism PATH:hsa00150










3292
HSD17B1, EDH17B2, EDHB17,

1.1.1.62



HSD17


3293
HSD17B3, EDH17B3

1.1.1.62


3294
HSD17B2, EDH17B2

1.1.1.62


3295
HSD17B4

1.1.1.62


3296
HSD17BP1, EDH17B1, EDHB17,

1.1.1.62



HSD17


51478
HSD17B7, PRAP

1.1.1.62


412
STS, ARSC, ARSC1, SSDD

3.1.6.2


414
ARSD

3.1.6.1


415
ARSE, CDPX1, CDPXR, CDPX

3.1.6.1


11185
INMT

2.1.1.—


24140
JM23

2.1.1.—


29104
N6AMT1, PRED28

2.1.1.—


29960
FJH1

2.1.1.—


3276
HRMT1L2, HCP1, PRMT1

2.1.1.—


51628
LOC51628

2.1.1.—


54743
HASJ4442

2.1.1.—


27292
HSA9761

2.1.1.—







4. Nucleotide Metabolism


4.1 Purine metabolism PATH:hsa00230










11164
NUDT5, HYSAH1, YSA1H

3.6.1.13


5471
PPAT, GPAT
PRPP + GLN -> PPI + GLU + PRAM
2.4.2.14


2618
GART, PGFT, PRGS
PRAM + ATP + GLY <-> ADP + PI + GAR
6.3.4.13




FGAM + ATP -> ADP + PI + AIR
6.3.3.1




GAR + FTHF -> THF + FGAR
2.1.2.2


5198
PFAS, FGARAT, KIAA0361, PURL
FGAR + ATP + GLN -> GLU + ADP + PI + FGAM
6.3.5.3


10606
ADE2H1
CAIR + ATP + ASP <-> ADP + PI + SAICAR
6.3.2.6




CAIR <-> AIR + CO2
4.1.1.21


5059
PAICS, AIRC, PAIS
CAIR + ATP + ASP <-> ADP + PI + SAICAR
6.3.2.6


158
ADSL
ASUC <-> FUM + AMP
4.3.2.2


471
ATIC, PURH
AICAR + FTHF <-> THF + PRFICA
2.1.2.3




PRFICA <-> IMP
3.5.4.10


3251
HPRT1, HPRT, HGPRT
HYXAN + PRPP -> PPI + IMP
2.4.2.8




GN + PRPP -> PPI + GMP


3614
IMPDH1
IMP + NAD -> NADH + XMP
1.1.1.205


3615
IMPDH2
IMP + NAD -> NADH + XMP
1.1.1.205


8833
GMPS

6.3.5.2


14923


2987
GUK1
GMP + ATP <-> GDP + ADP
2.7.4.8




DGMP + ATP <-> DGDP + ADP




GMP + DATP <-> GDP + DADP


2988
GUK2
GMP + ATP <-> GDP + ADP
2.7.4.8




DGMP + ATP <-> DGDP + ADP




GMP + DATP <-> GDP + DADP


10621
RPC39

2.7.7.6


10622
RPC32

2.7.7.6


10623
RPC62

2.7.7.6


11128
RPC155

2.7.7.6


25885
DKFZP586M0122

2.7.7.6


30834
ZNRD1

2.7.7.6


51082
LOC51082

2.7.7.6


51728
LOC51728

2.7.7.6


5430
POLR2A, RPOL2, POLR2, POLRA

2.7.7.6


5431
POLR2B, POL2RB

2.7.7.6


5432
POLR2C

2.7.7.6


5433
POLR2D, HSRBP4, HSRPB4

2.7.7.6


5434
POLR2E, RPB5, XAP4

2.7.7.6


5435
POLR2F, RPB6, HRBP14.4

2.7.7.6


5436
POLR2G, RPB7

2.7.7.6


5437
POLR2H, RPB8, RPB17

2.7.7.6


5438
POLR2I

2.7.7.6


5439
POLR2J

2.7.7.6


5440
POLR2K, RPB7.0

2.7.7.6


5441
POLR2L, RPB7.6, RPB10

2.7.7.6


5442
POLRMT, APOLMT

2.7.7.6


54479
FLJ10816, Rpo1-2

2.7.7.6


55703
FLJ10388

2.7.7.6


661
BN51T

2.7.7.6


9533
RPA40, RPA39

2.7.7.6


10721
POLQ

2.7.7.7


11232
POLG2, MTPOLB, HP55, POLB

2.7.7.7


23649
POLA2

2.7.7.7


5422
POLA

2.7.7.7


5423
POLB

2.7.7.7


5424
POLD1, POLD

2.7.7.7


5425
POLD2

2.7.7.7


5426
POLE

2.7.7.7


5427
POLE2

2.7.7.7


5428
POLG

2.7.7.7


5980
REV3L, POLZ, REV3

2.7.7.7


7498
XDH

1.1.3.22





1.1.1.204


9615
GDA KIAA1258, CYPIN, NEDASIN

3.5.4.3


2766
GMPR

1.6.6.8


51292
LOC51292

1.6.6.8


7377
UOX

1.7.3.3


6240
RRM1
ADP + RTHIO -> DADP + OTHIO
1.17.4.1




GDP + RTHIO -> DGDP + OTHIO




CDP + RTHIO -> DCDP + OTHIO




UDP + RTHIO -> DUDP + OTHIO


6241
RRM2
ADP + RTHIO -> DADP + OTHIO
1.17.4.1




GDP + RTHIO -> DGDP + OTHIO




CDP + RTHIO -> DCDP + OTHIO




UDP + RTHIO -> DUDP + OTHIO


4860
NP, PNP
AND + PI <-> AD + R1P
2.4.2.1




GSN + PI <-> GN + R1P




DA + PI <-> AD + R1P




DG + PI <-> GN + R1P




DIN + PI <-> HYXAN + R1P




INS + PI <-> HYXAN + R1P




XTSINE + PI <-> XAN + R1P


1890
ECGF1, hPD-ECGF
DU + PI <-> URA + DR1P
2.4.2.4




DT + PI <-> THY + DR1P


353
APRT
AD + PRPP -> PPI + AMP
2.4.2.7


132
ADK
ADN + ATP -> AMP + ADP
2.7.1.20


1633
DCK

2.7.1.74


1716
DGUOK

2.7.1.113


203
AK1
ATP + AMP <-> 2 ADP
2.7.4.3




GTP + AMP <-> ADP + GDP




ITP + AMP <-> ADP + IDP


204
AK2
ATP + AMP <-> 2 ADP
2.7.4.3




GTP + AMP <-> ADP + GDP




ITP + AMP <-> ADP + IDP


205
AK3
ATP + AMP <-> 2 ADP
2.7.4.3




GTP + AMP <-> ADP + GDP




ITP + AMP <-> ADP + IDP


26289
AK5
ATP + AMP <-> 2 ADP
2.7.4.3




GTP + AMP <-> ADP + GDP




ITP + AMP <-> ADP + IDP


4830
NME1, NM23, NM23-H1
UDP + ATP <-> UTP + ADP
2.7.4.6




CDP + ATP <-> CTP + ADP




GDP + ATP <-> GTP + ADP




IDP + ATP <-> ITP + IDP




DGDP + ATP <-> DGTP + ADP




DUDP + ATP <-> DUTP + ADP




DCDP + ATP <-> DCTP + ADP




DTDP + ATP <-> DTTP + ADP




DADP + ATP <-> DATP + ADP


4831
NME2, NM23-H2
UDP + ATP <-> UTP + ADP
2.7.4.6




CDP + ATP <-> CTP + ADP




GDP + ATP <-> GTP + ADP




IDP + ATP <-> ITP + IDP




DGDP + ATP <-> DGTP + ADP




DUDP + ATP <-> DUTP + ADP




DCDP + ATP <-> DCTP + ADP




DTDP + ATP <-> DTTP + ADP




DADP + ATP <-> DATP + ADP


4832
NME3, DR-nm23, DR-NM23
UDP + ATP <-> UTP + ADP
2.7.4.6




CDP + ATP <-> CTP + ADP




GDP + ATP <-> GTP + ADP




IDP + ATP <-> ITP + IDP




DGDP + ATP <-> DGTP + ADP




DUDP + ATP <-> DUTP + ADP




DCDP + ATP <-> DCTP + ADP




DTDP + ATP <-> DTTP + ADP




DADP + ATP <-> DATP + ADP


4833
NME4
UDPm + ATPm <-> UTPm + ADPm
2.7.4.6




CDPm + ATPm <-> CTPm + ADPm




GDPm + ATPm <-> GTPm + ADPm




IDPm + ATPm <-> ITPm + IDPm




DGDPm + ATPm <-> DGTPm + ADPm




DUDPm + ATPm <-> DUTPm + ADPm




DCDPm + ATPm <-> DCTPm + ADPm




DTDPm + ATPm <-> DTTPm + ADPm




DADPm + ATPm <-> DATPm + ADPm


22978
NT5B, PNT5, NT5B-PENDING
AMP + H2O -> PI + ADN
3.1.3.5




GMP -> PI + GSN




CMP -> CYTD + PI




UMP -> PI + URI




IMP -> PI + INS




DUMP -> DU + PI




DTMP -> DT + PI




DAMP -> DA + PI




DGMP -> DG + PI




DCMP -> DC + PI




XMP -> PI + XTSINE


4877
NT3
AMP -> PI + ADN
3.1.3.5




GMP -> PI + GSN




CMP -> CYTD + PI




UMP -> PI + URI




IMP -> PI + INS




DUMP -> DU + PI




DTMP -> DT + PI




DAMP -> DA + PI




DGMP -> DG + PI




DCMP -> DC + PI




XMP -> PI + XTSINE


4907
NT5, CD73
AMP -> PI + ADN
3.1.3.5




GMP -> PI + GSN




CMP -> CYTD + PI




UMP -> PI + URI




IMP -> PI + INS




DUMP -> DU + PI




DTMP -> DT + PI




DAMP -> DA + PI




DGMP -> DG + PI




DCMP -> DC + PI




XMP -> PI + XTSINE


7370
UMPH2
AMP -> PI + ADN
3.1.3.5




GMP -> PI + GSN




CMP -> CYTD + PI




UMP -> PI + URI




IMP -> PI + INS




DUMP -> DU + PI




DTMP -> DT + PI




DAMP -> DA + PI




DGMP -> DG + PI




DCMP -> DC + PI




XMP -> PI + XTSINE


10846
PDE10A
cAMP -> AMP
3.1.4.17




cAMP -> AMP




cdAMP -> dAMP




cIMP -> IMP




cGMP -> GMP




cCMP -> CMP


27115
PDE7B
cAMP -> AMP
3.1.4.17




cAMP -> AMP




cdAMP -> dAMP




cIMP -> IMP




cGMP -> GMP




cCMP -> CMP


5136
PDE1A
cAMP -> AMP
3.1.4.17




cAMP -> AMP




cdAMP -> dAMP




cIMP -> IMP




cGMP -> GMP




cCMP -> CMP


5137
PDE1C, HCAM3
cAMP -> AMP
3.1.4.17




cAMP -> AMP




cdAMP -> dAMP




cIMP -> IMP




cGMP -> GMP




cCMP -> CMP


5138
PDE2A
cAMP -> AMP
3.1.4.17




cAMP -> AMP




cdAMP -> dAMP




cIMP -> IMP




cGMP -> GMP




cCMP -> CMP


5139
PDE3A, CGI-PDE
cAMP -> AMP
3.1.4.17




cAMP -> AMP




cdAMP -> dAMP




cIMP -> IMP




cGMP -> GMP




cCMP -> CMP


5140
PDE3B
cAMP -> AMP
3.1.4.17




cAMP -> AMP




cdAMP -> dAMP




cIMP -> IMP




cGMP -> GMP




cCMP -> CMP


5141
PDE4A, DPDE2
cAMP -> AMP
3.1.4.17


5142
PDE4B, DPDE4, PDEIVB
cAMP -> AMP
3.1.4.17


5143
PDE4C, DPDE1
cAMP -> AMP
3.1.4.17


5144
PDE4D, DPDE3
cAMP -> AMP
3.1.4.17


5145
PDE6A, PDEA, CGPR-A
cGMP -> GMP
3.1.4.17


5146
PDE6C, PDEA2
cGMP -> GMP
3.1.4.17


5147
PDE6D
cGMP -> GMP
3.1.4.17


5148
PDE6G, PDEG
cGMP -> GMP
3.1.4.17


5149
PDE6H
cGMP -> GMP
3.1.4.17


5152
PDE9A
cAMP -> AMP
3.1.4.17




cAMP -> AMP




cdAMP -> dAMP




cIMP -> IMP




cGMP -> GMP




cCMP -> CMP


5153
PDES1B
cAMP -> AMP
3.1.4.17




cAMP -> AMP




cdAMP -> dAMP




cIMP -> IMP




cGMP -> GMP




cCMP -> CMP


5158
PDE6B, CSNB3, PDEB
cGMP -> GMP
3.1.4.17


8654
PDE5A
cGMP -> GMP
3.1.4.17


100
ADA
ADN -> INS + NH3
3.5.4.4




DA -> DIN + NH3


270
AMPD1, MADA
AMP -> IMP + NH3
3.5.4.6


271
AMPD2
AMP -> IMP + NH3
3.5.4.6


272
AMPD3
AMP -> IMP + NH3
3.5.4.6


953
ENTPD1, CD39

3.6.1.5


3704
ITPA

3.6.1.19


107
ADCY1
ATP -> cAMP + PPI
4.6.1.1


108
ADCY2, HBAC2
ATP -> cAMP + PPI
4.6.1.1


109
ADCY3, AC3, KIAA0511
ATP -> cAMP + PPI
4.6.1.1


110
ADCY4
ATP -> cAMP + PPI
4.6.1.1


111
ADCY5
ATP -> cAMP + PPI
4.6.1.1


112
ADCY6
ATP -> cAMP + PPI
4.6.1.1


113
ADCY7, KIAA0037
ATP -> cAMP + PPI
4.6.1.1


114
ADCY8, ADCY3, HBAC1
ATP -> cAMP + PPI
4.6.1.1


115
ADCY9
ATP -> cAMP + PPI
4.6.1.1


2977
GUCY1A2, GUC1A2, GC-SA2

4.6.1.2


2982
GUCY1A3, GUC1A3, GUCSA3, GC-

4.6.1.2



SA3


2983
GUCY1B3, GUC1B3, GUCSB3, GC-

4.6.1.2



SB3


2984
GUCY2C, GUC2C, STAR

4.6.1.2


2986
GUCY2F, GUC2F, GC-F, GUC2DL,

4.6.1.2



RETGC-2


3000
GUCY2D, CORD6, GUC2D, LCA1,

4.6.1.2



GUC1A4, LCA, retGC


4881
NPR1, ANPRA, GUC2A, NPRA

4.6.1.2


4882
NPR2, ANPRB, GUC2B, NPRB,

4.6.1.2



NPRBi


159
ADSS
IMP + GTP + ASP -> GDP + PI + ASUC
6.3.4.4


318
NUDT2, APAH1

3.6.1.17


5167
ENPP1, M6S1, NPPS, PCA1, PC-1,

3.6.1.9



PDNP1


5168
ENPP2, ATX, PD-IALPHA, PDNP2

3.6.1.9


5169
ENPP3, PD-IBETA, PDNP3

3.6.1.9





3.1.4.1


2272
FHIT

3.6.1.29







4.2 Pyrimidine metabolism PATH:hsa00240










790
CAD
GLN + 2 ATP + CO2 -> GLU + CAP + 2 ADP + PI
6.3.5.5




CAP + ASP -> CAASP + PI
2.1.3.2




CAASP <-> DOROA
3.5.2.3


1723
DHODH
DOROA + O2 <-> H2O2 + OROA
1.3.3.1


7372
UMPS, OPRT
OMP -> CO2 + UMP
4.1.1.23




OROA + PRPP <-> PPI + OMP
2.4.2.10


51727
LOC51727
ATP + UMP <-> ADP + UDP
2.7.4.14




CMP + ATP <-> ADP + CDP




DCMP + ATP <-> ADP + DCDP


50808
AKL3L

2.7.4.10


1503
CTPS
UTP + GLN + ATP -> GLU + CTP + ADP + PI
6.3.4.2




ATP + UTP + NH3 -> ADP + PI + CTP


7371
UMPK, TSA903
URI + ATP -> ADP + UMP
2.7.1.48




URI + GTP -> UMP + GDP




CYTD + GTP -> GDP + CMP


7378
UP
URI + PI <-> URA + R1P
2.4.2.3


1806
DPYD, DPD

1.3.1.2


1807
DPYS, DHPase, DHPASE, DHP

3.5.2.2


51733
LOC51733

3.5.1.6


7296
TXNRD1, TXNR
OTHIO + NADPH -> NADP + RTHIO
1.6.4.5


1854
DUT
DUTP -> PPI + DUMP
3.6.1.23


7298
TYMS, TMS, TS
DUMP + METTHF -> DHF + DTMP
2.1.1.45


978
CDA, CDD
CYTD -> URI + NH3
3.5.4.5




DC -> NH3 + DU


1635
DCTD
DCMP <-> DUMP + NH3
3.5.4.12


7083
TK1
DU + ATP -> DUMP + ADP
2.7.1.21




DT + ATP -> ADP + DTMP


7084
TK2
DUm + ATPm -> DUMPm + ADPm
2.7.1.21




DTm + ATPm -> ADPm + DTMPm


1841
DTYMK, TYMK, CDC8
DTMP + ATP <-> ADP + DTDP
2.7.4.9







4.3 Nucleotide sugars metabolism PATH:hsa00520










23483
TDPGD

4.2.1.46


1486
CTBS, CTB

3.2.1.—







5. Amino Acid Metabolism


5.1 Glutamate metabolism PATH:hsa00251










8659
ALDH4, P5CDH
P5C + NAD + H2O -> NADH + GLU
1.5.1.12


2058
EPRS, QARS, QPRS
GLU + ATP -> GTRNA + AMP + PPI
6.1.1.17





6.1.1.15


2673
GFPT1, GFA, GFAT, GFPT
F6P + GLN -> GLU + GA6P
2.6.1.16


9945
GFPT2, GFAT2
F6P + GLN -> GLU + GA6P
2.6.1.16


5859
QARS

6.1.1.18


2729
GLCLC, GCS, GLCL
CYS + GLU + ATP -> GC + PI + ADP
6.3.2.2


2730
GLCLR
CYS + GLU + ATP -> GC + PI + ADP
6.3.2.2


2937
GSS, GSHS
GLY + GC + ATP -> RGT + PI + ADP
6.3.2.3


2936
GSR
NADPH + OGT -> NADP + RGT
1.6.4.2


5188
PET112L, PET112

6.3.5.—







5.2 Alanine and aspartate metabolism PATH:hsa00252










4677
NARS, ASNRS
ATP + ASP + TRNA -> AMP + PPI + ASPTRNA
6.1.1.22


435
ASL
ARGSUCC -> FUM + ARG
4.3.2.1


189
AGXT, SPAT
SERm + PYRm <-> ALAm + 3HPm
2.6.1.51




ALA + GLX <-> PYR + GLY
2.6.1.44


16
AARS

6.1.1.7


1615
DARS

6.1.1.12


445
ASS, CTLN1, ASS1
CITR + ASP + ATP <-> AMP + PPI + ARGSUCC
6.3.4.5


443
ASPA, ASP, ACY2

3.5.1.15


1384
CRAT, CAT1
ACCOA + CAR -> COA + ACAR
2.3.1.7


8528
DDO

1.4.3.1







5.3 Glycine, serine and threonine metabolism PATH:hsa00260










5723
PSPH, PSP
3PSER + H2O -> PI + SER
3.1.3.3


29968
PSA
PHP + GLU <-> AKG + 3PSER
2.6.1.52




OHB + GLU <-> PHT + AKG


26227
PHGDH, SERA, PGDH, PGD, PGAD
3PG + NAD <-> NADH + PHP
1.1.1.95


23464
GCAT, KBL

2.3.1.29


211
ALAS1, ALAS
SUCCOA + GLY -> ALAV + COA + CO2
2.3.1.37


212
ALAS2, ANH1, ASB
SUCCOA + GLY -> ALAV + COA + CO2
2.3.1.37


4128
MAOA
AMA + H2O + FAD -> NH3 + FADH2 + MTHGXL
1.4.3.4


4129
MAOB
AMA + H2O + FAD -> NH3 + FADH2 + MTHGXL
1.4.3.4


26
ABP1, AOC1, DAO

1.4.3.6


314
AOC2, DAO2, RAO

1.4.3.6


8639
AOC3, VAP-1, VAP1, HPAO

1.4.3.6


2731
GLDC
GLY + LIPO <-> SAP + CO2
1.4.4.2


1610
DAO, DAMOX

1.4.3.3


2617
GARS

6.1.1.14


2628
GATM

2.1.4.1


2593
GAMT

2.1.1.2


23761
PISD, PSSC, DKFZP566G2246,
PS -> PE + CO2
4.1.1.65



DJ858B16


635
BHMT

2.1.1.5


29958
DMGDH

1.5.99.2


875
CBS
SER + HCYS -> LLCT + H2O
4.2.1.22


6301
SARS, SERS

6.1.1.11


10993
SDS, SDH
SER -> PYR + NH3 + H2O
4.2.1.13


6897
TARS

6.1.1.3







5.4 Methionine metabolism PATH:hsa00271










4143
MAT1A, MATA1, SAMS1, MAT, SAMS
MET + ATP + H2O -> PPI + PI + SAM
2.5.1.6


4144
MAT2A, MATA2, SAMS2, MATII
MET + ATP + H2O -> PPI + PI + SAM
2.5.1.6


1786
DNMT1, MCMT, DNMT
SAM + DNA -> SAH + DNA5MC
2.1.1.37


10768
AHCYL1, XPVKONA
SAH + H2O -> HCYS + ADN
3.3.1.1


191
AHCY, SAHH
SAH + H2O -> HCYS + ADN
3.3.1.1


4141
MARS, METRS, MTRNS

6.1.1.10


4548
MTR
HCYS + MTHF -> THF + MET
2.1.1.13







5.5 Cysteine metabolism PATH:hsa00272










833
CARS

6.1.1.16


1036
CDO1
CYS + O2 <-> CYSS
1.13.11.20


8509
NDST2, HSST2, NST2

2.8.2.—







5.6 Valine, leucine and isoleucine degradation PATH:hsa00280










586
BCAT1, BCT1, ECA39, MECA39
AKG + ILE -> OMVAL + GLU
2.6.1.42




AKG + VAL -> OIVAL + GLU




AKG + LEU -> OICAP + GLU


587
BCAT2, BCT2
OICAPm + GLUm <-> AKGm + LEUm
2.6.1.42




OMVALm + GLUm <-> AKGm + ILEm


5014
OVD1A

1.2.4.4


593
BCKDHA, MSUD1
OMVALm + COAm + NADm -> MBCOAm + NADHm + CO2m
1.2.4.4




OIVALm + COAm + NADm -> IBCOAm + NADHm + CO2m




OICAPm + COAm + NADm -> IVCOAm + NADHm + CO2m


594
BCKDHB, E1B
OMVALm + COAm + NADm -> MBCOAm + NADHm + CO2m
1.2.4.4




OIVALm + COAm + NADm -> IBCOAm + NADHm + CO2m




OICAPm + COAm + NADH -> IVCOAm + NADHm + CO2m


3712
IVD
IVCOAm + FADm -> MCRCOAm + FADH2m
1.3.99.10


316
AOX1, AO

1.2.3.1


4164
MCCC1
MCRCOAm + ATPm + CO2m + H2Om -> MGCOAm + ADPm + Pim
6.4.1.4


4165
MCCC2
MCRCOAm + ATPm + CO2m + H2Om -> MGCOAm + ADPm + Pim
6.4.1.4







5.7 Valine, leucine and isoleucine biosynthesis PATH:hsa00290










23395
KIAA0028, LARS2

6.4.1.4


3926
LARS

6.4.1.4


3376
IARS, ILRS

6.1.1.5


7406
VARS1, VARS

6.1.1.9


7407
VARS2, G7A

6.1.1.9







5.8 Lysine biosynthesis PATH:hsa00300










3735
KARS, KIAA0070
ATP + LYS + LTRNA -> AMP + PPI + LLTRNA
6.1.1.6







5.9 Lysine degradation PATH:hsa00310










8424
BBOX, BBH, GAMMA-BBH, G-BBH

1.14.11.1


5351
PLOD, LLH

1.14.11.4


5352
PLOD2

1.14.11.4


8985
PLOD3, LH3

1.14.11.4


10157
LKR/SDH, AASS
LYS + NADPH + AKG -> NADP + H2O + SAC
1.5.1.9




SAC + H2O + NAD -> GLU + NADH + AASA







5.10 Arginine and proline metabolism PATH:hsa00330










5009
OTC
ORNm + CAPm -> CITRm + Pim + Hm
2.1.3.3


383
ARG1
ARG -> ORN + UREA
3.5.3.1


384
ARG2
ARG -> ORN + UREA
3.5.3.1


4842
NOS1, NOS

1.14.13.39


4843
NOS2A, NOS2

1.14.13.39


4846
NOS3, ECNOS

1.14.13.39


4942
OAT
ORN + AKG <-> GLUGSAL + GLU
2.6.1.13


5831
PYCR1, P5C, PYCR
P5C + NADPH -> PRO + NADP
1.5.1.2




P5C + NADH -> PRO + NAD




PHC + NADPH -> HPRO + NADP




PHC + NADH -> HPRO + NAD


5033
P4HA1, P4HA

1.14.11.2


5917
RARS
ATP + ARG + ATRNA -> AMP + PPI + ALTRNA
6.1.1.19


1152
CKB, CKBB
PCRE + ADP -> CRE + ATP
2.7.3.2


1156
CKBE

2.7.3.2


1158
CKM, CKMM

2.7.3.2


1159
CKMT1, CKMT, UMTCK

2.7.3.2


1160
CKMT2, SMTCK

2.7.3.2


6723
SRM, SPS1, SRML1
PTRSC + SAM -> SPRMD + 5MTA
2.5.1.16


262
AMD1, ADOMETDC
SAM <-> DSAM + CO2
4.1.1.50


263
AMDP1, AMD, AMD2
SAM <-> DSAM + CO2
4.1.1.50


1725
DHPS
SPRMD + Qm -> DAPRP + QH2m
1.5.99.6


6611
SMS
DSAM + SPRMD -> 5MTA + SPRM
2.5.1.22


4953
ODC1
ORN -> PTRSC + CO2
4.1.1.17


6303
SAT, SSAT

2.3.1.57







5.11 Histidine metabolism PATH:hsa00340










10841
FTCD
FIGLU + THF -> NFTHF + GLU
2.1.2.5





4.3.1.4


3067
HDC

4.1.1.22


1644
DDC, AADC

4.1.1.28


3176
HNMT

2.1.1.8


218
ALDH3
ACAL + NAD -> NADH + AC
1.2.1.5


220
ALDH6
ACAL + NAD -> NADH + AC
1.2.1.5


221
ALDH7, ALDH4
ACAL + NAD -> NADH + AC
1.2.1.5


222
ALDH8
ACAL + NAD -> NADH + AC
1.2.1.5


3035
HARS
ATP + HIS + HTRNA -> AMP + PPI + HHTRNA
6.1.1.21







5.12 Tyrosine metabolism PATH:hsa00350










6898
TAT
AKG + TYR -> HPHPYR + GLU
2.6.1.5


3242
HPD, PPD
HPHPYR + O2 -> HGTS + CO2
1.13.11.27


3081
HGD, AKU, HGO
HGTS + O2 -> MACA
1.13.11.5


2954
GSTZ1, MAAI
MACA -> FACA
5.2.1.2





2.5.1.18


2184
FAH
FACA + H2O -> FUM + ACA
3.7.1.2


7299
TYR, OCAIA

1.14.18.1


7054
TH, TYH

1.14.16.2


1621
DBH

1.14.17.1


5409
PNMT, PENT

2.1.1.28


1312
COMT

2.1.1.6


7173
TPO, TPX

1.11.1.8







5.13 Phenylalanine metabolism PATH:hsa00360










501
ATQ1

1.2.1.—







5.14 Tryptophan metabolism PATH:hsa00380










6999
TDO2, TPH2, TRPO, TDO
TRP + O2 -> FKYN
1.13.11.11


8564
KMO
KYN + NADPH + O2 -> HKYN + NADP + H2O
1.14.13.9


8942
KYNU
KYN -> ALA + AN
3.7.1.3




HKYN + H2O -> HAN + ALA


23498
HAAO, HAO, 3-HAO
HAN + O2 -> CMUSA
1.13.11.6


7166
TPH, TPRH

1.14.16.4


438
ASMT, HIOMT, ASMTY

2.1.1.4


15
AANAT, SNAT

2.3.1.87


3620
INDO, IDO

1.13.11.42


10352
WARS2
ATPm + TRPm + TRNAm -> AMPm + PPIm + TRPTRNAm
6.1.1.2


7453
WARS, IFP53, IFI53, GAMMA-2
ATP + TRP + TRNA -> AMP + PPI + TRPTRNA
6.1.1.2


4734
NEDD4, KIAA0093

6.3.2.—







5.15 Phenylalanine, tyrosine and tryptophan biosynthesis PATH:hsa00400










5053
PAH, PKU1
PHE + THBP + O2 -> TYR + DHBP + H2O
1.14.16.1


10667
FARS1

6.1.1.20


2193
FARSL, CML33

6.1.1.20


10056
PheHB

6.1.1.20


8565
YARS, TYRRS, YTS, YRS

6.1.1.1







5.16 Urea cycle and metabolism of amino groups PATH:hsa00220










5832
PYCS

2.7.2.11




GLUP + NADH -> NAD + PI + GLUGSAL
1.2.1.41




GLUP + NADPH -> NADP + PI + GLUGSAL


95
ACY1

3.5.1.14







6. Metabolism of Other Amino Acids


6.1 beta-Alanine metabolism PATH:hsa00410


6.2 Taurine and hypotaurine metabolism PATH:hsa00430










2678
GGT1, GTG, D22S672, D22S732,
RGT + ALA -> CGLY + ALAGLY
2.3.2.2



GGT


2679
GGT2, GGT
RGT + ALA -> CGLY + ALAGLY
2.3.2.2


2680
GGT3
RGT + ALA -> CGLY + ALAGLY
2.3.2.2


2687
GGTLA1, GGT-REL, DKFZP566O011
RGT + ALA -> CGLY + ALAGLY
2.3.2.2







6.3 Aminophosphonate metabolism PATH:hsa00440










5130
PCYT1A, CTPCT, CT, PCYT1
PCHO + CTP -> CDPCHO + PPI
2.7.7.15


9791
PTDSS1, KIAA0024, PSSA
CDPDG + SER <-> CMP + PS
2.7.8.—







6.4 Selenoamino acid metabolism PATH:hsa00450










22928
SPS2

2.7.9.3


22929
SPS, SELD

2.7.9.3







6.5 Cyanoamino acid metabolism PATH:hsa00460


6.6 D-Glutamine and D-glutamate metabolism PATH:hsa00471


6.7 D-Arginine and D-ornithine metabolism PATH:hsa00472


6.9 Glutathione metabolism PATH:hsa00480










5182
PEPB

3.4.11.4


2655
GCTG

2.3.2.4


2876
GPX1, GSHPX1
2 RGT + H2O2 <-> OGT
1.11.1.9


2877
GPX2, GSHPX-GI
2 RGT + H2O2 <-> OGT
1.11.1.9


2878
GPX3
2 RGT + H2O2 <-> OGT
1.11.1.9


2879
GPX4
2 RGT + H2O2 <-> OGT
1.11.1.9


2880
GPX5
2 RGT + H2O2 <-> OGT
1.11.1.9


2881
GPX6
2 RGT + H2O2 <-> OGT
1.11.1.9


2938
GSTA1

2.5.1.18


2939
GSTA2, GST2

2.5.1.18


2940
GSTA3

2.5.1.18


2941
GSTA4

2.5.1.18


2944
GSTM1, GST1, MU

2.5.1.18


2946
GSTM2, GST4

2.5.1.18


2947
GSTM3, GST5

2.5.1.18


2948
GSTM4

2.5.1.18


2949
GSTM5

2.5.1.18


2950
GSTP1, FAEES3, DFN7, GST3, PI

2.5.1.18


2952
GSTT1

2.5.1.18


2953
GSTT2

2.5.1.18


4257
MGST1, GST12, MGST, MGST-I

2.5.1.18


4258
MGST2, GST2, MGST-II

2.5.1.18


4259
MGST3, GST-III

2.5.1.18







7. Metabolism of Complex Carbohydrates


7.1 Starch and sucrose metabolism PATH:hsa00500










6476
SI

3.2.1.10





3.2.1.48


11181
TREH, TRE, TREA
TRE -> 2 GLC
3.2.1.28


2990
GUSB

3.2.1.31


2632
GBE1
GLYCOGEN + PI -> G1P
2.4.1.18


5834
PYGB
GLYCOGEN + PI -> G1P
2.4.1.1


5836
PYGL
GLYCOGEN + PI -> G1P
2.4.1.1


5837
PYGM
GLYCOGEN + PI -> G1P
2.4.1.1


2997
GYS1, GYS
UDPG -> UDP + GLYCOGEN
2.4.1.11


2998
GYS2
UDPG -> UDP + GLYCOGEN
2.4.1.11


276
AMY1A, AMY1

3.2.1.1


277
AMY1B, AMY1

3.2.1.1


278
AMY1C, AMY1

3.2.1.1


279
AMY2A, AMY2

3.2.1.1


280
AMY2B, AMY2

3.2.1.1


178
AGL, GDE

2.4.1.25





3.2.1.33


10000
AKT3, PKBG, RAC-GAMMA, PRKBG

2.7.1.—


1017
CDK2

2.7.1.—


1018
CDK3

2.7.1.—


1019
CDK4, PSK-J3

2.7.1.—


1020
CDK5, PSSALRE

2.7.1.—


1021
CDK6, PLSTIRE

2.7.1.—


1022
CDK7, CAK1, STK1, CDKN7

2.7.1.—


1024
CDK8, K35

2.7.1.—


1025
CDK9, PITALRE, CDC2L4

2.7.1.—


10298
PAK4

2.7.1.—


10746
MAP3K2, MEKK2

2.7.1.—


1111
CHEK1, CHK1

2.7.1.—


11200
RAD53, CHK2, CDS1, HUCDS1

2.7.1.—


1195
CLK1, CLK

2.7.1.—


1326
MAP3K8, COT, EST, ESTF, TPL-2

2.7.1.—


1432
MAPK14, CSBP2, CSPB1, PRKM14,

2.7.1.—



PRKM15, CSBP1, P38, MXI2


1452
CSNK1A1

2.7.1.—


1453
CSNK1D, HCKID

2.7.1.—


1454
CSNK1E, HCKIE

2.7.1.—


1455
CSNK1G2

2.7.1.—


1456
CSNK1G3

2.7.1.—


1612
DAPK1, DAPK

2.7.1.—


1760
DMPK, DM, DMK, DM1

2.7.1.—


1859
DYRK1A, DYRK1, DYRK, MNB, MNBH

2.7.1.—


208
AKT2, RAC-BETA, PRKBB, PKBBETA

2.7.1.—


269
AMHR2, AMHR

2.7.1.—


27330
RPS6KA6, RSK4

2.7.1.—


2868
GPRK2L, GPRK4

2.7.1.—


2869
GPRK5, GRK5

2.7.1.—


2870
GPRK6, GRK6

2.7.1.—


29904
HSU93850

2.7.1.—


30811
HUNK

2.7.1.—


3611
ILK, P59

2.7.1.—


3654
IRAK1, IRAK

2.7.1.—


369
ARAF1, PKS2, RAFA1

2.7.1.—


370
ARAF2P, PKS1, ARAF2

2.7.1.—


3984
LIMK1, LIMK

2.7.1.—


3985
LIMK2

2.7.1.—


4117
MAK

2.7.1.—


4140
MARK3, KP78

2.7.1.—


4215
MAP3K3, MAPKKK3, MEKK3

2.7.1.—


4216
MAP3K4, MAPKKK4, MTK1, MEKK4,

2.7.1.—



KIAA0213


4217
MAP3K5, ASK1, MAPKKK5, MEKK5

2.7.1.—


4293
MAP3K9, PRKE1, MLK1

2.7.1.—


4294
MAP3K10, MLK2, MST

2.7.1.—


4342
MOS

2.7.1.—


4751
NEK2, NLK1

2.7.1.—


4752
NEK3

2.7.1.—


5058
PAK1, PAKalpha

2.7.1.—


5062
PAK2, PAK65, PAKgamma

2.7.1.—


5063
PAK3, MRX30, PAK3beta

2.7.1.—


5127
PCTK1, PCTGAIRE

2.7.1.—


5128
PCTK2

2.7.1.—


5129
PCTK3, PCTAIRE

2.7.1.—


5292
PIM1, PIM

2.7.1.—


5347
PLK, PLK1

2.7.1.—


5562
PRKAA1

2.7.1.—


5563
PRKAA2, AMPK, PRKAA

2.7.1.—


5578
PRKCA, PKCA

2.7.1.—


5579
PRKCB1, PKCB, PRKCB, PRKCB2

2.7.1.—


5580
PRKCD

2.7.1.—


5581
PRKCE

2.7.1.—


5582
PRKCG, PKCC, PKCG

2.7.1.—


5583
PRKCH, PKC-L, PRKCL

2.7.1.—


5584
PRKCI, DXS1179E, PKCI

2.7.1.—


5585
PRKCL1, PAK1, PRK1, DBK, PKN

2.7.1.—


5586
PRKCL2, PRK2

2.7.1.—


5588
PRKCQ

2.7.1.—


5590
PRKCZ

2.7.1.—


5594
MAPK1, PRKM1, P41MAPK,

2.7.1.—



P42MAPK, ERK2, ERK, MAPK2,



PRKM2


5595
MAPK3, ERK1, PRKM3, P44ERK1,

2.7.1.—



P44MAPK


5597
MAPK6, PRKM6, P97MAPK, ERK3

2.7.1.—


5598
MAPK7, BMK1, ERK5, PRKM7

2.7.1.—


5599
MAPK8, JNK, JNK1, SAPK1, PRKM8,

2.7.1.—



JNK1A2


5601
MAPK9, JNK2, PRKM9, P54ASAPK,

2.7.1.—



JUNKINASE


5602
MAPK10, JNK3, PRKM10, P493F12,

2.7.1.—



P54BSAPK


5603
MAPK13, SAPK4, PRKM13,

2.7.1.—



P38DELTA


5604
MAP2K1, MAPKK1, MEK1, MKK1,

2.7.1.—



PRKMK1


5605
MAP2K2, MEK2, PRKMK2

2.7.1.—


5606
MAP2K3, MEK3, MKK3, PRKMK3

2.7.1.—


5607
MAP2K5, MEK5, PRKMK5

2.7.1.—


5608
MAP2K6, MEK6, MKK6, SAPKK3,

2.7.1.—



PRKMK6


5609
MAP2K7, MAPKK7, MKK7, PRKMK7,

2.7.1.—



JNKK2


5610
PRKR, EIF2AK1, PKR

2.7.1.—


5613
PRKX, PKX1

2.7.1.—


5894
RAF1

2.7.1.—


613
BCR, CML, PHL, BCR1, D22S11,

2.7.1.—



D22S662


6195
RPS6KA1, HU-1, RSK, RSK1,

2.7.1.—



MAPKAPK1A


6196
RPS6KA2, HU-2, MAPKAPK1C, RSK,

2.7.1.—



RSK3


6197
RPS6KA3, RSK2, HU-2, HU-3, RSK,

2.7.1.—



MAPKAPK1B, ISPK-1


6198
RPS6KB1, STK14A

2.7.1.—


6199
RPS6KB2, P70-BETA, P70S6KB

2.7.1.—


6300
MAPK12, ERK6, PRKM12, SAPK3,

2.7.1.—



P38GAMMA, SAPK-3


6416
MAP2K4, JNKK1, MEK4, PRKMK4,

2.7.1.—



SERK1, MKK4


6446
SGK

2.7.1.—


658
BMPR1B, ALK-6, ALK6

2.7.1.—


659
BMPR2, BMPR-II, BMPR3, BRK-3

2.7.1.—


673
BRAF

2.7.1.—


6792
STK9

2.7.1.—


6794
STK11, LKB1, PJS

2.7.1.—


6885
MAP3K7, TAK1

2.7.1.—


699
BUB1

2.7.1.—


701
BUB1B, BUBR1, MAD3L

2.7.1.—


7016
TESK1

2.7.1.—


7272
TTK, MPS1L1

2.7.1.—


7867
MAPKAPK3, 3PK, MAPKAP3

2.7.1—


8408
ULK1

2.7.1.—


8558
CDK10, PISSLRE

2.7.1.—


8621
CDC2L5, CDC2L, CHED

2.7.1.—


8737
RIPK1, RIP

2.7.1.—


8814
CDKL1, KKIALRE

2.7.1.—


8899
PRP4, PR4H

2.7.1.—


9064
MAP3K6, MAPKKK6

2.7.1.—


9149
DYRK1B

2.7.1.—


92
ACVR2, ACTRII

2.7.1.—


9201
DCAMKL1, KIAA0369

2.7.1.—


93
ACVR2B

2.7.1.—


983
CDC2

2.7.1.—


984
CDC2L1

2.7.1.—


5205
FIC1, BRIC, PFIC1, PFIC, ATP8B1

3.6.1.—




DHPP -> DHP + PI




GTP -> GSN + 3 PI




DGTP -> DG + 3 PI







7.2 Glycoprotein biosynthesis PATH:hsa00510










1798
DPAGT1, DPAGT, UGAT, UAGT,

2.7.8.15



D11S366, DGPT, DPAGT2, GPT


29880
ALG5

2.4.1.117


8813
DPM1
GDPMAN + DOLP -> GDP + DOLMANP
2.4.1.83


1650
DDOST, OST, OST48, KIAA0115

2.4.1.119


6184
RPN1

2.4.1.119


6185
RPN2

2.4.1.119


10130
P5

5.3.4.1


10954
PDIR

5.3.4.1


11008
PDI

5.3.4.1


2923
GRP58, ERp57, ERp60, ERp61,

5.3.4.1



GRP57, P58, PI-PLC, ERP57, ERP60,



ERP61


5034
P4HB, PROHB, PO4DB, ERBA2L

5.3.4.1


7841
GCS1

3.2.1.106


4121
MAN1A1, MAN9, HUMM9

3.2.1.113


4245
MGAT1, GLYT1, GLCNAC-TI, GNT-I,

2.4.1.101



MGAT


4122
MAN2A2, MANA2X

3.2.1.114


4124
MAN2A1, MANA2

3.2.1.114


4247
MGAT2, CDGS2, GNT-II, GLONACTII,

2.4.1.143



GNT2


4248
MGAT3, GNT-III

2.4.1.144


6487
SIAT6, ST3GALII

2.4.99.6


6480
SIAT1

2.4.99.1


2339
FNTA, FPTA, PGGT1A

2.5.1.—


2342
FNTB, FPTB

2.5.1.—


5229
PGGT1B, BGGI, GGTI

2.5.1.—


5875
RABGGTA

2.5.1.—


5876
RABGGTB

2.5.1.—


1352
COX10

2.5.1.—







7.3 Glycoprotein degradation PATH:hsa00511










4758
NEU1, NEU

3.2.1.18


3073
HEXA, TSD

3.2.1.52


3074
HEXB

3.2.1.52


4123
MAN2C1, MANA, MANA1, MAN6A8

3.2.1.24


4125
MAN2B1, MANB, LAMAN

3.2.1.24


4126
MANBA, MANB1

3.2.1.25


2517
FUCA1

3.2.1.51


2519
FUCA2

3.2.1.51


175
AGA, AGU

3.5.1.26







7.4 Aminosugars metabolism PATH:hsa005300










6675
UAP1, SPAG2, AGX1
UTP + NAGA1P <-> UDPNAG + PPI
2.7.7.23


10020
GNE, GLCNE

5.1.3.14


22951
CMAS

2.7.7.43


1727
DIA1

1.6.2.2


4669
NAGLU, NAG

3.2.1.50







7.5 Lipopolysaccharide biosynthesis PATH:hsa00540










6485
SIAT5, SAT3, STZ

2.4.99.—


7903
SIAT8D, PST, PST1, ST8SIA-IV

2.4.99.—


8128
SIAT8B, STX, ST8SIA-II

2.4.99.—







7.7 Glycosaminoglycan degradation PATH:hsa00531










3423
IDS, MPS2, SIDS

3.1.6.13


3425
IDUA, IDA

3.2.1.76


411
ARSB

3.1.6.12


2799
GNS, G6S

3.1.6.14


2588
GALNS, MPS4A, GALNAC6S, GAS

3.1.6.4







8. Metabolism of Complex Lipids


8.1 Glycerolipid metabolism PATH:hsa00561










10554
AGPAT1, LPAAT-ALPHA, G15
AGL3P + 0.017 C100ACP + 0.062 C120ACP + 0.100 C140ACP + 0.270
2.3.1.51




C160ACP + 0.169 C161ACP + 0.055 C180ACP + 0.235




C181ACP + 0.093 C182ACP -> PA + ACP


10555
AGPAT2, LPAAT-BETA
AGL3P + 0.017 C100ACP + 0.062 C120ACP + 0.100 C140ACP + 0.270
2.3.1.51




C160ACP + 0.169 C161ACP + 0.055 C180ACP + 0.235




C181ACP + 0.093 C182ACP -> PA + ACP


1606
DGKA, DAGK, DAGK1

2.7.1.107


1608
DGKG, DAGK3

2.7.1.107


1609
DGKQ, DAGK4

2.7.1.107


8525
DGKZ, DAGK5, HDGKZETA

2.7.1.107


8526
DGKE, DAGK6, DGK

2.7.1.107


8527
DGKD, DGKDELTA, KIAA0145

2.7.1.107


1120
CHKL
ATP + CHO -> ADP + PCHO
2.7.1.32



EKI1
ATP + ETHM -> ADP + PETHM
2.7.1.82


1119
CHK, CKI
ATP + CHO -> ADP + PCHO
2.7.1.32


43
ACHE, YT

3.1.1.7


1103
CHAT

2.3.1.6


5337
PLD1

3.1.4.4


26279
PLA2G2D, SPLA2S

3.1.1.4


30814
PLA2G2E

3.1.1.4


5319
PLA2G1B, PLA2, PLA2A, PPLA2

3.1.1.4


5320
PLA2G2A, MOM1, PLA2B, PLA2L

3.1.1.4


5322
PLA2G5

3.1.1.4


8398
PLA2G6, IPLA2

3.1.1.4


8399
PLA2G10, SPLA2

3.1.1.4


1040
CDS1
PA + CTP <-> CDPDG + PPI
2.7.7.41


10423
PIS
CDPDG + MYOI -> CMP + PINS
2.7.8.11


2710
GK
GL + ATP -> GL3P + ADP
2.7.1.30


2820
GPD2
GL3Pm + FADm -> T3P2m + FADH2m
1.1.99.5


2819
GPD1
T3P2 + NADH <-> GL3P + NAD
1.1.1.8


248
ALPI
AHTD -> DHP + 3 PI
3.1.3.1


249
ALPL, HOPS, TNSALP
AHTD -> DHP + 3 PI
3.1.3.1


250
ALPP
AHTD -> DHP + 3 PI
3.1.3.1


251
ALPPL2
AHTD -> DHP + 3 PI
3.1.3.1


439
ASNA1, ARSA-I

3.6.1.16


8694
DGAT, ARGP1
DAGLY + 0.017 C100ACP + 0.062 C120ACP + 0.100 C140ACP + 0.270
2.3.1.20




C160ACP + 0.169 C161ACP + 0.055 C180ACP + 0.235




C181ACP + 0.093 C182ACP -> TAGLY + ACP


3989
LIPB

3.1.1.3


3990
LIPC, HL

3.1.1.3


5406
PNLIP

3.1.1.3


5407
PNLIPRP1, PLRP1

3.1.1.3


5408
PNLIPRP2, PLRP2

3.1.1.3


8513
LIPF, HGL, HLAL

3.1.1.3


4023
LPL, LIPD

3.1.1.34


8443
GNPAT, DHAPAT, DAP-AT

2.3.1.42


8540
AGPS, ADAP-S, ADAS, ADHAPS,

2.5.1.26



ADPS, ALDHPSY


4186
MDCR, MDS, LIS1

3.1.1.47


5048
PAFAH1B1, LIS1, MDCR, PAFAH

3.1.1.47


5049
PAFAH1B2

3.1.1.47


5050
PAFAH1B3

3.1.1.47


5051
PAFAH2, HSD-PLA2

3.1.1.47


7941
PLA2G7, PAFAH, LDL-PLA2

3.1.1.47







8.2 Inositol phosphate metabolism PATH:hsa00562










5290
PIK3CA
ATP + PINS -> ADP + PINSP
2.7.1.137


5291
PIK3CB, PIK3C1
ATP + PINS -> ADP + PINSP
2.7.1.137


5293
PIK3CD
ATP + PINS -> ADP + PINSP
2.7.1.137


5294
PIK3CG
ATP + PINS -> ADP + PINSP
2.7.1.137


5297
PIK4CA, PI4K-ALPHA
ATP + PINS -> ADP + PINS4P
2.7.1.67


5305
PIP5K2A
PINS4P + ATP -> D45PI + ADP
2.7.1.68


5330
PLCB2
D45PI -> TPI + DAGLY
3.1.4.11


5331
PLCB3
D45PI -> TPI + DAGLY
3.1.4.11


5333
PLCD1
D45PI -> TPI + DAGLY
3.1.4.11


5335
PLCG1, PLC1
D45PI -> TPI + DAGLY
3.1.4.11


5336
PLCG2
D45PI -> TPI + DAGLY
3.1.4.11


3612
IMPA1, IMPA
MI1P -> MYOI + PI
3.1.3.25


3613
IMPA2
MI1P -> MYOI + PI
3.1.3.25


3628
INPP1

3.1.3.57


3632
INPP5A


3633
INPP5B

3.1.3.56


3636
INPPL1, SHIP2

3.1.3.56


4952
OCRL, LOCR, OCRL1, INPP5F

3.1.3.56


8867
SYNJ1, INPP5G

3.1.3.56


3706
ITPKA

2.7.1.127


51477
ISYNA1
G6P -> MI1P
5.5.1.4


3631
INPP4A, INPP4

3.1.3.66


8821
INPP4B

3.1.3.66







8.3 Sphingophospholipid biosynthesis PATH:hsa00570










6609
SMPD1, NPD

3.1.4.12







8.4 Phospholipid degradation PATH:hsa00580










1178
CLC

3.1.1.5


5321
PLA2G4A, CPLA2-ALPHA, PLA2G4

3.1.1.5







8.5 Sphingoglycolipid metabolism PATH:hsa00600










10558
SPTLC1, LCB1, SPTI
PALCOA + SER -> COA + DHSPH + CO2
2.3.1.50


9517
SPTLC2, KIAA0526, LCB2
PALCOA + SER -> COA + DHSPH + CO2
2.3.1.50


427
ASAH, AC, PHP32

3.5.1.23


7357
UGCG, GCS

2.4.1.80


2629
GBA, GLUC

3.2.1.45


2583
GALGT, GALNACT

2.4.1.92


6489
SIAT8A, SIAT8, ST8SIA-I

2.4.99.8


6481
SIAT2

2.4.99.2


4668
NAGA, D22S674, GALB

3.2.1.49


9514
CST

2.8.2.11


410
ARSA, MLD

3.1.6.8







8.6 Blood group glycolipid biosynthesis - lact series PATH:hsa00601










28
ABO

2.4.1.40





2.4.1.37


2525
FUT3, LE

2.4.1.65


2527
FUT5, FUC-TV

2.4.1.65


2528
FUT6

2.4.1.65


2523
FUT1, H, HH

2.4.1.69


2524
FUT2, SE

2.4.1.69







8.7 Blood group glycolipid biosynthesis - neolact series PATH:hsa00602










2651
GCNT2, IGNT, NACGT1, NAGCT1

2.4.1.150







8.8 Prostaglandin and leukotriene metabolism PATH:hsa00590










239
ALOX12, LOG12

1.13.11.31


246
ALOX15

1.13.11.33


240
ALOX5

1.13.11.34


4056
LTC4S

2.5.1.37


4048
LTA4H

3.3.2.6


4051
CYP4F3, CYP4F, LTB4H

1.14.13.30


8529
CYP4F2

1.14.13.30


5742
PTGS1, PGHS-1

1.14.99.1


5743
PTGS2, COX-2, COX2

1.14.99.1


27306
PGDS

5.3.99.2


5730
PTGDS

5.3.99.2


5740
PTGIS, CYP8, PGIS

5.3.99.4


6916
TBXAS1, CYP5

5.3.99.5


873
CBR1, CBR

1.1.1.184





1.1.1.189





1.1.1.197


874
CBR3

1.1.1.184







9. Metabolism of Cofactors and Vitamins


9.2 Riboflavin metabolism PATH:hsa00740










52
ACP1

3.1.3.48




FMN -> RIBOFLAV + PI
3.1.3.2


53
ACP2
FMN -> RIBOFLAV + PI
3.1.3.2


54
ACP5, TRAP
FMN -> RIBOFLAV + PI
3.1.3.2


55
ACPP, PAP
FMN -> RIBOFLAV + PI
3.1.3.2







9.3 Vitamin B6 metabolism PATH:hsa00750










8566
PDXK, PKH, PNK
PYRDX + ATP -> P5P + ADP
2.7.1.35




PDLA + ATP -> PDLA5P + ADP




PL + ATP -> PL5P + ADP







9.4 Nicotinate and nicotinamide metabolism PATH:hsa00760










23475
QPRT
QA + PRPP -> NAMN + CO2 + PPI
2.4.2.19


4837
NNMT

2.1.1.1


683
BST1, CD157
NAD -> NAM + ADPRIB
3.2.2.5


952
CD38
NAD -> NAM + ADPRIB
3.2.2.5


23530
NNT

1.6.1.2







9.5 Pantothenate and CoA biosynthesis PATH:hsa00770


9.6 Biotin metabolism PATH:hsa00780










3141
HLCS, HCS

6.3.4.—





6.3.4.9





6.3.4.10





6.3.4.11





6.3.4.15


686
BTD

3.5.1.12







9.7 Folate biosynthesis PATH:hsa00790










2643
GCH1, DYT5, GCH, GTPCH1
GTP -> FOR + AHTD
3.5.4.16


1719
DHFR
DHF + NADPH -> NADP + THF
1.5.1.3


2356
FPGS
THF + ATP + GLU <-> ADP + PI + THFG
6.3.2.17


8836
GGH, GH

3.4.19.9


5805
PTS

4.6.1.10


6697
SPR

1.1.1.153


5860
QDPR, DHPR, PKU2
NADPH + DHBP -> NADP + THBP
1.6.99.7







9.8 One carbon pool by folate PATH:hsa00670










10840
FTHFD

1.5.1.6


10588
MTHFS
ATP + FTHF -> ADP + PI + MTHF
6.3.3.2







9.10 Porphyrin and chlorophyll metabolism PATH:hsa00860










210
ALAD
2 ALAV -> PBG
4.2.1.24


3145
HMBS, PBGD, UPS
4 PBG -> HMB + 4 NH3
4.3.1.8


7390
UROS
HMB -> UPRG
4.2.1.75


7389
UROD
UPRG -> 4 CO2 + CPP
4.1.1.37


1371
CPO, CPX
O2 + CPP -> 2 CO2 + PPHG
1.3.3.3


5498
PPOX, PPO
O2 + PPHGm -> PPIXm
1.3.3.4


2235
FECH, FCE
PPIXm -> PTHm
4.99.1.1


3162
HMOX1, HO-1

1.14.99.3


3163
HMOX2, HO-2

1.14.99.3


644
BLVRA, BLVR

1.3.1.24


645
BLVRB, FLR

1.3.1.24





1.6.99.1


2232
FDXR, ADXR

1.18.1.2


3052
HCCS, CCHL

4.4.1.17


1356
CP

1.16.3.1







9.11 Ubiquinone biosynthesis PATH:hsa00130










4938
OAS1, IFI-4, OIAS

2.7.7.—


4939
OAS2, P69

2.7.7.—


5557
PRIM1

2.7.7.—


5558
PRIM2A, PRIM2

2.7.7.—


5559
PRIM2B, PRIM2

2.7.7.—


7015
TERT, EST2, TCS1, TP2, TRT

2.7.7.—


8638
OASL, TRIP14

2.7.7.—







10. Metabolism of Other Substances


10.1 Terpenoid biosynthesis PATH:hsa00900


10.2 Flavonoids, stilbene and lignin biosynthesis PATH:hsa00940


10.3 Alkaloid biosynthesis I PATH:hsa00950


10.4 Alkaloid biosynthesis II PATH:hsa00960


10.6 Streptomycin biosynthesis PATH:hsa00521


10.7 Erythromycin biosynthesis PATH:hsa00522


10.8 Tetracycline biosynthesis PATH:hsa00253


10.14 gamma-Hexachlorocyclohexane degradation PATH:hsa00361










5444
PON1, ESA, PON

3.1.8.1





3.1.1.2


5445
PON2

3.1.1.2





3.1.8.1







10.18 1,2-Dichloroethane degradation PATH:hsa00631


10.20 Tetrachloroethene degradation PATH:hsa00625










2052
EPHX1, EPHX, MEH

3.3.2.3


2053
EPHX2

3.3.2.3







10.21 Styrene degradation PATH:hsa00643


11. Transcription (condensed)


11.1 RNA polymerase PATH:hsa03020


11.2 Transcription factors PATH:hsa03022


12. Translation (condensed)


12.1 Ribosome PATH:hsa03010


12.2 Translation factors PATH:hsa03012










1915
EEF1A1, EF1A, ALPHA, EEF-1,

3.6.1.48



EEF1A


1917
EEF1A2, EF1A

3.6.1.48


1938
EEF2, EF2, EEF-2

3.6.1.48







12.3 Aminoacyl-tRNA biosynthesis PATH:hsa00970


13. Sorting and Degradation (condensed)


13.1 Protein export PATH:hsa03060










23478
SPC18

3.4.21.89







13.4 Proteasome PATH:hsa03050










5687
PSMA6, IOTA, PROS27

3.4.99.46


5683
PSMA2, HC3, MU, PMSA2, PSC2

3.4.99.46


5685
PSMA4, HC9

3.4.99.46


5688
PSMA7, XAPC7

3.4.99.46


5686
PSMA5, ZETA, PSC5

3.4.99.46


5682
PSMA1, HC2, NU, PROS30

3.4.99.46


5684
PSMA3, HC8

3.4.99.46


5698
PSMB9, LMP2, RING12

3.4.99.46


5695
PSMB7, Z

3.4.99.46


5691
PSMB3, HC10-II

3.4.99.46


5690
PSMB2, HC7-I

3.4.99.46


5693
PSMB5, LMPX, MB1

3.4.99.46


5689
PSMB1, HC5, PMSB1

3.4.99.46


5692
PSMB4, HN3, PROS26

3.4.99.46







14. Replication and Repair


14.1 DNA polymerase PATH:hsa03030


14.2 Replication Complex PATH:hsa03032










23626
SPO11

5.99.1.3


7153
TOP2A, TOP2

5.99.1.3


7155
TOP2B

5.99.1.3


7156
TOP3A, TOP3

5.99.1.2


8940
TOP3B

5.99.1.2







22. Enzyme Complex


22.1 Electron Transport System, Complex I PATH:hsa03100


22.2 Electron Transport System, Complex II PATH:hsa03150


22.3 Electron Transport System, Complex III PATH:hsa03140


22.4 Electron Transport System, Complex IV PATH:hsa03130


22.5 ATP Synthase PATH:hsa03110


22.8 ATPases PATH:hsa03230


23. Unassigned


23.1 Enzymes










5538
PPT1, CLN1, PPT, INCL
C160ACP + H2O -> C160 + ACP
3.1.2.22







23.2 Non-enzymes










22934
RPIA, RPI
RL5P <-> R5P
5.3.1.6


5250
SLC25A3, PHC
PI + H <-> Hm + PIm


6576

CIT + MALm <-> CITm + MAL


51166
LOC51166
AADP + AKG -> GLU + KADP
2.6.1.39


5625
PRODH
PRO + FAD -> P5C + FADH2
1.5.3.—


6517
SLC2A4, GLUT4
GLCxt -> GLC


6513
SLC2A1, GLUT1, GLUT
GLCxt -> GLC


26275
HIBCH, HIBYL-COA-H
HIBCOAm + H2Om -> HIBm + COAm
3.1.2.4


23305
KIAA0837, ACS2, LACS5, LACS2
C160 + COA + ATP -> AMP + PPI + C160COA


8611
PPAP2A, PAP-2A
PA + H2O -> DAGLY + PI


8612
PPAP2C, PAP-2C
PA + H2O -> DAGLY + PI


8613
PPAP2B, PAP-2B
PA + H2O -> DAGLY + PI


56994
LOC56994
CDPCHO + DAGLY -> PC + CMP


10400
PEMT, PEMT2
SAM + PE -> SAH + PMME


5833
PCYT2, ET
PETHM + CTP -> CDPETN + PPI


10390
CEPT1
CDPETN + DAGLY <-> CMP + PE


8394
PIP5K1A
PINS4P + ATP -> D45PI + ADP


8395
PIP5K1B, STM7, MSS4
PINS4P + ATP -> D45PI + ADP


8396
PIP5K2B
PINS4P + ATP -> D45PI + ADP


23396
PIP5K1C, KIAA0589, PIP5K-GAMMA
PINS4P + ATP -> D45PI + ADP







24. Our own reactions which need to be found in KEGG










GL3P <-> GL3Pm




T3P2 <-> T3P2m



PYR <-> PYRm + Hm



ADP + ATPm + PI + H -> Hm + ADPm + ATP + PIm



AKG + MALm <-> AKGm + MAL



ASPm + GLU + H -> Hm + GLUm + ASP



GDP + GTPm + PI + H -> Hm + GDPm + GTP + PIm



C160Axt + FABP -> C160FP + ALBxt



C160FP -> C160 + FABP



C180Axt + FABP -> C180FP + ALBxt



C180FP -> C180 + FABP



C161Axt + FABP -> C161FP + ALBxt



C161FP -> C161 + FABP



C181Axt + FABP -> C181FP + ALBxt



C181FP -> C181 + FABP



C182Axt + FABP -> C182FP + ALBxt



C182FP -> C182 + FABP



C204Axt + FABP -> C204FP + ALBxt



C204FP -> C204 + FABP



O2xt -> O2



O2 <-> O2m



ACTACm + SUCCOAm -> SUCCm + AACCOAm



3HB -> 3HBm



MGCOAm + H2Om -> H3MCOAm
4.2.1.18



OMVAL -> OMVALm



OIVAL -> OIVALm



OICAP -> OICAPm



C160CAR <-> C160CARm



CAR <-> CARm



DMMCOAm -> LMMCOAm
5.1.99.1


amino acid metabolism



THR -> NH3 + H2O + OBUT
4.2.1.16



THR + NAD -> CO2 + NADH + AMA
1.1.1.103



THR + NAD + COA -> NADH + ACCOA + GLY



AASA + NAD -> NADH + AADP
1.2.1.31



FKYN + H2O -> FOR + KYN
3.5.1.9



CMUSA -> CO2 + AM6SA
4.1.1.45



AM6SA + NAD -> AMUCO + NADH
1.2.1.32



AMUCO + NADPH -> KADP + NADP + NH4
1.5.1.—



CYSS + AKG <-> GLU + SPYR



URO + H2O -> 4I5P
4.2.1.49



4I5P + H2O -> FIGLU
3.5.2.7



GLU <-> GLUm + Hm



ORN + Hm -> ORNm



ORN + Hm + CITRm <-> CITR + ORNm



GLU + ATP + NADPH -> NADP + ADP + PI + GLUGSAL



GLYAm + ATPm -> ADPm + 2PGm



AM6SA -> PIC



SPYR + H2O -> H2SO3 + PYR



P5C <-> GLUGSAL


fatty acid synthesis



MALCOA + ACP <-> MALACP + COA
2.3.1.39



ACCOA + ACP <-> ACACP + COA



ACACP + 4 MALACP + 8 NADPH -> 8 NADP + C100ACP + 4



CO2 + 4 ACP



ACACP + 5 MALACP + 10 NADPH -> 10 NADP + C120ACP + 5



CO2 + 5 ACP



ACACP + 6 MALACP + 12 NADPH -> 12 NADP + C140ACP + 6



CO2 + 6 ACP



ACACP + 6 MALACP + 11 NADPH -> 11 NADP + C141ACP + 6



CO2 + 6 ACP



ACACP + 7 MALACP + 14 NADPH -> 14 NADP + C160ACP + 7



CO2 + 7 ACP



ACACP + 7 MALACP + 13 NADPH -> 13 NADP + C161ACP + 7



CO2 + 7 ACP



ACACP + 8 MALACP + 16 NADPH -> 16 NADP + C180ACP + 8



CO2 + 8 ACP



ACACP + 8 MALACP + 15 NADPH -> 15 NADP + C181ACP + 8



CO2 + 8 ACP



ACACP + 8 MALACP + 14 NADPH -> 14 NADP + C182ACP + 8



CO2 + 8 ACP



C160COA + CAR -> C160CAR + COA



C160CARm + COAm -> C160COAm + CARm


fatty acid degredation



GL3P + 0.017 C100ACP + 0.062 C120ACP + 0.1 C140ACP + 0.27



C160ACP + 0.169 C161ACP + 0.055 C180ACP + 0.235



C181ACP + 0.093 C182ACP -> AGL3P + ACP



TAGLYm + 3 H2Om -> GLm + 3 C160m


Phospholipid metabolism



SAM + PMME -> SAH + PDME



PDME + SAM -> PC + SAH



PE + SER <-> PS + ETHM


Muscle contraction



MYOACT + ATP -> MYOATP + ACTIN



MYOATP + ACTIN -> MYOADPAC



MYOADPAC -> ADP + PI + MYOACT + CONTRACT
















TABLE 2





// Homo Sapiens Core Metabolic Network //















// Glycolysis //


−1 GLC −1 ATP +1 G6P +1 ADP 0 HK1


−1 G6P −1 H2O +1 GLC +1 PI 0 G6PC


−1 G6P +1 F6P 0 GPIR


−1 F6P −1 ATP +1 FDP +1 ADP 0 PFKL


−1 FDP −1 H2O +1 F6P +1 PI 0 FBP1


−1 FDP +1 T3P2 +1 T3P1 0 ALDOAR


−1 T3P2 +1 T3P1 0 TPI1R


−1 T3P1 −1 PI −1 NAD +1 NADH +1 13PDG 0 GAPDR


−1 13PDG −1 ADP +1 3PG +1 ATP 0 PGK1R


−1 13PDG +1 23PDG 0 PGAM1


−1 23PDG −1 H2O +1 3PG +1 PI 0 PGAM2


−1 3PG +1 2PG 0 PGAM3R


−1 2PG +1 PEP +1 H2O 0 ENO1R


−1 PEP −1 ADP +1 PYR +1 ATP 0 PKLR


−1 PYRm −1 COAm −1 NADm +1 NADHm +1 CO2m +1 ACCOAm 0


PDHAl


−1 NAD −1 LAC +1 PYR +1 NADH 0 LDHAR


−1 G1P +1 G6P 0 PGM1R


// TCA //


−1 ACCOAm −1 OAm −1 H2Om +1 COAm +1 CITm 0 CS


−1 CIT +1 ICIT 0 ACO1R


−1 CITm +1 ICITm 0 ACO2R


−1 ICIT −1 NADP +1 NADPH +1 CO2 +1 AKG 0 IDH1


−1 ICITm −1 NADPm +1 NADPHm +1 CO2m +1 AKGm 0 IDH2


−1 ICITm −1 NADm +1 CO2m +1 NADHm +1 AKGm 0 IDH3A


−1 AKGm −1 NADm −1 COAm +1 CO2m +1 NADHm +1 SUCCOAm 0


OGDH


−1 GTPm −1 SUCCm −1 COAm +1 GDPm +1 PIm +1 SUCCOAm 0


SUCLG1R


−1 ATPm −1 SUCCm −1 COAm +1 ADPm +1 PIm +1 SUCCOAm 0


SUCLA2R


−1 FUMm −1 H2Om +1 MALm 0 FHR


−1 MAL −1 NAD +1 NADH +1 OA 0 MDH1R


−1 MALm −1 NADm +1 NADHm +1 OAm 0 MDH2R


−1 PYRm −1 ATPm −1 CO2m +1 ADPm +1 OAm +1 PIm 0 PC


−1 OA −1 GTP +1 PEP +1 GDP +1 CO2 0 PCK1


−1 OAm −1 GTPm +1 PEPm +1 GDPm +1 CO2m 0 PCK2


−1 ATP −1 CIT −1 COA −1 H2O +1 ADP +1 PI +1 ACCOA +1 OA 0


ACLY


// PPP //


−1 G6P −1 NADP +1 D6PGL +1 NADPH 0 G6PDR


−1 D6PGL −1 H2O +1 D6PGC 0 PGLS


−1 D6PGC −1 NADP +1 NADPH +1 CO2 +1 RL5P 0 PGD


−1 RL5P +1 X5P 0 RPER


−1 R5P −1 X5P +1 T3P1 +1 S7P 0 TKT1R


−1 X5P −1 E4P +1 F6P +1 T3P1 0 TKT2R


−1 T3P1 −1 S7P +1 E4P +1 F6P 0 TALDO1R


−1 RL5P +1 R5P 0 RPIAR


// Glycogen //


−1 G1P −1 UTP +1 UDPG +1 PPI 0 UGP1


−1 UDPG +1 UDP +1 GLYCOGEN 0 GYS1


−1 GLYCOGEN −1 PI +1 G1P 0 GBE1


// ETS //


−1 MALm −1 NADPm +1 CO2m +1 NADPHm +1 PYRm 0 ME3


−1 MALm −1 NADm +1 CO2m +1 NADHm +1 PYRm 0 ME2


−1 MAL −1 NADP +1 CO2 +1 NADPH +1 PYR 0 ME1


−1 NADHm −1 Qm −4 Hm +1 QH2m +1 NADm +4 H 0 MTND1


−1 SUCCm −1 FADm +1 FUMm +1 FADH2m 0 SDHC1R


−1 FADH2m −1 Qm +1 FADm +1 QH2m 0 SDHC2R


−1 O2m −4 FEROm −4 Hm +4 FERIm +2 H2Om +4 H 0 UQCRFS1


−1 QH2m −2 FERIm −4 Hm +1 Qm +2 FEROm +4 H 0 COX5BL4


−1 ADPm −1 PIm −3 H +1 ATPm +3 Hm +1 H2Om 0 MTAT


−1 ADP −1 ATPm −1 PI −1 H +1 Hm +1 ADPm +1 ATP +1 PIm 0


ATPMC


−1 GDP −1 GTPm −1 PI −1 H +1 Hm +1 GDPm +1 GTP +1 PIm 0


GTPMC


−1 PPI +2 PI 0 PP


−1 ACCOA −1 ATP −1 CO2 +1 MALCOA +1 ADP +1 PI 0 ACACAR


−1 GDP −1 ATP +1 GTP +1 ADP 0 GOT3R


// Transporters //


−1 CIT −1 MALm +1 CITm +1 MAL 0 CITMCR


−1 PYR −1 H +1 PYRm +1 Hm 0 PYRMCR


// Glycerol Phosphate Shuttle //


−1 GL3Pm −1 FADm +1 T3P2m +1 FADH2m 0 GPD2


−1 T3P2 −1 NADH +1 GL3P +1 NAD 0 GPD1


−1 GL3P +1 GL3Pm 0 GL3PMCR


−1 T3P2 +1 T3P2m 0 T3P2MCR


// Malate/Aspartate Shuttle //


−1 OAm −1 GLUm +1 ASPm +1 AKGm 0 GOT1R


−1 ASP −1 AKG +1 OA +1 GLU 0 GOT2R


−1 AKG −1 MALm +1 AKGm +1 MAL 0 MALMCR


−1 ASPm −1 GLU −1 H +1 Hm +1 GLUm +1 ASP 0 ASPMC


// Exchange Fluxes //


+1 GLC 0 GLCexR


+1 PYR 0 PYRexR


+1 CO2 0 CO2exR


+1 O2 0 O2exR


+1 PI 0 PIexR


+1 H2O 0 H2OexR


+1 LAC 0 LACexR


+1 CO2m 0 CO2min


−1 CO2m 0 CO2mout


+1 O2m 0 O2min


−1 O2m 0 O2mout


+1 H2Om 0 H2Omin


−1 H2Om 0 H2Omout


+1 PIm 0 PImin


−1 PIm 0 PImout


// Output //


−1 ATP +1 ADP +1 PI 0 Output


0.0 end


end E 0


max


1 Output


0 end


0 GLCexR 1


−1000 PYRexR 0


−1000 LACexR 0


0 end 0


rev. rxn 33


nonrev. rxn 31


total rxn 64


matrix columns 97


unique enzymes 52


















TABLE 3





Abbrev.
Reaction
Rxn Name







Glycolysis




HK1
GLC + ATP -> G6P + ADP
HK1


G6PC, G6PT
G6P + H2O -> GLC + PI
G6PC


GPI
G6P <-> F6P
GPI


PFKL
F6P + ATP -> FDP + ADP
PFKL


FBP1, FBP
FDP + H2O -> F6P + PI
FBP1


ALDOA
FDP <-> T3P2 + T3P1
ALDOA


TPI1
T3P2 <-> T3P1
TPI1


GAPD, GAPDH
T3P1 + PI + NAD <-> NADH + 13PDG
GAPD


PGK1, PGKA
13PDG + ADP <-> 3PG + ATP
PGK1


PGAM1, PGAMA
13PDG <-> 23PDG
PGAM1



23PDG + H2O -> 3PG + PI
PGAM2



3PG <-> 2PG
PGAM3


ENO1, PPH, ENO1L1
2PG <-> PEP + H2O
ENO1


PKLR, PK1
PEP + ADP -> PYR + ATP
PKLR


PDHA1, PHE1A, PDHA
PYRm + COAm + NADm -> + NADHm + CO2m + ACCOAm
PDHA1


LDHA, LDH1
NAD + LAC <-> PYR + NADH
LDHA


PGM1
G1P <-> G6P
PGM1


TCA


CS
ACCOAm + OAm + H2Om -> COAm + CITm
CS


ACO1, IREB1, IRP1
CIT <-> ICIT
ACO1


ACO2
CITm <-> ICITm
ACO2


IDH1
ICIT + NADP -> NADPH + CO2 + AKG
IDH1


IDH2
ICITm + NADPm -> NADPHm + CO2m + AKGm
IDH2


IDH3A
ICITm + NADm -> CO2m + NADHm + AKGm
IDH3A


OGDH
AKGm + NADm + COAm -> CO2m + NADHm + SUCCOAm
OGDH


SUCLG1, SUCLA1
GTPm + SUCCm + COAm <-> GDPm + PIm + SUCCOAm
SUCLG1


SUCLA2
ATPm + SUCCm + COAm <-> ADPm + PIm + SUCCOAm
SUCLA2


FH
FUMm + H2Om <-> MALm
FH


MDH1
MAL + NAD <-> NADH + OA
MDH1


MDH2
MALm + NADm <-> NADHm + OAm
MDH2


PC, PCB
PYRm + ATPm + CO2m -> ADPm + OAm + PIm
PC


ACLY, ATPCL, CLATP
ATP + CIT + COA + H2O -> ADP + PI + ACCOA + OA
ACLY


PCK1
OA + GTP -> PEP + GDP + CO2
PCK1


PPP


G6PD, G6PD1
G6P + NADP <-> D6PGL + NADPH
G6PD


PGLS, 6PGL
D6PGL + H2O -> D6PGC
PGLS


PGD
D6PGC + NADP -> NADPH + CO2 + RL5P
PGD


RPE
RL5P <-> X5P
RPE


TKT
R5P + X5P <-> T3P1 + S7P
TKT1



X5P + E4P <-> F6P + T3P1
TKT2


TALDO1
T3P1 + S7P <-> E4P + F6P
TALDO1


UGP1
G1P + UTP -> UDPG + PPI
UGP1


ACACA, ACAC, ACC
ACCOA + ATP + CO2 <-> MALCOA + ADP + PI + H
ACACA


ETS


ME3
MALm + NADPm -> CO2m + NADPHm + PYRm
ME3


MTND1
NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
MTND1


SDHC
SUCCm + FADm <-> FUMm + FADH2m
SDHC1



FADH2m + Qm <-> FADm + QH2m
SDHC2


UQCRFS1, RIS1
O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
UQCRFS1


COX5BL4
QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
COX5BL4


MTATP6
ADPm + PIm + 3 H -> ATPm + 3 Hm + H2Om
MTAT


PP, SID6-8061
PPI -> 2 PI
PP


Malate Aspartate shunttle


GOT1
OAm + GLUm <-> ASPm + AKGm
GOT1


GOT2
OA + GLU <-> ASP + AKG
GOT2



GDP + ATP <-> GTP + ADP
GOT3


Glycogen


GBE1
GLYCOGEN + PI -> G1P
GBE1


GYS1, GYS
UDPG -> UDP + GLYCOGEN
GYS1


Glycerol Phosphate Shunttle


GPD2
GL3Pm + FADm -> T3P2m + FADH2m
GPD2


GPD1
T3P2 + NADH -> GL3P + NAD
GPD1


RPIA, RPI
RL5P <-> R5P
RPIA


Mitochondria Transport
CIT + MALm <-> CITm + MAL
CITMC



GL3P <-> GL3Pm
GL3PMC



T3P2 <-> T3P2m
T3P2MC



PYR <-> PYRm + Hm
PYRMC



ADP + ATPm + PI + H -> Hm + ADPm + ATP + PIm
ATPMC



AKG + MALm <-> AKGm + MAL
MALMC



ASPm + GLU + H -> Hm + GLUm + ASP
ASPMC



GDP + GTPm + PI + H -> Hm + GDPm + GTP + PIm
GTPMC
















TABLE 4







Metabolic Reaction for Muscle Cells








Reaction
Rxt Name












GLC + ATP -> G6P + ADP
0
HK1


G6P <-> F6P
0
GPI


F6P + ATP -> FDP + ADP
0
PFKL1


FDP + H2O -> F6P + PI
0
FBP1


FDP <-> T3P2 + T3P1
0
ALDOA


T3P2 <-> T3P1
0
TPI1


T3P1 + PI + NAD <-> NADH + 13PDG
0
GAPD


13PDG + ADP <-> 3PG + ATP
0
PGK1


3PG <-> 2PG
0
PGAM3


2PG <-> PEP + H2O
0
ENO1


PEP + ADP -> PYR + ATP
0
PK1


PYRm + COAm + NADm -> + NADHm + CO2m + ACCOAm
0
PDHA1


NAD + LAC <-> PYR + NADH
0
LDHA


G1P <-> G6P
0
PGM1


ACCOAm + OAm + H2Om -> COAm + CITm
0
CS


CIT <-> ICIT
0
ACO1


CITm <-> ICITm
0
ACO2


ICIT + NADP -> NADPH + CO2 + AKG
0
IDH1


ICITm + NADPm -> NADPHm + CO2m + AKGm
0
IDH2


ICITm + NADm -> CO2m + NADHm + AKGm
0
IDH3A


AKGm + NADm + COAm -> CO2m + NADHm + SUCCOAm
0
OGDH


GTPm + SUCCm + COAm <-> GDPm + PIm + SUCCOAm
0
SUCLG1


ATPm + SUCCm + COAm <-> ADPm + PIm + SUCCOAm
0
SUCLA2


FUMm + H2Om <-> MALm
0
FH


MAL + NAD <-> NADH + OA
0
MDH1


MALm + NADm <-> NADHm + OAm
0
MDH2


PYRm + ATPm + CO2m -> ADPm + OAm + PIm
0
PC


ATP + CIT + COA + H2O -> ADP + PI + ACCOA + OA
0
ACLY


OA + GTP -> PEP + GDP + CO2
0
PCK1


OAm + GTPm -> PEPm + GDPm + CO2m
0
PCK2


G6P + NADP <-> D6PGL + NADPH
0
G6PD


D6PGL + H2O -> D6PGC
0
H6PD


D6PGC + NADP -> NADPH + CO2 + RL5P
0
PGD


RL5P <-> X5P
0
RPE


R5P + X5P <-> T3P1 + S7P
0
TKT1


X5P + E4P <-> F6P + T3P1
0
TKT2


T3P1 + S7P <-> E4P + F6P
0
TALDO1


RL5P <-> R5P
0
RPIA


G1P + UTP -> UDPG + PPI
0
UGP1


GLYCOGEN + PI -> G1P
0
GBE1


UDPG -> UDP + GLYCOGEN
0
GYS1


MALm + NADm -> CO2m + NADHm + PYRm
0
ME2


MALm + NADPm -> CO2m + NADPHm + PYRm
0
ME3


MAL + NADP -> CO2 + NADPH + PYR
0
HUMNDME


NADHm + Qm + 4 Hm -> QH2m + NADm + 4 H
0
MTND1


SUCCm + FADm <-> FUMm + FADH2m
0
SDHC1


FADH2m + Qm <-> FADm + QH2m
0
SDHC2


O2m + 4 FEROm + 4 Hm -> 4 FERIm + 2 H2Om + 4 H
0
UQCRFS1


QH2m + 2 FERIm + 4 Hm -> Qm + 2 FEROm + 4 H
0
COX5BL4


ADPm + PIm + 3 H -> ATPm + 3 Hm + H2Om
0
MTAT1


ADP + ATPm + PI + H -> Hm + ADPm + ATP + PIm
0
ATPMC


GDP + GTPm + PI + H -> Hm + GDPm + GTP + PIm
0
GTPMC


PPI -> 2 PI
0
PP


GDP + ATP <-> GTP + ADP
0
NME1


ACCOA + ATP + CO2 <-> MALCOA + ADP + PI + H
0
ACACA


MALCOA + ACP <-> MALACP + COA
0
FAS1_1


ACCOA + ACP <-> ACACP + COA
0
FAS1_2


ACACP + 4 MALACP + 8 NADPH -> 8 NADP + C100ACP + 4 CO2 + 4 ACP
0
C100SY


ACACP + 5 MALACP + 10 NADPH -> 10 NADP + C120ACP + 5 CO2 + 5
0
C120SY


ACP


ACACP + 6 MALACP + 12 NADPH -> 12 NADP + C140ACP + 6 CO2 + 6
0
C140SY


ACP


ACACP + 6 MALACP + 11 NADPH -> 11 NADP + C141ACP + 6 CO2 + 6
0
C141SY


ACP


ACACP + 7 MALACP + 14 NADPH -> 14 NADP + C160ACP + 7 CO2 + 7
0
C160SY


ACP


ACACP + 7 MALACP + 13 NADPH -> 13 NADP + C161ACP + 7 CO2 + 7
0
C161SY


ACP


ACACP + 8 MALACP + 16 NADPH -> 16 NADP + C180ACP + 8 CO2 + 8
0
C180SY


ACP


ACACP + 8 MALACP + 15 NADPH -> 15 NADP + C181ACP + 8 CO2 + 8
0
C181SY


ACP


ACACP + 8 MALACP + 14 NADPH -> 14 NADP + C182ACP + 8 CO2 + 8
0
C182SY


ACP


C160ACP + H2O -> C160 + ACP
0
PPT1


C160 + COA + ATP -> AMP + PPI + C160COA
0
KIAA


C160COA + CAR -> C160CAR + COA
0
C160CA


C160CARm + COAm -> C160COAm + CARm
0
C160CB


C160CARm + COAm + FADm + NADm -> FADH2m + NADHm + C140COAM + ACCOAM
0
HADHA


C140COAm + 7 COAm + 7 FADm + 7 NADm -> 7 FADH2m + 7 NADHm + 7
0
HADH2


ACCOAm


TAGLYm + 3 H2Om -> GLm + 3 C160m
0
TAGRXN


GL3P + 0.017 C100ACP + 0.062 C120ACP + 0.1 C140ACP + 0.27
0
GAT1


C160ACP + 0.169 C161ACP + 0.055 C180ACP + 0.235 C181ACP + 0.093


C182ACP -> AGL3P + ACP


AGL3P + 0.017 C100ACP + 0.062 C120ACP + 0.100 C140ACP + 0.270
0
AGPAT1


C160ACP + 0.169 C161ACP + 0.055 C180ACP + 0.235 C181ACP + 0.093


C182ACP -> PA + ACP


ATP + CHO -> ADP + PCHO
0
CHKLT1


PCHO + CTP -> CDPCHO + PPI
0
PCYT1A


CDPCHO + DAGLY -> PC + CMP
0
LOC


SAM + PE -> SAH + PMME
0
PEMT


SAM + PMME -> SAH + PDME
0
MFPS


PDME + SAM -> PC + SAH
0
PNMNM


G6P -> MI1P
0
ISYNA1


MI1P -> MYOI + PI
0
IMPA1


PA + CTP <-> CDPDG + PPI
0
CDS1


CDPDG + MYOI -> CMP + PINS
0
PIS


ATP + PINS -> ADP + PINSP
0
PIK3CA


ATP + PINS -> ADP + PINS4P
0
PIK4CA


PINS4P + ATP -> D45PI + ADP
0
PIP5K1


D45PI -> TPI + DAGLY
0
PLCB2


PA + H2O -> DAGLY + PI
0
PPAP2A


DAGLY + 0.017 C100ACP + 0.062 C120ACP + 0.100 C140ACP + 0.270
0
DGAT


C160ACP + 0.169 C161ACP + 0.055 C180ACP + 0.235 C181ACP + 0.093


C182ACP -> TAGLY + ACP


CDPDG + SER <-> CMP + PS
0
PTDS


CDPETN + DAGLY <-> CMP + PE
0
CEPT1


PE + SER <-> PS + ETHM
0
PESER


ATP + ETHM -> ADP + PETHM
0
EKI1


PETHM + CTP -> CDPETN + PPI
0
PCYT2


PS -> PE + CO2
0
PISD


3HBm + NADm -> NADHm + Hm + ACTACm
0
BDH


ACTACm + SUCCOAm -> SUCCm + AACOAm
0
3OCT


THF + SER <-> GLY + METTHF
0
SHMT1


THFm + SERm <-> GLYm + METTHFm
0
SHMT2


SERm + PYRm <-> ALAm + 3HPm
0
AGXT


3PG + NAD <-> NADH + PHP
0
PHGDH


PHP + GLU <-> AKG + 3PSER
0
PSA


3PSER + H2O -> PI + SER
0
PSPH


3HPm + NADHm -> NADm + GLYAm
0
GLYD


SER -> PYR + NH3 + H2O
0
SDS


GLYAm + ATPm -> ADPm + 2PGm
0
GLTK


PYR + GLU <-> AKG + ALA
0
GPT


GLUm + CO2m + 2 ATPm -> 2 ADPm + 2 PIm + CAPm
0
CPS1


AKGm + NADHm + NH3m <-> NADm + H2Om + GLUm
0
GLUD1


AKGm + NADPHm + NH3m <-> NADPm + H2Om + GLUm
0
GLUD2


GLUm + NH3m + ATPm -> GLNm + ADPm + PIm
0
GLUL


ASPm + ATPm + GLNm -> GLUm + ASNm + AMPm + PPIm
0
ASNS


ORN + AKG <-> GLUGSAL + GLU
0
OAT


GLU <-> GLUm + Hm
0
GLUMT


GLU + ATP + NADPH -> NADP + ADP + PI + GLUGSAL
0
P5CS


GLUP + NADH -> NAD + PI + GLUGSAL
0
PYCS


P5C <-> GLUGSAL
0
SPTC


HIS -> NH3 + URO
0
HAL


URO + H2O -> 4I5P
0
UROH


4I5P + H2O -> FIGLU
0
IMPR


FIGLU + THF -> NFTHF + GLU
0
FTCD


MET + ATP + H2O -> PPI + PI + SAM
0
MAT1A


SAM + DNA -> SAH + DNA5MC
0
DNMT1


SAH + H2O -> HCYS + ADN
0
AHCYL1


HCYS + MTHF -> THF + MET
0
MTR


SER + HCYS -> LLCT + H2O
0
CBS


LLCT + H2O -> CYS + HSER
0
CTH1


OBUT + NH3 <-> HSER
0
CTH2


CYS + O2 <-> CYSS
0
CDO1


CYSS + AKG <-> GLU + SPYR
0
CYSAT


SPYR + H2O -> H2SO3 + PYR
0
SPTB


LYS + NADPH + AKG -> NADP + H2O + SAC
0
LKR1


SAC + H2O + NAD -> GLU + NADH + AASA
0
LKR2


AASA + NAD -> NADH + AADP
0
2ASD


AADP + AKG -> GLU + KADP
0
LOC5


TRP + O2 -> FKYN
0
TDO2


FKYN + H2O -> FOR + KYN
0
KYNF


KYN + NADPH + O2 -> HKYN + NADP + H2O
0
KMO


HKYN + H2O -> HAN + ALA
0
KYNU2


HAN + O2 -> CMUSA
0
HAAO


CMUSA -> CO2 + AM6SA
0
ACSD


AM6SA -> PIC
0
SPTA


AM6SA + NAD -> AMUCO + NADH
0
AMSD


AMUCO + NADPH -> KADP + NADP + NH4
0
2AMR


ARG -> ORN + UREA
0
ARG2


ORN + Hm -> ORNm
0
ORNMT


ORN + Hm + CITRm <-> CITR + ORNm
0
ORNCITT


ORNm + CAPm -> CITRm + Pim + Hm
0
OTC


CITR + ASP + ATP <-> AMP + PPI + ARGSUCC
0
ASS


ARGSUCC -> FUM + ARG
0
ASL


PRO + FAD -> P5C + FADH2
0
PRODH


P5C + NADPH -> PRO + NADP
0
PYCR1


THR -> NH3 + H2O + OBUT
0
WTDH


THR + NAD -> CO2 + NADH + AMA
0
TDH


AMA + H2O + FAD -> NH3 + FADH2 + MTHGXL
0
MAOA


GLYm + THFm + NADm <-> METTHFm + NADHm + CO2m + NH3m
0
AMT


PHE + THBP + O2 -> TYR + DHBP + H2O
0
PAH


NADPH + DHBP -> NADP + THBP
0
QDPR


AKG + TYR -> HPHPYR + GLU
0
TAT


HPHPYR + O2 -> HGTS + CO2
0
HPD


HGTS + O2 -> MACA
0
HGD


MACA -> FACA
0
GSTZ1


FACA + H2O -> FUM + ACA
0
FAH


AKG + ILE -> OMVAL + GLU
0
BCAT1A


OMVALm + COAm + NADm -> MBCOAm + NADHm + CO2m
0
BCKDHAA


MBCOAm + FADm -> MCCOAm + FADH2m
0
ACADMA


MCCOAm + H2Om -> MHVCOAm
0
ECHS1B


MHVCOAm + NADm -> MAACOAm + NADHm
0
EHHADHA


MAACOAm -> ACCOAm + PROPCOAm
0
ACAA2


2 ACCOAm <-> COAm + AACCOAm
0
ACATm1


AKG + VAL -> OIVAL + GLU
0
BCAT1B


OIVALm + COAm + NADm -> IBCOAm + NADHm + CO2m
0
BCKDHAB


IBCOAm + FADm -> MACOAm + FADH2m
0
ACADSB


MACOAm + H2Om -> HIBCOAm
0
EHHADHC


HIBCOAm + H2Om -> HIBm + COAm
0
HIBCHA


HIBm + NADm -> MMAm + NADHm
0
EHHADHB


MMAm + COAm + NADm -> NADHm + CO2m + PROPCOAm
0
MMSDH


PROPCOAm + CO2m + ATPm -> ADPm + PIm + DMMCOAm
0
PCCA


DMMCOAm -> LMMCOAm
0
HIBCHF


LMMCOAm -> SUCCOAm
0
MUT


AKG + LEU -> OICAP + GLU
0
BCAT1C


OICAPm + COAm + NADm -> IVCOAm + NADHm + CO2m
0
BCKDHAC


OICAPm + COAm + NADH -> IVCOAm + NADHm + CO2m
0
BCKDHBC


OICAPm + COAm + NADHm -> IVCOAm + NADHm + CO2m
0
DBTC


IVCOAm + FADm -> MCRCOAm + FADH2m
0
IVD


MCRCOAm + ATPm + CO2m + H2Om -> MGCOAm + ADPm + Pim
0
MCCC1


MGCOAm + H2Om -> H3MCOAm
0
HIBCHB


H3MCOAm -> ACCOAm + ACTACm
0
HMGCL


MYOACT + ATP -> MYOATP + ACTIN
0
MYOSA


MYOATP + ACTIN -> MYOADPAC
0
MYOSB


MYOADPAC -> ADP + PI + MYOACT + CONTRACT
0
MYOSC


PCRE + ADP -> CRE + ATP
0
CREATA


AMP + H2O -> PI + ADN
0
CREATB


ATP + AMP <-> 2 ADP
0
CREATC


O2 <-> O2m
0
O2MT


3HB -> 3HBm
0
HBMT


CIT + MALm <-> CITm + MAL
0
CITMC


PYR <-> PYRm + Hm
0
PYRMC


C160CAR + COAm -> C160COAm + CAR
0
C160CM


OMVAL -> OMVALm
0
HIBCHC


OIVAL -> OIVALm
0
HIBCHD


OICAP -> OICAPm
0
HIBCHE


GL <-> GLm
0
GLMT


GL3Pm + FADm -> T3P2m + FADH2m
0
GPD2


T3P2 + NADH <-> GL3P + NAD
0
GPD1


GL3P <-> GL3Pm
0
GL3PMC


T3P2 <-> T3P2m
0
T3P2MC


OAm + GLUm <-> ASPm + AKGm
0
GOT1


OA + GLU <-> ASP + AKG
0
GOT2


AKG + MALm <-> AKGm + MAL
0
MALMC


ASPm + GLU + H -> Hm + GLUm + ASP
0
ASPMC


GLCxt -> GLC
0
GLUT4


O2xt -> O2
0
O2UP


C160Axt + FABP -> C160FP + ALBxt
0
FAT1


C160FP -> C160 + FABP
0
FAT2


C180Axt + FABP -> C180FP + ALBxt
0
FAT3


C180FP -> C180 + FABP
0
FAT4


C161Axt + FABP -> C161FP + ALBxt
0
FAT5


C161FP -> C161 + FABP
0
FAT6


C181Axt + FABP -> C181FP + ALBxt
0
FAT7


C181FP -> C181 + FABP
0
FAT8


C182Axt + FABP -> C182FP + ALBxt
0
FAT9


C182FP -> C182 + FABP
0
FAT10


C204Axt + FABP -> C204FP + ALBxt
0
FAT11


C204FP -> C204 + FABP
0
FAT12


PYRxt + HEXT <-> PYR + H
0
PYRUP


LACxt + HEXT <-> LAC + HEXT
0
LACUP


H <-> HEXT
0
HextUP


CO2 <-> CO2m
0
CO2MT


H2O <-> H2Om
0
H2OMT


ATP + AC + COA -> AMP + PPI + ACCOA
0
FLJ2


C160CAR <-> C160CARm
0
C160MT


CARm <-> CAR
0
CARMT


CO2xt <-> CO2
0
CO2UP


H2Oxt <-> H2O
0
H2OUP


PIxt + HEXT <-> HEXT + PI
0
PIUP


<-> GLCxt
0
GLCexR


<-> PYRxt
0
PYRexR


<-> CO2xt
0
CO2exR


<-> O2xt
0
O2exR


<-> PIxt
0
PlexR


<-> H2Oxt
0
H2OexR


<-> LACxt
0
LACexR


<-> C160Axt
0
C160AexR


<-> C161Axt
0
C161AexR


<-> C180Axt
0
C180AexR


<-> C181Axt
0
C181AexR


<-> C182Axt
0
C182AexR


<-> C204Axt
0
C204AexR


<-> ALBxt
0
ALBexR


<-> 3HB
0
HBexR


<-> GLYCOGEN
0
GLYex


<-> PCRE
0
PCREex


<-> TAGLYm
0
TAGmex


<-> ILE
0
ILEex


<-> VAL
0
VALex


<-> CRE
0
CREex


<-> ADN
0
ADNex


<-> PI
0
Plex
















TABLE 5





Human Cell Types















Keratinizing epithelial cells


Epidermal keratinocyte (differentiating epidermal cell)


Epidermal basal cell (stem cell)


Keratinocyte of fingernails and toenails


Nail bed basal cell (stem cell)


Medullary hair shaft cell


Cortical hair shaft cell


Cuticular hair shaft cell


Cuticular hair root sheath cell


Hair root sheath cell of Huxley's layer


Hair root sheath cell of Henle's layer


External hair root sheath cell


Hair matrix cell (stem cell)


Wet stratified barrier epithelial cells


Surface epithelial cell of stratified squamous epithelium of cornea, tongue, oral cavity,


esophagus, anal canal, distal urethra and vagina


basal cell (stem cell) of epithelia of cornea, tongue, oral cavity, esophagus, anal canal, distal


urethra and vagina


Urinary epithelium cell (lining urinary bladder and urinary ducts)


Exocrine secretory epithelial cells


Salivary gland mucous cell (polysaccharide-rich secretion)


Salivary gland serous cell (glycoprotein enzyme-rich secretion)


Von Ebner's gland cell in tongue (washes taste buds)


Mammary gland cell (milk secretion)


Lacrimal gland cell (tear secretion)


Ceruminous gland cell in ear (wax secretion)


Eccrine sweat gland dark cell (glycoprotein secretion)


Eccrine sweat gland clear cell (small molecule secretion)


Apocrine sweat gland cell (odoriferous secretion, sex-hormone sensitive)


Gland of Moll cell in eyelid (specialized sweat gland)


Sebaceous gland cell (lipid-rich sebum secretion)


Bowman's gland cell in nose (washes olfactory epithelium)


Brunner's gland cell in duodenum (enzymes and alkaline mucus)


Seminal vesicle cell (secretes seminal fluid components, including fructose for swimming


sperm)


Prostate gland cell (secretes seminal fluid components)


Bulbourethral gland cell (mucus secretion)


Bartholin's gland cell (vaginal lubricant secretion)


Gland of Littre cell (mucus secretion)


Uterus endometrium cell (carbohydrate secretion)


Isolated goblet cell of respiratory and digestive tracts (mucus secretion)


Stomach lining mucous cell (mucus secretion)


Gastric gland zymogenic cell (pepsinogen secretion)


Gastric gland oxyntic cell (hydrogen chloride secretion)


Pancreatic acinar cell (bicarbonate and digestive enzyme secretion)


Paneth cell of small intestine (lysozyme secretion)


Type II pneumocyte of lung (surfactant secretion)


Clara cell of lung


Hormone secreting cells


Anterior pituitary cells


Somatotropes


Lactotropes


Thyrotropes


Gonadotropes


Corticotropes


Intermediate pituitary cell, secreting melanocyte-stimulating hormone


Magnocellular neurosecretory cells


secreting oxytocin


secreting vasopressin


Gut and respiratory tract cells secreting serotonin


secreting endorphin


secreting somatostatin


secreting gastrin


secreting secretin


secreting cholecystokinin


secreting insulin


secreting glucagon


secreting bombesin


Thyroid gland cells


thyroid epithelial cell


parafollicular cell


Parathyroid gland cells


Parathyroid chief cell


oxyphil cell


Adrenal gland cells


chromaffin cells


secreting steroid hormones (mineralcorticoids and gluco corticoids)


Leydig cell of testes secreting testosterone


Theca interna cell of ovarian follicle secreting estrogen


Corpus luteum cell of ruptured ovarian follicle secreting progesterone


Kidney juxtaglomerular apparatus cell (renin secretion)


Macula densa cell of kidney


Peripolar cell of kidney


Mesangial cell of kidney


Epithelial absorptive cells (Gut, Exocrine Glands and Urogenital Tract)


Intestinal brush border cell (with microvilli)


Exocrine gland striated duct cell


Gall bladder epithelial cell


Kidney proximal tubule brush border cell


Kidney distal tubule cell


Ductulus efferens nonciliated cell


Epididymal principal cell


Epididymal basal cell


Metabolism and storage cells


Hepatocyte (liver cell)


White fat cell


Brown fat cell


Liver lipocyte


Barrier function cells (Lung, Gut, Exocrine Glands and Urogenital Tract)


Type I pneumocyte (lining air space of lung)


Pancreatic duct cell (centroacinar cell)


Nonstriated duct cell (of sweat gland, salivary gland, mammary gland, etc.)


Kidney glomerulus parietal cell


Kidney glomerulus podocyte


Loop of Henle thin segment cell (in kidney)


Kidney collecting duct cell


Duct cell (of seminal vesicle, prostate gland, etc.)


Epithelial cells lining closed internal body cavities


Blood vessel and lymphatic vascular endothelial fenestrated cell


Blood vessel and lymphatic vascular endothelial continuous cell


Blood vessel and lymphatic vascular endothelial splenic cell


Synovial cell (lining joint cavities, hyaluronic acid secretion)


Serosal cell (lining peritoneal, pleural, and pericardial cavities)


Squamous cell (lining perilymphatic space of ear)


Squamous cell (lining endolymphatic space of ear)


Columnar cell of endolymphatic sac with microvilli (lining endolymphatic space of ear)


Columnar cell of endolymphatic sac without microvilli (lining endolymphatic space of ear)


Dark cell (lining endolymphatic space of ear)


Vestibular membrane cell (lining endolymphatic space of ear)


Stria vascularis basal cell (lining endolymphatic space of ear)


Stria vascularis marginal cell (lining endolymphatic space of ear)


Cell of Claudius (lining endolymphatic space of ear)


Cell of Boettcher (lining endolymphatic space of ear)


Choroid plexus cell (cerebrospinal fluid secretion)


Pia-arachnoid squamous cell


Pigmented ciliary epithelium cell of eye


Nonpigmented ciliary epithelium cell of eye


Corneal endothelial cell


Ciliated cells with propulsive function


Respiratory tract ciliated cell


Oviduct ciliated cell (in female)


Uterine endometrial ciliated cell (in female)


Rete testis cilated cell (in male)


Ductulus efferens ciliated cell (in male)


Ciliated ependymal cell of central nervous system (lining brain cavities)


Extracellular matrix secretion cells


Ameloblast epithelial cell (tooth enamel secretion)


Planum semilunatum epithelial cell of vestibular apparatus of ear (proteoglycan secretion)


Organ of Corti interdental epithelial cell (secreting tectorial membrane covering hair cells)


Loose connective tissue fibroblasts


Corneal fibroblasts


Tendon fibroblasts


Bone marrow reticular tissue fibroblasts


Other nonepithelial fibroblasts


Blood capillary pericyte


Nucleus pulposus cell of intervertebral disc


Cementoblast/cementocyte (tooth root bonelike cementum secretion)


Odontoblast/odontocyte (tooth dentin secretion)


Hyaline cartilage chondrocyte


Fibrocartilage chondrocyte


Elastic cartilage chondrocyte


Osteoblast/osteocyte


Osteoprogenitor cell (stem cell of osteoblasts)


Hyalocyte of vitreous body of eye


Stellate cell of perilymphatic space of ear


Contractile cells


Red skeletal muscle cell (slow)


White skeletal muscle cell (fast)


Intermediate skeletal muscle cell


nuclear bag cell of Muscle spindle


nuclear chain cell of Muscle spindle


Satellite cell (stem cell)


Ordinary heart muscle cell


Nodal heart muscle cell


Purkinje fiber cell


Smooth muscle cell (various types)


Myoepithelial cell of iris


Myoepithelial cell of exocrine glands


Red Blood Cell


Blood and immune system cells


Erythrocyte (red blood cell)


Megakaryocyte (platelet precursor)


Monocyte


Connective tissue macrophage (various types)


Epidermal Langerhans cell


Osteoclast (in bone)


Dendritic cell (in lymphoid tissues)


Microglial cell (in central nervous system)


Neutrophil granulocyte


Eosinophil granulocyte


Basophil granulocyte


Mast cell


Helper T cell


Suppressor T cell


Cytotoxic T cell


B cells


Natural killer cell


Reticulocyte


Stem cells and committed progenitors for the blood and immune system (various types)


Sensory transducer cells


Photoreceptor rod cell of eye


Photoreceptor blue-sensitive cone cell of eye


Photoreceptor green-sensitive cone cell of eye


Photoreceptor red-sensitive cone cell of eye


Auditory inner hair cell of organ of Corti


Auditory outer hair cell of organ of Corti


Type I hair cell of vestibular apparatus of ear (acceleration and gravity)


Type II hair cell of vestibular apparatus of ear (acceleration and gravity)


Type I taste bud cell


Olfactory receptor neuron


Basal cell of olfactory epithelium (stem cell for olfactory neurons)


Type I carotid body cell (blood pH sensor)


Type II carotid body cell (blood pH sensor)


Merkel cell of epidermis (touch sensor)


Touch-sensitive primary sensory neurons (various types)


Cold-sensitive primary sensory neurons


Heat-sensitive primary sensory neurons


Pain-sensitive primary sensory neurons (various types)


Proprioceptive primary sensory neurons (various types)


Autonomic neuron cells


Cholinergic neural cell (various types)


Adrenergic neural cell (various types)


Peptidergic neural cell (various types)


Sense organ and peripheral neuron supporting cells


Inner pillar cell of organ of Corti


Outer pillar cell of organ of Corti


Inner phalangeal cell of organ of Corti


Outer phalangeal cell of organ of Corti


Border cell of organ of Corti


Hensen cell of organ of Corti


Vestibular apparatus supporting cell


Type I taste bud supporting cell


Olfactory epithelium supporting cell


Schwann cell


Satellite cell (encapsulating peripheral nerve cell bodies)


Enteric glial cell


Central nervous system neurons and glial cells


Neuron cells (large variety of types, still poorly classified)


Astrocyte (various types)


Oligodendrocyte


Lens cells


Anterior lens epithelial cell


Crystallin-containing lens fiber cell


Pigment cells


Melanocyte


Retinal pigmented epithelial cell


Germ cells


Oogonium/Oocyte


Spermatid


Spermatocyte


Spermatogonium cell (stem cell for spermatocyte)


Spermatozoon


Nurse cells


Ovarian follicle cell


Sertoli cell (in testis)


Thymus epithelial cell
















TABLE 6







Human Tissues












Epithelial Tissue



  Unilaminar (simple) epithelia



    Squamous



    Cuboidal



    Columnar



    Sensory



    Myoepitheliocyte



  Multilaminar eipithelia



    Replacing or stratified squamous epithelia



    Stratified cuboidal and columnar eipithelia



  Urothelium (transitional epithelium)



    Seminiferous eipthelium



  Glands



    Exocrine glands



      Ducts and Tubules



    Endocrine glands



Nervous Tissue



  Neurons



    Multipolar Neurons in CNS



  Nerves



    Nerves of the PNS



  Receptors



    Miessner's and Pacinian Corpuscles



Connective Tissues



  Fluid Connective Tissues



    Lymph



    Blood



  Connective Tissues Proper



    Loose Connective Tissues



      Areolar



    Loose Connective Tissues and Inflammation



      Adipose



      Reticular



    Dense Connective Tissues



      Regular(collagen)



      Irregular(collagen)



      Regular(elastic)



  Supportive Connective Tissues



    Osseous Tissue



      Compact



      Cancellous



    Cartilage



      Hyaline



      Elastic



      Fibrocartilage



Muscle Tissue



  Non-striated



    Smooth Muscle



  Striated



    Skeletal Muscle



    Cardiac Muscle













Systems
Major Structures
Functions





Skeletal
Bones, cartilage, tendons, ligaments, and joints
provides structure; supports and protects internal organs


Muscular
Muscles (skeletal, cardiac, and smooth)
provides structure; supports and moves trunk and limbs; moves




substances through body


Integumentary
Skin, hair nails, breast
protects against pathogens; helps regulate body temperature


Circulatory
Heart, blood vessels, blood
transports nutrients and wastes to and from all body tissues


Respiratory
Trachea, air passages, lungs
carries air into and out of lungs, where gases (oxygen and carbon




dioxide) are exchanged


Immune
Lymph nodes and vessels, white blood cells
provides protection against infection and disease


Digestive
Mouth, esophagus, stomach, liver, pancreas,
stores and digests food; absorbs nutrients; eliminates waste



duodenum, jejunum, ileum, caecum,



rectum, gallbladder, pancreas,



small and large intestines


Excretory and Urinary
Kidneys, ureters, bladder, urethra
eliminate waste; maintains water and chemical balance


Nervous
Brain, spinal cord, nerves, sense organs,
controls and coordinates body movements and senses; controls



receptors, dorsal root ganglion
consciousness and creativity; helps monitor and maintain other body




systems


Endocrine
Endocrine glands, pineal gland, pituitary gland,
maintain homeostasis; regulates metabolism, water and mineral



adrenal gland, thyroid gland, and hormones
balance, growth and sexual development, and reproduction


Lymphatic
Lymph nodes, spleen, lymph vessels
cleans and returns tissue fluid to the blood and destroys pathogens that




enter the body


Reproductive
Ovaries, uterus, fallopian tube, mammary glands
produce gametes and offspring



(in females), vas deferens, prostate, testes (in males),



umbilical cord, placenta
















TABLE 7





Cells of the Liver

















Hepatocytes



Perisinusoidal (Ito) cells



Endotheliocytes



Macrophages (Kupffer cells)



Lymphocytes (pit cells)



Cells of the biliary tree



Cuboidal epitheliocytes



Columnar epitheliocytes



Connective tissue cells

















TABLE 15







Adipocyte-myocyte reactions











Reaction



Protein


Abbreviation
Reaction Name
Equation
Subsystem
Classification





G6PASEer_ac
glucose-6-phosphatase
[f]: g6p + h2o --> glc-D + pi
Glycolysis/Gluconeogenesis
EC-3.1.3.9


G6PASEer_mc
glucose-6-phosphatase
[u]: g6p + h2o --> glc-D + pi
Glycolysis/Gluconeogenesis
EC-3.1.3.9


PFK26_ac
6-phosphofructo-2-kinase
[a]: atp + f6p --> adp + f26bp + h
Glycolysis/Gluconeogenesis
EC-2.7.1.105


PGI_ac
glucose-6-phosphate
[a]: g6p <==> f6p
Glycolysis/Gluconeogenesis
EC-5.3.1.9



isomerase


PGK_ac
phosphoglycerate kinase
[a]: 13dpg + adp <==> 3pg + atp
Glycolysis/Gluconeogenesis
EC-2.7.2.3


PGM_ac
phosphoglycerate mutase
[a]: 3pg <==> 2pg
Glycolysis/Gluconeogenesis
EC-5.4.2.1


PYK_ac
pyruvate kinase
[a]: adp + h + pep --> atp + pyr
Glycolysis/Gluconeogenesis
EC-2.7.1.40


TPI_ac
triose-phosphate
[a]: dhap <==> g3p
Glycolysis/Gluconeogenesis
EC-5.3.1.1



isomerase


ACONTm_ac
Aconitate hydratase
[b]: cit <==> icit
Central Metabolism
EC-4.2.1.3


ACONTm_mc
Aconitate hydratase
[z]: cit <==> icit
Central Metabolism
EC-4.2.1.3


AKGDm_ac
2-oxoglutarate
[b]: akg + coa + nad --> co2 + nadh + succoa
Central Metabolism



dehydrogenase,



mitochondrial


AKGDm_mc
2-oxoglutarate
[z]: akg + coa + nad --> co2 + nadh + succoa
Central Metabolism



dehydrogenase,



mitochondrial


CITL2_ac
Citrate lyase (ATP-
[a]: atp + cit + coa --> accoa + adp + oaa + pi
Central Metabolism
EC-4.1.3.8



requiring)


CITL2_mc
Citrate lyase (ATP-
[y]: atp + cit + coa --> accoa + adp + oaa + pi
Central Metabolism
EC-4.1.3.8



requiring)


CSm_ac
citrate synthase
[b]: accoa + h2o + oaa --> cit + coa + h
Central Metabolism
EC-4.1.3.7


CSm_mc
citrate synthase
[z]: accoa + h2o + oaa --> cit + coa + h
Central Metabolism
EC-4.1.3.7


ENO_ac
enolase
[a]: 2pg <==> h2o + pep
Central Metabolism
EC-4.2.1.11


ENO_mc
enolase
[y]: 2pg <==> h2o + pep
Central Metabolism
EC-4.2.1.11


FBA_ac
fructose-bisphosphate
[a]: fdp <==> dhap + g3p
Central Metabolism
EC-4.1.2.13



aldolase


FBA_mc
fructose-bisphosphate
[y]: fdp <==> dhap + g3p
Central Metabolism
EC-4.1.2.13



aldolase


F8P26_ac
Fructose-2,6-
[a]: f26bp + h2o --> f6p + pi
Central Metabolism
EC-3.1.3.46



bisphosphate 2-



phosphatase


FBP26_mc
Fructose-2,6-
[y]: f26bp + h2o --> f6p + pi
Central Metabolism
EC-3.1.3.46



bisphosphate 2-



phosphatase


FBP_ac
fructose-bisphosphatase
[a]: fdp + h2o --> f6p + pi
Central Metabolism
EC-3.1.3.11


FBP_mc
fructose-bisphosphatase
[y]: fdp + h2o --> f6p + pi
Central Metabolism
EC-3.1.3.11


FUMm_ac
fumarase, mitochondrial
[b]: fum + h2o <==> mal-L
Central Metabolism
EC-4.2.1.2


FUMm_mc
fumarase, mitochondrial
[z]: fum + h2o <==> mal-L
Central Metabolism
EC-4.2.1.2


G3PD1_ac
glycerol-3-phosphate
[a]: glyc3p + nad <==> dhap + h + nadh
Central Metabolism
EC-1.1.1.94



dehydrogenase (NAD),



adipocyte


G3PD_mc
Glycerol-3-phosphate
[y]: dhap + h + nadh --> glyc3p + nad
Central Metabolism
EC-1.1.1.8



dehydrogenase (NAD)


G3PDm_ac
glycerol-3-phosphate
[b]: fad + glyc3p --> dhap + fadh2
Central Metabolism
EC-1.1.99.5



dehydrogenase


G3PDm_mc
glycerol-3-phosphate
[z]: fad + glyc3p --> dhap + fadh2
Central Metabolism
EC-1.1.99.5



dehydrogenase


G6PDH_ac
glucose 6-phosphate
[a]: g6p + nadp --> 6pgl + h + nadph
Central Metabolism
EC-1.1.1.49



dehydrogenase


G6PDH_mc
glucose 6-phosphate
[y]: g6p + nadp --> 6pgl + h + nadph
Central Metabolism
EC-1.1.1.49



dehydrogenase


GAPD_ac
glyceraldehyde-3-
[a]: g3p + nad + pi <==> 13dpg + h + nadh
Central Metabolism
EC-1.2.1.12



phosphate dehydrogenase



(NAD)


GAPD_mc
glyceraldehyde-3-
[y]: g3p + nad + pi <==> 13dpg + h + nadh
Central Metabolism
EC-1.2.1.12



phosphate dehydrogenase



(NAD)


GL3Ptm_ac
glycerol-3-phosphate
glyc3p[a] <==> glyc3p[b]
Central Metabolism



transport, adipocyte



mitochondrial


GLCP_ac
glycogen phosphorylase
[a]: glycogen + pi --> g1p
Central Metabolism
EC-2.4.1.1


HCO3Em_ac
HCO3 equilibration
[b]: co2 + h2o <==> h + hco3
Central Metabolism
EC-4.2.1.1



reaction, mitochondrial


HCO3Em_mc
HCO3 equilibration
[z]: co2 + h2o <==> h + hco3
Central Metabolism
EC-4.2.1.1



reaction, mitochondrial


HEX1_ac
hexokinase (D-
[a]: atp + glc-D --> adp + g6p + h
Central Metabolism
EC-2.7.1.2



glucose:ATP)


HEX1_mc
hexokinase (D-
[y]: atp + glc-D --> adp + g6p + h
Central Metabolism
EC-2.7.1.2



glucose:ATP)


ICDHxm_ac
Isocitrate dehydrogenase
[b]: icit + nad --> akg + co2 + nadh
Central Metabolism
EC-1.1.1.41



(NAD+)


ICDHxm_mc
Isocitrate dehydrogenase
[z]: icit + nad --> akg + co2 + nadh
Central Metabolism
EC-1.1.1.41



(NAD+)


ICDHym_ac
Isocitrate dehydrogenase
[b]: icit + nadp --> akg + co2 + nadph
Central Metabolism
EC-1.1.1.42



(NADP+)


ICDHym_mc
Isocitrate dehydrogenase
[z]: icit + nadp --> akg + co2 + nadph
Central Metabolism
EC-1.1.1.42



(NADP+)


LDH_L_mc
L-lactate dehydrogenase
[y]: lac-L + nad <==> h + nadh + pyr
Central Metabolism
EC-1.1.1.27


MDH_ac
malate dehydrogenase
[a]: mal-L + nad <==> h + nadh + oaa
Central Metabolism
EC-1.1.1.37


MDH_mc
malate dehydrogenase
[y]: mal-L + nad <==> h + nadh + oaa
Central Metabolism
EC-1.1.1.37


MDHm_ac
malate dehydrogenase,
[b]: mal-L + nad <==> h + nadh + oaa
Central Metabolism
EC-1.1.1.37



mitochondrial


MDHm_mc
malate dehydrogenase,
[z]: mal-L + nad <==> h + nadh + oaa
Central Metabolism
EC-1.1.1.37



mitochondrial


ME1m_ac
malic enzyme (NAD),
[b]: mal-L + nad --> co2 + nadh + pyr
Central Metabolism
EC-1.1.1.38



mitochondrial


ME1m_mc
malic enzyme (NAD),
[z]: mal-L + nad --> co2 + nadh + pyr
Central Metabolism
EC-1.1.1.38



mitochondrial


ME2_ac
malic enzyme (NADP)
[a]: mal-L + nadp --> co2 + nadph + pyr
Central Metabolism
EC-1.1.1.40


ME2_mc
malic enzyme (NADP)
[y]: mal-L + nadp --> co2 + nadph + pyr
Central Metabolism
EC-1.1.1.40


ME2m_ac
malic enzyme (NADP),
[b]: mal-L + nadp --> co2 + nadph + pyr
Central Metabolism
EC-1.1.1.40



mitochondrial


ME2m_mc
malic enzyme (NADP),
[z]: mal-L + nadp --> co2 + nadph + pyr
Central Metabolism
EC-1.1.1.40



mitochondrial


PCm_mc
pyruvate carboxylase,
[z]: atp + hco3 + pyr --> adp + h + oaa + pi
Central Metabolism
EC-6.4.1.1



mitochondrial


PDHm_mc
pyruvate dehydrogenase,
[z]: coa + nad + pyr --> accoa + co2 + nadh
Central Metabolism
EC-1.2.1.51



mitochondrial


PFK26_mc
6-phosphofructo-2-kinase
[y]: atp + f6p --> adp + f26bp + h
Central Metabolism
EC-2.7.1.105


PFK_ac
phosphofructokinase
[a]: atp + f6p --> adp + fdp + h
Central Metabolism
EC-2.7.1.11


PFK_mc
phosphofructokinase
[y]: atp + f6p --> adp + fdp + h
Central Metabolism
EC-2.7.1.11


PGDH_mc
phosphogluconate
[y]: 6pgc + nadp --> co2 + nadph + ru5p-D
Central Metabolism
EC-1.1.1.44



dehydrogenase


PGI_mc
glucose-6-phosphate
[y]: g6p <==> f6p
Central Metabolism
EC-5.3.1.9



isomerase


PGK_mc
phosphoglycerate kinase
[y]: 13dpg + adp <==> 3pg + atp
Central Metabolism
EC-2.7.2.3


PGL_mc
6-
[y]: 6pgl + h2o --> 6pgc + h
Central Metabolism
EC-3.1.1.31



phosphogluconolactonase


PGM_mc
phosphoglycerate mutase
[y]: 3pg <==> 2pg
Central Metabolism
EC-5.4.2.1


PPA_ac
inorganic diphosphatase
[a]: h2o + ppi --> h + (2) pi
Central Metabolism
EC-3.6.1.1


PPA_mc
inorganic diphosphatase
[y]: h2o + ppi --> h + (2) pi
Central Metabolism
EC-3.6.1.1


PPCKG_ac
phosphoenolpyruvate
[a]: gtp + oaa --> co2 + gdp + pep
Central Metabolism
EC-4.1.1.32



carboxykinase (GTP)


PPCKG_mc
phosphoenolpyruvate
[y]: gtp + oaa --> co2 + gdp + pep
Central Metabolism
EC-4.1.1.32



carboxykinase (GTP)


PYK_mc
pyruvate kinase
[y]: adp + h + pep --> atp + pyr
Central Metabolism
EC-2.7.1.40


RPE_mc
ribulose 5-phosphate 3-
[y]: ru5p-D <==> xu5p-D
Central Metabolism
EC-5.1.3.1



epimerase


RPI_mc
ribose-5-phosphate
[y]: r5p <==> ru5p-D
Central Metabolism
EC-5.3.1.6



isomerase


SUCD1m_mc
succinate dehydrogenase
[z]: succ + ubq <==> fum + qh2
Central Metabolism
EC-1.3.5.1


SUCD3m_mc
succinate dehydrogenase
[z]: fadh2 + ubq <==> fad + qh2
Central Metabolism



cytochrome b


SUCOASAm_mc
Succinate—CoA ligase
[z]: atp + coa + succ <==> adp + pi + succoa
Central Metabolism
EC-6.2.1.4



(ADP-forming)


SUCOASGm_mc
Succinate—CoA ligase
[z]: coa + gtp + succ <==> gdp + pi + succoa
Central Metabolism
EC-6.2.1.4



(GDP-forming)


TAL_mc
transaldolase
[y]: g3p + s7p <==> e4p + f6p
Central Metabolism
EC-2.2.1.2


TKT1_mc
transketolase
[y]: r5p + xu5p-D <==> g3p + s7p
Central Metabolism
EC-2.2.1.1


TKT2_mc
transketolase
[y]: e4p + xu5p-D <==> f6p + g3p
Central Metabolism
EC-2.2.1.1


TPI_mc
triose-phosphate
[y]: dhap <==> g3p
Central Metabolism
EC-5.3.1.1



isomerase


SUCOASAm_ac
Succinate—CoA ligase
[b]: atp + coa + succ <==> adp + pi + succoa
Citrate Cycle (TCA)
EC-6.2.1.4



(ADP-forming)


SUCOASGm_ac
Succinate—CoA ligase
[b]: coa + gtp + succ <==> gdp + pi + succoa
Citrate Cycle (TCA)
EC-6.2.1.4



(GDP-forming)


PGDH_ac
phosphogluconate
[a]: 6pgc + nadp --> co2 + nadph + ru5p-D
Pentose Phosphate
EC-1.1.1.44



dehydrogenase

Cycle


PGL_ac
6-
[a]: 6pgl + h2o --> 6pgc + h
Pentose Phosphate
EC-3.1.1.31



phosphogluconolactonase

Cycle


RPE_ac
ribulose 5-phosphate 3-
[a]: ru5p-D <==> xu5p-D
Pentose Phosphate
EC-5.1.3.1



epimerase

Cycle


RPI_ac
ribose-5-phosphate
[a]: r5p <==> ru5p-D
Pentose Phosphate
EC-5.3.1.6



isomerase

Cycle


TAL_ac
transaldolase
[a]: g3p + s7p <==> e4p + f6p
Pentose Phosphate
EC-2.2.1.2





Cycle


TKT1_ac
transketolase
[a]: r5p + xu5p-D <==> g3p + s7p
Pentose Phosphate
EC-2.2.1.1





Cycle


TKT2_ac
transketolase
[a]: e4p + xu5p-D <==> f6p + g3p
Pentose Phosphate
EC-2.2.1.1





Cycle


PCm_ac
pyruvate carboxylase,
[b]: atp + hco3 + pyr --> adp + h + oaa + pi
Pyruvate metabolism
EC-6.4.1.1



mitochondrial


PDHm_ac
pyruvate dehydrogenase,
[b]: coa + nad + pyr --> accoa + co2 + nadh
Pyruvate metabolism
EC-1.2.1.51



mitochondrial


ATPM_ac
ATP maintenance
[a]: atp + h2o --> adp + h + pi
Energy Metabolism



requirment


ATPM_mc
ATP maintenance
[y]: atp + h2o --> adp + h + pi
Energy Metabolism



requirment


ATPS4m_ac
ATP synthase, adipocyte
adp[b] + (4) h[a] + pi[b] --> atp[b] + (3) h[b] +
Energy Metabolism
EC-3.6.1.14,



mitochondrial
h2o[b]


ATPS4m_mc
ATP synthase, myocyte
adp[z] + (4) h[y] + pi[z] --> atp[z] + (3) h[z] +
Energy Metabolism
EC-3.6.1.14,



mitochondrial
h2o[y]


ATPSis_ac
ATPase, adipocyte
atp[a] + h2o[a] --> adp[a] + h[i] + pi[a]
Energy Metabolism
EC-3.6.3.6,



cytosolic


ATPSis_mc
ATPase, myocyte
atp[y] + h2o[y] --> adp[y] + h[c] + pi[y]
Energy Metabolism
EC-3.6.3.6,



cytosolic


CREATK_mc
creatine kinase, myocyte
[y]: atp + creat <==> adp + creatp
Energy Metabolism
EC-2.7.3.2



cytosol


CREATPD_mc
creatine phosphate
[y]: creatp --> crtn + h + pi
Energy Metabolism



dephosphorylation,



spontaneous


CYOO4m_ac
cytochrome c oxidase
(4) focytc[b] + (8) h[b] + o2[b] -->
Energy Metabolism
EC-1.9.3.1,



(adipocyte mitochondrial 4
(4) ficytc[b] + (4) h[a] + (2) h2o[b]



protons)


CYOO4m_mc
cytochrome c oxidase
(4) focytc[z] + (8) h[z] + o2[z] -->
Energy Metabolism
EC-1.9.3.1,



(myocyte mitochondrial 4
(4) ficytc[z] + (4) h[y] + (2) h2o[z]



protons)


CYOR4m_ac
ubiquinol cytochrome c
(2) ficytc[b] + (2) h[b] + qh2[b] -->
Energy Metabolism
EC-1.10.2.2,



reductase, adipocyte
(2) focytc[b] + (4) h[a] + ubq[b]


CYOR4m_mc
ubiquinol cytochrome c
(2) ficytc[z] + (2) h[z] + qh2[z] -->
Energy Metabolism
EC-1.10.2.2,



reductase, myocyte
(2) focytc[z] + (4) h[y] + ubq[z]


NADH4m_mc
NADH dehydrogenase,
(5) h[z] + nadh[z] + ubq[z] --> (4)
Energy Metabolism
EC-1.6.99.3,



mitochondrial
h[y] + nad[z] + qh2[z]


NADH4m_ac
NADH dehydrogenase,
(5) h[b] + nadh[b] + ubq[b] --> (4)
Oxidative
EC-1.6.99.3,



adipocyte mitochondrial
h[a] + nad[b] + qh2[b]
phosphorylation


SUCD1m_ac
succinate dehydrogenase
[b]: succ + ubq <==> fum + qh2
Oxidative
EC-1.3.5.1





phosphorylation


SUCD3m_ac
succinate dehydrogenase
[b]: fadh2 + ubq <==> fad + qh2
Oxidative



cytochrome b

phosphorylation


GALUi_ac
UTP-glucose-1-phosphate
[a]: g1p + h + utp --> ppi + udpg
Galactose metabolism
EC-2.7.7.9



uridylyltransferase



(irreversible)


PGMT_ac
phosphoglucomutase
[a]: g1p <==> g6p
Galactose metabolism
EC-5.4.2.2


GALUi_mc
UTP-glucose-1-phosphate
[y]: g1p + h + utp --> ppi + udpg
Carbohydrate
EC-2.7.7.9



uridylyltransferase

Metabolism



(irreversible)


GLCP_mc
glycogen phosphorylase
[y]: glycogen + pi --> g1p
Carbohydrate
EC-2.4.1.1





Metabolism


GLYGS_ac
glycogen synthase
[a]: udpg --> glycogen + h + udp
Carbohydrate
EC-2.4.1.11



(UDPGlc)

Metabolism


GLYGS_mc
glycogen synthase
[y]: udpg --> glycogen + h + udp
Carbohydrate
EC-2.4.1.11



(UDPGlc)

Metabolism


PGMT_mc
phosphoglucomutase
[y]: g1p <==> g6p
Carbohydrate
EC-5.4.2.2





Metabolism


ACACT10m_ac
acetyl-CoA C-
[b]: 2maacoa + coa --> accoa + ppcoa
Amino Acid
EC-2.3.1.16



acyltransferase, adipocyte

Metabolism



mitochondrial


ACOAD3m_ac
acyl-CoA dehydrogenase,
[b]: 2mbcoa + fad <==> 2mb2coa + fadh2
Amino Acid
EC-1.3.99.3



adipocyte mitochondrial

Metabolism


ASPO_D_ac
D-aspartate oxidase
[a]: asp-D + h2o + o2 --> h + h2o2 + nh3 + oaa
Amino Acid
EC-1.4.3.16





Metabolism


ASPR_ac
aspartase racemase,
[a]: asp-D <==> asp-L
Amino Acid
EC-5.1.1.13



adipocyte cytosolic

Metabolism


ASPTA1_ac
aspartate transaminase
[a]: akg + asp-L <==> glu-L + oaa
Amino Acid
EC-2.6.1.1





Metabolism


ASPTA1_mc
aspartate transaminase
[y]: akg + asp-L <==> glu-L + oaa
Amino Acid
EC-2.6.1.1





Metabolism


ASPTA1m_ac
aspartate transaminase,
[b]: akg + asp-L <==> glu-L + oaa
Amino Acid
EC-2.6.1.1



mitochondrial

Metabolism


ASPTA1m_mc
aspartate transaminase,
[z]: akg + asp-L <==> glu-L + oaa
Amino Acid
EC-2.6.1.1



mitochondrial

Metabolism


ECOAH3m_ac
enoyl-CoA hydratase,
[b]: 2mb2coa + h2o <==>
Amino Acid
EC-4.2.1.17



adipocyte mitochondrial
3hmbcoa
Metabolism


HACD8m_ac
3-hydroxyacyl-CoA
[b]: 3hmbcoa + nad <==>
Amino Acid
EC-1.1.1.35



dehydrogenase (2-
2maacoa + h + nadh
Metabolism



Methylacetoacetyl-CoA),



adipocyte mitochondrial


ILETA_ac
isoleucine transaminase,
[a]: akg + ile-L <==> 3mop + glu-L
Amino Acid
EC-2.6.1.42



adipocyte cytosolic

Metabolism


MOBD3m_ac
3-Methyl-2-oxobutanoate
[b]: 3mop + coa + nad --> 2mbcoa + co2 + nadh
Amino Acid



dehydrogenase, adipocyte

Metabolism



mitochondrial


CSNAT_mc
carnitine O-
[y]: accoa + crn --> acrn + coa
Carnitine Shuttle
EC-2.3.1.7



acetyltransferase,



myocyte cytosol


CSNATifm_mc
carnitine O-
[z]: acrn + coa --> accoa + crn
Carnitine Shuttle
EC-2.3.1.7



aceyltransferase, forward



reaction, myocyte



mitochondrial


PPS_ac
propionyl-CoA synthetase,
[a]: atp + coa + ppa <==> amp + ppcoa + ppi
Propanoate
EC-6.2.1.1



adipocyte cytosolic

Metabolism


PPSm_ac
propionyl-CoA synthetase,
[b]: atp + coa + ppa <==> amp + ppcoa + ppi
Propanoate
EC-6.2.1.1



adipocyte mitochondrial

Metabolism


ACACT10m_mc
acetyl-CoA C-
[z]: accoa + occoa <==> 3odcoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase (octanoyl-



CoA)


ACACT11m_mc
acetyl-CoA C-
[z]: accoa + nncoa <==> 3oedcoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase (nonanoyl-



CoA)


ACACT12m_mc
acetyl-CoA C-
[z]: accoa + dccoa <==> 3oddcoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase (decanoyl-



CoA)


ACACT13m_mc
acetyl-CoA C-
[z]: accoa + edcoa <==> 3otrdcoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase



(endecanoyl-CoA)


ACACT145m_mc
acetyl-CoA C-
[z]: accoa + cis-dd2coa <==>
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase
3otdecoa5 + coa



(dodecenoyl-CoA



C12:1CoA, n-3)


ACACT14m_mc
acetyl-CoA C-
[z]: accoa + ddcoa <==> 3otdcoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase



(dodecanoyl-CoA)


ACACT15m_mc
acetyl-CoA C-
[z]: accoa + trdcoa <==> 3opdcoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase



(tridecanoyl-CoA)


ACACT167m_mc
acetyl-CoA C-
[z]: accoa + tdecoa5 <==>
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase
3ohdecoa7 + coa



(tetradecenoyl-CoA



C14:1CoA, n-5)


ACACT16m_mc
acetyl-CoA C-
[z]: accoa + tdcoa <==> 3ohdcoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase



(tetradecanoyl-CoA)


ACACT189m_mc
acetyl-CoA C-
[z]: accoa + hdcoa7 <==>
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase
3oodcecoa9 + coa



(hexadecenoyl-CoA



C16:1CoA, n-7)


ACACT18m_mc
acetyl-CoA C-
[z]: accoa + pmtcoa <==>
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase (palmitoyl-
3oodcoa + coa



CoA C16:0CoA)


ACACT20m_mc
acetyl-CoA C-
[z]: accoa + strcoa <==> 3oescoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase



(octadecanoyl-CoA



C18:0CoA)


ACACT22p_mc
acetyl-CoA C-
[w]: accoa + ecsacoa <==>
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase
3odscoa + coa



(eicosanoyl-CoA



C20:0CoA)


ACACT4m_mc
acetyl-CoA C-
[z]: (2) accoa <==> aacoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase (acetyl-



CoA)


ACACT5m_mc
acetyl-CoA C-
[z]: accoa + ppcoa <==> 3optcoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase (propanoyl



CoA)


ACACT6m_mc
acetyl-CoA C-
[z]: accoa + btcoa <==> 3ohcoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase (butanoyl-



CoA)


ACACT7m_mc
acetyl-CoA C-
[z]: accoa + ptcoa <==> 3ohpcoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase (pentanoyl-



CoA)


ACACT8m_mc
acetyl-CoA C-
[z]: accoa + hxcoa <==> 3oocoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase (hexanoyl-



CoA)


ACACT9m_mc
acetyl-CoA C-
[z]: accoa + hpcoa <==> 3onncoa + coa
Fatty Acid Degradation
EC-2.3.1.16



acyltransferase (heptanoyl-



CoA)


ACOAD10m_mc
acyl-CoA dehydrogenase
[z]: dccoa + fad <==> dc2coa + fadh2
Fatty Acid Degradation
EC-1.3.99.13



(decanoyl-CoA C10:0CoA)


ACOAD11m_mc
acyl-CoA dehydrogenase
[z]: edcoa + fad <==> ed2coa + fadh2
Fatty Acid Degradation
EC-1.3.99.13



(endecanoyl-CoA)


ACOAD12m_mc
acyl-CoA dehydrogenase
[z]: ddcoa + fad <==> fadh2 + trans-dd2coa
Fatty Acid Degradation
EC-1.3.99.13



(dodecanoyl-CoA



C12:0CoA)


ACOAD13m_mc
acyl-CoA dehydrogenase
[z]: fad + trdcoa <==> fadh2 + trd2coa
Fatty Acid Degradation
EC-1.3.99.13



(tridecanoyl-CoA)


ACOAD145m_mc
acyl-CoA dehydrogenase
[z]: fad + tdecoa5 <==> fadh2 + tde2coa5
Fatty Acid Degradation
EC-1.3.99.13



(tetradecenoyl-CoA,



C14:1CoA, n-5)


ACOAD14m_mc
acyl-CoA dehydrogenase
[z]: fad + tdcoa <==> fadh2 + td2coa
Fatty Acid Degradation
EC-1.3.99.13



(tetradecanoyl-CoA)


ACOAD15m_mc
acyl-CoA dehydrogenase
[z]: fad + pdcoa <==> fadh2 + pd2coa
Fatty Acid Degradation
EC-1.3.99.13



(pentadecanoyl-CoA)


ACOAD167m_mc
acyl-CoA dehydrogenase
[z]: fad + hdcoa7 <==> fadh2 + hde2coa7
Fatty Acid Degradation
EC-1.3.99.13



(hexadecenoyl-CoA,



C16:1CoA, n-7)


ACOAD16m_mc
acyl-CoA dehydrogenase
[z]: fad + pmtcoa <==> fadh2 + hdd2coa
Fatty Acid Degradation
EC-1.3.99.13



(hexadecanoyl-CoA



C16:0CoA)


ACOAD189m_mc
acyl-CoA dehydrogenase
[z]: fad + odecoa9 <==> fadh2 + ode2coa9
Fatty Acid Degradation
EC-1.3.99.13



(octadecenoyl-CoA,



C18:1CoA, n-9)


ACOAD18m_mc
acyl-CoA dehydrogenase
[z]: fad + strcoa <==> fadh2 + od2coa
Fatty Acid Degradation
EC-1.3.99.13



(Stearyl-CoA, C18:0CoA)


ACOAD20m_mc
acyl-CoA dehydrogenase
[z]: ecsacoa + fad <==> es2coa + fadh2
Fatty Acid Degradation
EC-1.3.99.13



(eicosanoyl-CoA,



C20:0CoA)


ACOAD22p_mc
acyl-CoA dehydrogenase
[w]: dcsacoa + fad <==> ds2coa + fadh2
Fatty Acid Degradation
EC-1.3.99.13



(docosanoyl-CoA,



C22:0CoA)


ACOAD4m_mc
acyl-CoA dehydrogenase
[z]: btcoa + fad <==> b2coa + fadh2
Fatty Acid Degradation
EC-1.3.99.13



(butanoyl-CoA C4:0CoA)


ACOAD5m_mc
acyl-CoA dehydrogenase
[z]: fad + ptcoa <==> fadh2 + pt2coa
Fatty Acid Degradation
EC-1.3.99.13



(pentanoyl-CoA)


ACOAD6m_mc
acyl-CoA dehydrogenase
[z]: fad + hxcoa <==> fadh2 + hx2coa
Fatty Acid Degradation
EC-1.3.99.13



(hexanoyl-CoA C8:0CoA)


ACOAD7m_mc
acyl-CoA dehydrogenase
[z]: fad + hpcoa <==> fadh2 + hp2coa
Fatty Acid Degradation
EC-1.3.99.13



(heptanoyl-CoA)


ACOAD8m_mc
acyl-CoA dehydrogenase
[z]: fad + occoa <==> fadh2 + oc2coa
Fatty Acid Degradation
EC-1.3.99.13



(octanoyl-CoA C8:0CoA)


ACOAD9m_mc
acyl-CoA dehydrogenase
[z]: fad + nncoa <==> fadh2 + nn2coa
Fatty Acid Degradation
EC-1.3.99.13



(nonanoyl-CoA)


CRNDST_mc
carnitine
[y]: crn + dcsacoa --> coa + dcsacrn
Fatty Acid Degradation
EC-2.3.1.21



docosanoyltransferase,



myocyte


CRNDSTp_mc
carnitine
coa[w] + dcsacrn[y] <==> crn[y] + dcsacoa[w]
Fatty Acid Degradation



docosanoyltransferase II,



myocyte


CRNDT_mc
carnitine
[y]: crn + ddcoa <==> coa + ddcrn
Fatty Acid Degradation
EC-2.3.1.21



dodecanoyltransferase,



myocyte


CRNDTm_mc
carnitine
coa[z] + ddcrn[y] <==> crn[y] + ddcoa[z]
Fatty Acid Degradation



dodecanoyltransferase II,



myocyte


CRNET_mc
carnitine
[y]: crn + ecsacoa <==> coa + ecsacrn
Fatty Acid Degradation
EC-2.3.1.21



eicosanoyltransferase,



myocyte


CRNETm_mc
carnitine
coa[z] + ecsacrn[y] <==> crn[y] + ecsacoa[z]
Fatty Acid Degradation



eicosanoyltransferase II,



myocyte


CRNETp_mc
carnitine
coa[w] + ecsacrn[y] <==> crn[y] + ecsacoa[w]
Fatty Acid Degradation



eicosanoyltransferase II,



myocyte


CRNODET_mc
carnitine 9-cis-
[y]: crn + odecoa9 <==> coa + odecrn9
Fatty Acid Degradation
EC-2.3.1.21



octadecenoyltransferase,



myocyte


CRNOT_mc
carnitine
[y]: crn + strcoa <==> coa + strcrn
Fatty Acid Degradation
EC-2.3.1.21



octadecanoyltransferase,



myocyte


CRNOTm_mc
carnitine
coa[z] + strcrn[y] <==> crn[y] + strcoa[z]
Fatty Acid Degradation



octadecanoyltransferase



II, myocyte


CRNPTDT_mc
carnitine
[y]: crn + pdcoa <==> coa + pdcrn
Fatty Acid Degradation
EC-2.3.1.21



pentadecanoyltransferase,



myocyte


CRNPT_mc
carnitine O-
[y]: crn + pmtcoa --> coa + pmtcrn
Fatty Acid Degradation
EC-2.3.1.21



palmitoyltransferase,



myocyte


CRNPTm_mc
carnitine O-
coa[z] + pmtcrn[y] --> crn[y] + pmtcoa[z]
Fatty Acid Degradation



palmitoyltransferase II,



myocyte


CRNTT_mc
carnitine
[y]: crn + tdcoa <==> coa + tdcrn
Fatty Acid Degradation
EC-2.3.1.21



tetradecanoyltransferase,



myocyte


CRNTTm_mc
carnitine
coa[z] + tdcrn[y] <==> crn[y] + tdcoa[z]
Fatty Acid Degradation



tetradecanoyltransferase



II, myocyte


DDCIm_mc
dodecenoyl-CoA D-
[z]: cis-dd2coa <==> trans-dd2coa
Fatty Acid Degradation
EC-5.3.3.8



isomerase, myocyte



mitochondrial


ECOAH10m_mc
3-hydroxyacyl-CoA
[z]: 3hdcoa <==> dc2coa + h2o
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxydecanoyl-CoA)


ECOAH11m_mc
3-hydroxyacyl-CoA
[z]: 3hedcoa <==> ed2coa + h2o
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxyendecanoyl-CoA)


ECOAH12m_mc
3-hydroxyacyl-CoA
[z]: 3hddcoa <==> h2o + trans-
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-
dd2coa



hydroxydodecanoyl-CoA)


ECOAH13m_mc
3-hydroxyacyl-CoA
[z]: 3htrdcoa <==> h2o + trd2coa
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxytridecanoyl-CoA)


ECOAH145m_mc
3-hydroxyacyl-CoA
[z]: 3htdecoa5 <==> h2o + tde2coa5
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxytetradecenoyl-



CoA, C14:1CoA, n-5)


ECOAH14m_mc
3-hydroxyacyl-CoA
[z]: 3htdcoa <==> h2o + td2coa
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxytetradecanoyl-



CoA)


ECOAH15m_mc
3-hydroxyacyl-CoA
[z]: 3hpdcoa <==> h2o + pd2coa
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxypentadecanoyl-



CoA)


ECOAH167m_mc
3-hydroxyacyl-CoA
[z]: 3hhdecoa7 <==> h2o + hde2coa7
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxyhexadecenoyl-



CoA, C16:1CoA, n-7)


ECOAH16m_mc
3-hydroxyacyl-CoA
[z]: 3hhdcoa <==> h2o + hdd2coa
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxyhexadecanoyl-



CoA)


ECOAH189m_mc
3-hydroxyacyl-CoA
[z]: 3hodecoa9 <==> h2o + ode2coa9
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxyoctadecenoyl-



CoA, C18:1CoA, n-9)


ECOAH18m_mc
3-hydroxyacyl-CoA
[z]: 3hodcoa <==> h2o + od2coa
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxyoctadecanoyl-



CoA, C18:0CoA)


ECOAH20m_mc
3-hydroxyacyl-CoA
[z]: 3hescoa <==> es2coa + h2o
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxyeicosanoyl-CoA,



C18:0CoA)


ECOAH22p_mc
3-hydroxyacyl-CoA
[w]: 3hdscoa <==> ds2coa + h2o
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxydocosanoyl-CoA,



C18:0CoA)


ECOAH4m_mc
3-hydroxyacyl-CoA
[z]: 3hbycoa <==> b2coa + h2o
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxybutanoyl-CoA)


ECOAH5m_mc
3-hydroxyacyl-CoA
[z]: 3hptcoa <==> h2o + pt2coa
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxypentanoyl-CoA)


ECOAH6m_mc
3-hydroxyacyl-CoA
[z]: 3hhcoa <==> h2o + hx2coa
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxyhexanoyl-CoA)


ECOAH7m_mc
3-hydroxyacyl-CoA
[z]: 3hhpcoa <==> h2o + hp2coa
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxyheptanoyl-CoA)


ECOAH8m_mc
3-hydroxyacyl-CoA
[z]: 3hocoa <==> h2o + oc2coa
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxyoctanoyl-CoA)


ECOAH9m_mc
3-hydroxyacyl-CoA
[z]: 3hnncoa <==> h2o + nn2coa
Fatty Acid Degradation
EC-4.2.1.17



dehydratase (3-



hydroxynonanoyl-CoA)


HACD10m_mc
3-hydroxyacyl-CoA
[z]: 3odcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hdcoa + nad



oxodecanoyl-CoA)


HACD11m_mc
3-hydroxyacyl-CoA
[z]: 3oedcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hedcoa + nad



oxoendecanoyl-CoA)


HACD12m_mc
3-hydroxyacyl-CoA
[z]: 3oddcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hddcoa + nad



oxododecanoyl-CoA)


HACD13m_mc
3-hydroxyacyl-CoA
[z]: 3otrdcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3htrdcoa + nad



oxotridecanoyl-CoA)


HACD145m_mc
3-hydroxyacyl-CoA
[z]: 3otdecoa5 + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3htdecoa5 + nad



oxotetradecenoyl-CoA



C14:1CoA, n-5)


HACD14m_mc
3-hydroxyacyl-CoA
[z]: 3otdcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3htdcoa + nad



oxotetradecanoyl-CoA)


HACD15m_mc
3-hydroxyacyl-CoA
[z]: 3opdcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hpdcoa + nad



oxopentadecanoyl-CoA)


HACD167m_mc
3-hydroxyacyl-CoA
[z]: 3ohdecoa7 + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hhdecoa7 + nad



oxohexadecenoyl-CoA



C16:1CoA, n-7)


HACD16m_mc
3-hydroxyacyl-CoA
[z]: 3ohdcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hhdcoa + nad



oxohexadecanoyl-CoA)


HACD189m_mc
3-hydroxyacyl-CoA
[z]: 3oodcecoa9 + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hodecoa9 + nad



oxooctadecenoyl-CoA



C18:1CoA, n-9)


HACD18m_mc
3-hydroxyacyl-CoA
[z]: 3oodcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hodcoa + nad



oxooctadecanoyl-CoA



C18:0CoA)


HACD20m_mc
3-hydroxyacyl-CoA
[z]: 3oescoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hescoa + nad



oxoeicosanoyl-CoA



C18:0CoA)


HACD22p_mc
3-hydroxyacyl-CoA
[w]: 3odscoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hdscoa + nad



oxodocosanoyl-CoA



C18:0CoA)


HACD4m_mc
3-hydroxyacyl-CoA
[z]: aacoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hbycoa + nad



oxobutanoyl-CoA)


HACD5m_mc
3-hydroxyacyl-CoA
[z]: 3optcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hptcoa + nad



oxopentanoyl-CoA)


HACD6m_mc
3-hydroxyacyl-CoA
[z]: 3ohcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hhcoa + nad



oxohexanoyl-CoA)


HACD7m_mc
3-hydroxyacyl-CoA
[z]: 3ohpcoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hhpcoa + nad



oxoheptanoyl-CoA)


HACD8m_mc
3-hydroxyacyl-CoA
[z]: 3oocoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hocoa + nad



oxooctanoyl-CoA)


HACD9m_mc
3-hydroxyacyl-CoA
[z]: 3onncoa + h + nadh <==>
Fatty Acid Degradation
EC-1.1.1.35



dehydrogenase (3-
3hnncoa + nad



oxononanoyl-CoA)


MMEm_mc
methylmalonyl-CoA
[z]: mmcoa-S <==> mmcoa-R
Fatty Acid Degradation
EC-5.1.99.1



epimerase, myocyte



mitochondrial


MMMm_mc
R-methylmalonyl-CoA
[z]: mmcoa-R --> succoa
Fatty Acid Degradation
EC-5.4.99.2



mutase, myocyte



mitochondrial


PPCOACm_mc
Propionyl-CoA
[z]: atp + hco3 + ppcoa --> adp + h + mmcoa-
Fatty Acid Degradation
EC-6.4.1.3



carboxylase, myocyte
S + pi



mitochondrial


FACOAL120_mc
fatty-acid—CoA ligase
[y]: atp + coa + ddca <==> amp + ddcoa + ppi
Fatty Acid Metabolism
EC-6.2.1.3



(dodecanoate, C12:0),



myocyte


FACOAL140_mc
fatty-acid—CoA ligase
[y]: atp + coa + ttdca <==> amp + ppi + tdcoa
Fatty Acid Metabolism
EC-6.2.1.3



(tetradecanoate, C14:0),



myocyte


FACOAL150_mc
fatty-acid—CoA ligase
[y]: atp + coa + ptdca <==> amp + pdcoa + ppi
Fatty Acid Metabolism
EC-6.2.1.3



(pentadecanoate, C15:0),



myocyte


FACOAL160_mc
fatty-acid—CoA ligase
[y]: atp + coa + hdca <==> amp + pmtcoa + ppi
Fatty Acid Metabolism
EC-6.2.1.3



(hexadecanoate, C16:0),



myocyte


FACOAL180_mc
fatty-acid—CoA ligase
[y]: atp + coa + ocdca <==> amp + ppi + strcoa
Fatty Acid Metabolism
EC-6.2.1.3



(octadecanoate, C28:0),



myocyte


FACOAL181_9_mc
fatty-acid—CoA ligase
[y]: atp + coa + ocdcea9 <==>
Fatty Acid Metabolism
EC-6.2.1.3



(octadecenoate, C18:1 n-
amp + odecoa9 + ppi



9), myocyte


FACOAL200_mc
fatty-acid—CoA ligase
[y]: atp + coa + ecsa <==> amp + ecsacoa + ppi
Fatty Acid Metabolism
EC-6.2.1.3



(eicosanoate, C20:0),



myocyte


ACCOAC_ac
acetyl-CoA carboxylase
[a]: accoa + atp + hco3 --> adp + h + malcoa + pi
Fatty Acid Synthesis
EC-6.4.1.2


AGAT_ac_HS_ub
unbalanced 1-Acyl-
[a]: 1ag3p_HS + (0.00032)
Fatty Acid Synthesis



glycerol-3-phosphate
dcsacoa + (0.00698) ddcoa + (0.00024)



acyltransferase, adipocyte
dsecoa11 + (0.00056)



cytosol, Homo sapiens
dsecoa9 + (0.00172) dshcoa3 + (0.00163)



specific
dspcoa3 + (0.00016)




dspcoa6 + (0.00182) ecsacoa + (0.00272)




esdcoa6 + (0.00035)




esdcoa9 + (0.00148) esecoa11 + (0.00026)




esecoa7 + (0.00732)




esecoa9 + (0.00036) espcoa3 + (0.00027)




estcoa3 + (0.0023)




estcoa6 + (0.00027) ettcoa3 + (0.00311)




ettcoa6 + (0.02985)




hdcoa7 + (0.00582) hdcoa9 + (0.00295)




hpdcoa8 + (0.15761)




ocdycacoa6 + (0.00499) odcoa3 + (0.00039)




odcoa6 + (0.0026)




odecoa5 + (0.01831) odecoa7 + (0.39309)




odecoa9 + (0.00138)




osttcoa6 + (0.00375) pdcoa + (0.24351)




pmtcoa + (0.06379)




strcoa + (0.03728) tdcoa + (0.00244)




tdecoa5 + (0.00037)




tdecoa7 --> coa + pa_HS


DESAT141_5_ac
Myristicoyl-CoA
[a]: h + nadph + o2 + tdcoa --> (2)
Fatty Acid Synthesis
EC-1.14.19.1



desaturase (n-C14:0CoA ->
h2o + nadp + tdecoa5



C14:1CoA, n-5),



adipocyte


DESAT141_7_ac
Myristicoyl-CoA
[a]: h + nadph + o2 + tdcoa --> (2)
Fatty Acid Synthesis
EC-1.14.19.1



desaturase (n-C14:0CoA ->
h2o + nadp + tdecoa7



C14:1CoA, n-7),



adipocyte


DESAT161_7_ac
Palmitoyl-CoA desaturase
[a]: h + nadph + o2 + pmtcoa -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C16:0CoA ->
(2) h2o + hdcoa7 + nadp



C16:1CoA, n-7), adipocyte


DESAT161_9_ac
Palmitoyl-CoA desaturase
[a]: h + nadph + o2 + pmtcoa -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C16:0CoA ->
(2) h2o + hdcoa9 + nadp



C16:1CoA, n-9), adipocyte


DESAT171_8_ac
Palmitoyl-CoA desaturase
[a]: h + hpdcoa + nadph + o2 -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C17:0CoA ->
(2) h2o + hpdcoa8 + nadp



C17:1CoA, n-8), adipocyte


DESAT181_5_ac
stearoyl-CoA desaturase
[a]: h + nadph + o2 + strcoa -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C18:0CoA ->
(2) h2o + nadp + odecoa5



C18:1CoA, n-5), adipocyte


DESAT181_7_ac
stearoyl-CoA desaturase
[a]: h + nadph + o2 + strcoa -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C18:0CoA ->
(2) h2o + nadp + odecoa7



C18:1CoA, n-7), adipocyte


DESAT181_9_ac
stearoyl-CoA desaturase
[a]: h + nadph + o2 + strcoa -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C18:0CoA ->
(2) h2o + nadp + odecoa9



C18:1CoA, n-9), adipocyte


DESAT201_11_ac
stearoyl-CoA desaturase
[a]: ecsacoa + h + nadph + o2 -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C20:0CoA ->
esecoa11 + (2) h2o + nadp



C20:1CoA, n-11),



adipocyte


DESAT201_7_ac
stearoyl-CoA desaturase
[a]: ecsacoa + h + nadph + o2 -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C20:0CoA ->
esecoa7 + (2) h2o + nadp



C20:1CoA, n-7), adipocyte


DESAT201_9_ac
stearoyl-CoA desaturase
[a]: ecsacoa + h + nadph + o2 -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C20:0CoA ->
esecoa9 + (2) h2o + nadp



C20:1CoA, n-9), adipocyte


DESAT202_9_ac
stearoyl-CoA desaturase
[a]: ecsacoa + (2) h + (2) nadph + (2)
Fatty Acid Synthesis
EC-1.14.19.1



(lumped: n-C20:0CoA ->
o2 --> esdcoa9 + (4) h2o + (2)



C20:2CoA, n-9), adipocyte
nadp


DESAT221_11_ac
stearoyl-CoA desaturase
[a]: dcsacoa + h + nadph + o2 -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C22:0CoA ->
dsecoa11 + (2) h2o + nadp



C22:1CoA, n-11),



adipocyte


DESAT221_9_ac
stearoyl-CoA desaturase
[a]: dcsacoa + h + nadph + o2 -->
Fatty Acid Synthesis
EC-1.14.19.1



(n-C22:0CoA ->
dsecoa9 + (2) h2o + nadp



C22:1CoA, n-9), adipocyte


FACOAL120_ac
fatty-acid—CoA ligase
[a]: atp + coa + ddca <==> amp + ddcoa + ppi
Fatty Acid Synthesis
EC-6.2.1.3



(dodecanoate, C12:0),



adipocyte


FACOAL140_ac
fatty-acid—CoA ligase
[a]: atp + coa + ttdca <==> amp + ppi + tdcoa
Fatty Acid Synthesis
EC-6.2.1.3



(tetradecanoate, C14:0),



adipocyte


FACOAL141_5_ac
fatty-acid—CoA ligase
[a]: atp + coa + ttdcea5 <==> amp + ppi +
Fatty Acid Synthesis
EC-6.2.1.3



(tetradecenoate, C14:1 n-
tdecoa5



5), adipocyte


FACOAL141_7_ac
fatty-acid—CoA ligase
[a]: atp + coa + ttdcea7 <==> amp + ppi +
Fatty Acid Synthesis
EC-6.2.1.3



(tetradecenoate, C14:1 n-
tdecoa7



7), adipocyte


FACOAL150_ac
fatty-acid—CoA ligase
[a]: atp + coa + ptdca <==> amp + pdcoa + ppi
Fatty Acid Synthesis
EC-6.2.1.3



(heptadecanoate, C15:0),



adipocyte


FACOAL160_ac
fatty-acid—CoA ligase
[a]: atp + coa + hdca <==> amp + pmtcoa +
Fatty Acid Synthesis
EC-6.2.1.3



(hexadecanoate, C16:0),
ppi



adipocyte


FACOAL161_7_ac
fatty-acid—CoA ligase
[a]: atp + coa + hdcea7 <==> amp + hdcoa7 +
Fatty Acid Synthesis
EC-6.2.1.3



(hexadecenoate, C16:1 n-
ppi



7), adipocyte


FACOAL161_9_ac
fatty-acid—CoA ligase
[a]: atp + coa + hdcea9 <==> amp + hdcoa9 +
Fatty Acid Synthesis
EC-6.2.1.3



(hexadecenoate, C16:1 n-
ppi



9), adipocyte


FACOAL170_ac
fatty-acid—CoA ligase
[a]: atp + coa + hpdca <==> amp + hpdcoa + ppi
Fatty Acid Synthesis
EC-6.2.1.3



(heptadecanoate, C17:0),



adipocyte


FACOAL171_8_ac
fatty-acid—CoA ligase
[a]: atp + coa + hpdcea8 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(heptadecenoate, C17:1 n-
amp + hpdcoa8 + ppi



8), adipocyte


FACOAL180_ac
fatty-acid—CoA ligase
[a]: atp + coa + ocdca <==> amp + ppi + strcoa
Fatty Acid Synthesis
EC-6.2.1.3



(octadecanoate, C18:0),



adipocyte


FACOAL181_5_ac
fatty-acid—CoA ligase
[a]: atp + coa + ocdcea5 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(octadecenoate, C18:1 n-
amp + odecoa5 + ppi



5), adipocyte


FACOAL181_7_ac
fatty-acid—CoA ligase
[a]: atp + coa + ocdcea7 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(octadecenoate, C18:1 n-
amp + odecoa7 + ppi



7), adipocyte


FACOAL181_9_ac
fatty-acid—CoA ligase
[a]: atp + coa + ocdcea9 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(octadecenoate, C18:1 n-
amp + odecoa9 + ppi



9), adipocyte


FACOAL182_6_ac
fatty-acid—CoA ligase
[a]: atp + coa + ocddea6 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(octadecadienoate, C18:2
amp + ocdycacoa6 + ppi



n-6), adipocyte


FACOAL183_3_ac
fatty-acid—CoA ligase
[a]: atp + coa + ocdctra3 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(octadecadienoate, C18:3
amp + odcoa3 + ppi



n-3), adipocyte


FACOAL183_6_ac
fatty-acid—CoA ligase
[a]: atp + coa + ocdctra6 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(octadecadienoate, C18:3
amp + odcoa6 + ppi



n-6), adipocyte


FACOAL200_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecsa <==> amp + ecsacoa + ppi
Fatty Acid Synthesis
EC-6.2.1.3



(eicosanoate, C20:0),



adipocyte


FACOAL201_11_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecsea11 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(eicosenoate, C20:1 n-11),
amp + esecoa11 + ppi



adipocyte


FACOAL201_7_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecsea7 <==> amp + esecoa7 +
Fatty Acid Synthesis
EC-6.2.1.3



(eicosenoate, C20:1 n-7),
ppi



adipocyte


FACOAL201_9_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecsea9 <==> amp + esecoa9 +
Fatty Acid Synthesis
EC-6.2.1.3



(eicosenoate, C20:1 n-9),
ppi



adipocyte


FACOAL202_6_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecsdea6 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(eicosadienoate, C20:2 n-
amp + esdcoa6 + ppi



6), adipocyte


FACOAL202_9_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecsdea9 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(eicosadienoate, C20:2 n-
amp + esdcoa9 + ppi



9), adipocyte


FACOAL203_3_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecstea3 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(eicosatrienoate, C20:3 n-
amp + estcoa3 + ppi



6), adipocyte


FACOAL203_6_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecstea6 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(eicosatrienoate, C20:3 n-
amp + estcoa6 + ppi



6), adipocyte


FACOAL204_3_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecsttea3 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(eicosatetraenoate, C20:4
amp + ettcoa3 + ppi



n-3), adipocyte


FACOAL204_6_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecsttea6 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(eicosatetraenoate, C20:4
amp + ettcoa6 + ppi



n-6), adipocyte


FACOAL205_3_ac
fatty-acid—CoA ligase
[a]: atp + coa + ecspea3 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(eicosapentaenoate,
amp + espcoa3 + ppi



C20:5 n-3), adipocyte


FACOAL220_ac
fatty-acid—CoA ligase
[a]: atp + coa + dcsa <==> amp + dcsacoa + ppi
Fatty Acid Synthesis
EC-6.2.1.3



(docosanoate, C22:0),



adipocyte


FACOAL221_11_ac
fatty-acid—CoA ligase
[a]: atp + coa + dcsea11 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(docosenoate, C22:1 n-
amp + dsecoa11 + ppi



11), adipocyte


FACOAL221_9_ac
fatty-acid—CoA ligase
[a]: atp + coa + dcsea9 <==> amp + dsecoa9 +
Fatty Acid Synthesis
EC-6.2.1.3



(docosenoate, C22:1 n-9),
ppi



adipocyte


FACOAL224_6_ac
fatty-acid—CoA ligase
[a]: atp + coa + ocsttea6 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(ocosatetraenoate, C22:4
amp + osttcoa6 + ppi



n-6), adipocyte


FACOAL225_3_ac
fatty-acid—CoA ligase
[a]: atp + coa + dcspea3 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(docosapentaenoate,
amp + dspcoa3 + ppi



C22:5 n-3), adipocyte


FACOAL225_6_ac
fatty-acid—CoA ligase
[a]: atp + coa + dcspea6 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(docosapentaenoate,
amp + dspcoa6 + ppi



C22:5 n-6), adipocyte


FACOAL226_6_ac
fatty-acid—CoA ligase
[a]: atp + coa + dcshea3 <==>
Fatty Acid Synthesis
EC-6.2.1.3



(docosahexaenoate,
amp + dshcoa3 + ppi



C22:6 n-6), adipocyte


FAS100_ac
fatty acid synthase (n-
[a]: (3) h + malcoa + (2) nadph + octa
Fatty Acid Synthesis
EC-2.3.1.85



C10:0), adipocyte
--> co2 + coa + dca + h2o + (2)




nadp


FAS120_ac
fatty acid synthase (n-
[a]: dca + (3) h + malcoa + (2)
Fatty Acid Synthesis
EC-2.3.1.85



C12:0), adipocyte
nadph --> co2 + coa + ddca + h2o + (2)




nadp


FAS140_ac
fatty acid synthase (n-
[a]: ddca + (3) h + malcoa + (2)
Fatty Acid Synthesis
EC-2.3.1.85



C14:0), adipocyte
nadph --> co2 + coa + h2o + (2)




nadp + ttdca


FAS150_ac
fatty acid synthase
[a]: (17) h + (6) malcoa + (12)
Fatty Acid Synthesis



(C15:0), adipocyte cytosol
nadph + ppcoa --> (6) co2 + (7)




coa + (5) h2o + (12) nadp + ptdca


FAS160_ac
fatty acid synthase (n-
[a]: (3) h + malcoa + (2) nadph + ttdca
Fatty Acid Synthesis
EC-2.3.1.85



C16:0), adipocyte
--> co2 + coa + h2o + hdca + (2)




nadp


FAS170_ac
fatty acid synthase
[a]: (3) h + malcoa + (2) nadph + ptdca
Fatty Acid Synthesis



(C17:0), adipocyte cytosol
--> co2 + coa + h2o + hpdca + (2)




nadp


FAS180_ac
fatty acid synthase (n-
[a]: (3) h + hdca + malcoa + (2)
Fatty Acid Synthesis
EC-2.3.1.85



C18:0), adipocyte
nadph --> co2 + coa + h2o + (2)




nadp + ocdca


FAS200_ac
fatty acid synthase (n-
[a]: (3) h + malcoa + (2) nadph + ocdca
Fatty Acid Synthesis
EC-2.3.1.85



C20:0), adipocyte
--> co2 + coa + ecsa + h2o + (2)




nadp


FAS220_ac
fatty acid synthase (n-
[a]: ecsa + (3) h + malcoa + (2)
Fatty Acid Synthesis
EC-2.3.1.85



C22:0), adipocyte
nadph --> co2 + coa + dcsa + h2o + (2)




nadp


FAS80_L_ac
fatty acid synthase (n-
[a]: accoa + (8) h + (3) malcoa + (6)
Fatty Acid Synthesis
EC-23.1.85



C8:0), lumped reaction,
nadph --> (3) co2 + (4) coa + (2)



adipocyte
h2o + (6) nadp + octa


GAT1_ac_HS_ub
unbalanced glycerol 3-
[a]: (0.00032) dcsacoa + (0.00698)
Fatty Acid Synthesis



phosphate acyltransferase
ddcoa + (0.00024)



(glycerol 3-phosphate),
dsecoa11 + (0.00056) dsecoa9 + (0.00172)



adipocyte cytosol, Homo
dshcoa3 + (0.00163)



sapiens specific
dspcoa3 + (0.00016) dspcoa6 + (0.00182)




ecsacoa + (0.00272)




esdcoa6 + (0.00035) esdcoa9 + (0.00148)




esecoa11 + (0.00026)




esecoa7 + (0.00732) esecoa9 + (0.00036)




espcoa3 + (0.00027)




estcoa3 + (0.0023) estcoa6 + (0.00027)




ettcoa3 + (0.00311)




ettcoa6 + glyc3p + (0.02985)




hdcoa7 + (0.00582) hdcoa9 + (0.00295)




hpdcoa8 + (0.15761)




ocdycacoa6 + (0.00499) odcoa3 + (0.00039)




odcoa6 + (0.0026)




odecoa5 + (0.01831) odecoa7 + (0.39309)




odecoa9 + (0.00138)




osttcoa6 + (0.00375) pdcoa + (0.24351)




pmtcoa + (0.06379)




strcoa + (0.03728) tdcoa + (0.00244)




tdecoa5 + (0.00037)




tdecoa7 --> 1ag3p_HS + coa


12DGRH_ac_HS_ub
unbalanced diacylglycerol
[a]: 12dgr_HS + h2o --> (0.00032)
Triglycerol Degradation
EC-3.1.1.3



hydrolase, adipocyte
dcsa + (0.00024) dcsea11 + (0.00056)



cytosol, Homo sapiens
dcsea9 + (0.00172)



specific
dcshea3 + (0.00163) dcspea3 + (0.00016)




dcspea6 + (0.00698)




ddca + (0.00182) ecsa + (0.00272)




ecsdea6 + (0.00035) ecsdea9 + (0.00148)




ecsea11 + (0.00026)




ecsea7 + (0.00732) ecsea9 + (0.00036)




ecspea3 + (0.00027)




ecstea3 + (0.0023) ecstea6 + (0.00027)




ecsttea3 + (0.00311)




ecsttea6 + h + (0.24351) hdca + (0.02985)




hdcea7 + (0.00582)




hdcea9 + (0.00295) hpdcea8 + mglyc_HS +




(0.06379) ocdca + (0.0026)




ocdcea5 + (0.01831)




ocdcea7 + (0.39309) ocdcea9 + (0.00499)




ocdctra3 + (0.00039)




ocdctra6 + (0.15761) ocddea6 + (0.00138)




ocsttea6 + (0.00375)




ptdca + (0.03728) ttdca + (0.00244)




ttdcea5 + (0.00037)




ttdcea7


MGLYCH_ac_HS_ub
unbalanced monoglycerol
[a]: h2o + mglyc_HS --> (0.00032)
Triglycerol Degradation
EC-3.1.1.3



hydrolase, adipocyte
dcsa + (0.00024) dcsea11 + (0.00056)



cytosol, Homo sapiens
dcsea9 + (0.00172)



specific
dcshea3 + (0.00163) dcspea3 + (0.00016)




dcspea6 + (0.00698)




ddca + (0.00182) ecsa + (0.00272)




ecsdea6 + (0.00035) ecsdea9 + (0.00148)




ecsea11 + (0.00026)




ecsea7 + (0.00732) ecsea9 + (0.00036)




ecspea3 + (0.00027)




ecstea3 + (0.0023) ecstea6 + (0.00027)




ecsttea3 + (0.00311)




ecsttea6 + glyc + h + (0.24351)




hdca + (0.02985) hdcea7 + (0.00582)




hdcea9 + (0.00295)




hpdcea8 + (0.06379) ocdca + (0.0026)




ocdcea5 + (0.01831)




ocdcea7 + (0.39309) ocdcea9 + (0.00499)




ocdctra3 + (0.00039)




ocdctra6 + (0.15761) ocddea6 + (0.00138)




ocsttea6 + (0.00375)




ptdca + (0.03728) ttdca + (0.00244)




ttdcea5 + (0.00037)




ttdcea7


TRIGH_ac_HS_ub
unbalanced triacylglycerol
[a]: h2o + triglyc_HS -->
Triglycerol Degradation
EC-3.1.1.3



hydrolase, adipocyte
12dgr_HS + (0.00032) dcsa + (0.00024)



cytosol, Homo sapiens
dcsea11 + (0.00056)



specific
dcsea9 + (0.00172) dcshea3 + (0.00163)




dcspea3 + (0.00016)




dcspea6 + (0.00698) ddca + (0.00182)




ecsa + (0.00272)




ecsdea6 + (0.00035) ecsdea9 + (0.00148)




ecsea11 + (0.00026)




ecsea7 + (0.00732) ecsea9 + (0.00036)




ecspea3 + (0.00027)




ecstea3 + (0.0023) ecstea6 + (0.00027)




ecsttea3 + (0.00311)




ecsttea6 + h + (0.24351) hdca + (0.02985)




hdcea7 + (0.00582)




hdcea9 + (0.00295) hpdcea8 + (0.06379)




ocdca + (0.0026)




ocdcea5 + (0.01831) ocdcea7 + (0.39309)




ocdcea9 + (0.00499)




ocdctra3 + (0.00039) ocdctra6 + (0.15761)




ocddea6 + (0.00138)




ocsttea6 + (0.00375) ptdca + (0.03728)




ttdca + (0.00244)




ttdcea5 + (0.00037) ttdcea7


DAGPYP_ac_HS_ub
unbalanced diacylglycerol
[a]: h2o + pa_HS --> 12dgr_HS + pi
Triglycerol Synthesis
EC-3.1.3.4



pyrophosphate



phosphatase, adipocyte



cytosol, Homo sapiens



specific


TRIGS_ac_HS_ub
unbalanced triglycerol
[a]: 12dgr_HS + (0.00032)
Triglycerol Synthesis



synthesis, adipocyte
dcsacoa + (0.00698) ddcoa + (0.00024)



cytosol, Homo sapiens
dsecoa11 + (0.00056)



specific
dsecoa9 + (0.00172) dshcoa3 + (0.00163)




dspcoa3 + (0.00016)




dspcoa6 + (0.00182) ecsacoa + (0.00272)




esdcoa6 + (0.00035)




esdcoa9 + (0.00148) esecoa11 + (0.00026)




esecoa7 + (0.00732)




esecoa9 + (0.00036) espcoa3 + (0.00027)




estcoa3 + (0.0023)




estcoa6 + (0.00027) ettcoa3 + (0.00311)




ettcoa6 + (0.02985)




hdcoa7 + (0.00582) hdcoa9 + (0.00295)




hpdcoa8 + (0.15761)




ocdycacoa6 + (0.00499) odcoa3 + (0.00039)




odcoa6 + (0.0026)




odecoa5 + (0.01831) odecoa7 + (0.39309)




odecoa9 + (0.00138)




osttcoa6 + (0.00375) pdcoa + (0.24351)




pmtcoa + (0.06379)




strcoa + (0.03728) tdcoa + (0.00244)




tdecoa5 + (0.00037)




tdecoa7 --> coa + triglyc_HS


NDPK1_ac
nucleoside-diphosphate
[a]: atp + gdp <==> adp + gtp
Nucleotide Metabolism
EC-2.7.4.6



kinase (ATP:GDP)


NDPK1_mc
nucleoside-diphosphate
[y]: atp + gdp <==> adp + gtp
Nucleotide Metabolism
EC-2.7.4.6



kinase (ATP:GDP)


ADK1_mc
adenylate kinase, myocyte
[y]: amp + atp <==> (2) adp
Nucleotide Salvage
EC-2.7.4.3



cytosolic

Pathways


NTPP6m_ac
Nucleoside triphosphate
[b]: atp + h2o --> amp + h + ppi
Nucleotide Salvage



pyrophosphorylase (atp),

Pathways



adipocyte mitochondrial


ADK1_ac
adenylate kinase,
[a]: amp + atp <==> (2) adp
Nucleotide Savage
EC-2.7.4.3



adipocyte cytosolic

Pathway


CAT_ac
catalase, adipocyte
[a]: (2) h2o2 --> (2) h2o + o2
Other
EC-1.11.1.6



cytosolic


HCO3E_ac
carbonate dehydratase
[a]: co2 + h2o <==> h + hco3
Other
EC-4.2.1.1



(HCO3 equilibration



reaction), adipocyte



cytosolic


HCO3E_mc
carbonate dehydratase
[y]: co2 + h2o <==> h + hco3
Other
EC-4.2.1.1



(HCO3 equilibration



reaction), myocyte



cytosolic


HCO3Ei
carbonate dehydratase
[i]: co2 + h2o <==> h + hco3
Other
EC-4.2.1.1



(HCO3 equilibration



reaction), intra-organism


NH4DIS_ac
nh4 Dissociation
[a]: nh4 <==> h + nh3
Other


CONTRACTION_mc
muscle contraction,
[y]: myoactinADPPi --> adp + myoactin + pi
Contraction



myocyte cytosol


MYOADPPIA_mc
myosin-ADP-Pi
[y]: actin + myosinADPPi -->
Contraction



attachment, myocyte
myoactinADPPi



cytosol


MYOSINATPB_mc
mysosin ATP binding,
[y]: atp + myoactin --> actin + myosinATP
Contraction



myocyte cytosol


MYOSINATPH_mc
myosin-ATP hydrolysis,
[y]: h2o + myosinATP --> h + myosinADPPi
Contraction



myocyte cytosol


CREATt2is_mc
Creatine Na+ symporter,
creat[i] + na1[c] <==> creat[y] + na1
Transport



myocyte cytosol
[y]


CRTNtis_mc
creatinine transport,
crtn[i] <==> crtn[y]
Transport



myocyte cytosol


Clt_xo
chlorideion transport out
cl[e] --> cl[i]
Transport



via diffusion


DCSAtis_ac
docosanoate (C22:0)
dcsa[a] --> dcsa[i]
Transport



adipocyte transport


DCSEA11tis_ac
docosenoate (C22:1, n-
dcsea11[a] --> dcsea11[i]
Transport



11) adipocyte transport


DCSEA9tis_ac
docosenoate (C22:1, n-9)
dcsea9[a] --> dcsea9[i]
Transport



adipocyte transport


DCSHEA3t
docosahexaenoate
dcshea3[e] <==> dcshea3[i]
Transport



(C22:6, n-3) transport


DCSHEA3tis_ac
docosahexaenoate
dcshea3[i] <==> dcshea3[a]
Transport



(C22:6, n-3) adipocyte



transport


DCSPEA3t
Docosapentaenoate
dcspea3[e] <==> dcspea3[i]
Transport



(C22:5, n-3) transport


DCSPEA3tis_ac
Docosapentaenoate
dcspea3[i] <==> dcspea3[a]
Transport



(C22:5, n-3) adipocyte



transport


DCSPEA6t
Docosapentaenoate
dcspea6[e] <==> dcspea6[i]
Transport



(C22:5, n-6) transport


DCSPEA6tis_ac
Docosapentaenoate
dcspea6[i] <==> dcspea6[a]
Transport



(C22:5, n-6) adipocyte



transport


DDCAtis_ac
dodecanoate (C12:0)
ddca[a] --> ddca[i]
Transport



adipocyte transport


DDCAtis_mc
dodecanoate (C12:0)
ddca[i] --> ddca[y]
Transport



myocyte transport


ECSAtis_ac
eicosanoate (C20:0)
ecsa[a] --> ecsa[i]
Transport



adipocyte transport


ECSDEA6t
Eicosadienoate (C20:2, n-
ecsdea6[e] <==> ecsdea6[i]
Transport



6) transport


ECSDEA6tis_ac
Eicosadienoate (C20:2, n-
ecsdea6[i] <==> ecsdea6[a]
Transport



6) adipocyte transport


ECSDEA9tis_ac
eicosadienoate (C20:2, n-
ecsdea9[a] --> ecsdea9[i]
Transport



9) adipocyte transport


ECSEA11tis_ac
eicosenoate (C20:1, n-11)
ecsea11[a] --> ecsea11[i]
Transport



adipocyte transport


ECSEA7tis_ac
eicosenoate (C20:1, n-7)
ecsea7[a] --> ecsea7[i]
Transport



adipocyte transport


ECSEA9tis_ac
eicosenoate (C20:1, n-9)
ecsea9[a] --> ecsea9[i]
Transport



adipocyte transport


ECSFAtis_mc
eicosanoate transport (n-
ecsa[i] <==> ecsa[y]
Transport



C20:0)


ECSPEA3t
Eicosapentaenoate
ecspea3[e] <==> ecspea3[i]
Transport



(C20:5, n-3) transport


ECSPEA3tis_ac
Eicosapentaenoate
ecspea3[i] <==> ecspea3[a]
Transport



(C20:5, n-3) adipocyte



transport


ECSTEA3t
Eicosatrienoate (C20:3, n-
ecstea3[e] <==> ecstea3[i]
Transport



3) transport


ECSTEA3tis_ac
Eicosatrienoate (C20:3, n-
ecstea3[i] <==> ecstea3[a]
Transport



3) adipocyte transport


ECSTEA6t
Eicosatrienoate (C20:3, n-
ecstea6[e] <==> ecstea6[i]
Transport



6) transport


ECSTEA6tis_ac
Eicosatrienoate (C20:3, n-
ecstea6[i] <==> ecstea6[a]
Transport



6) adipocyte transport


ECSTTEA3t
Eicosatetraenoate (C20:4,
ecsttea3[e] <==> ecsttea3[i]
Transport



n-3) transport


ECSTTEA3tis_ac
Eicosatetraenoate (C20:4,
ecsttea3[i] <==> ecsttea3[a]
Transport



n-3) adipocyte transport


ECSTTEA6t
Eicosatetraenoate (C20:4,
ecsttea6[e] <==> ecsttea6[i]
Transport



n-6) transport


ECSTTEA6tis_ac
Eicosatetraenoate (C20:4,
ecsttea6[i] <==> ecsttea6[a]
Transport



n-6) adipocyte transport


GLYCt6is_ac
glycerol transport in/out
glyc[a] + h[a] <==> glyc[i] + h[i]
Transport



via symporter, adipocyte


HCO3t2
HCO3 transport out via
hco3[e] <==> hco3[i]
Transport



diffusion


HDCAtis_ac
hexadecanoate (C16:0)
hdca[a] --> hdca[i]
Transport



adipocyte transport


HDCAtis_mc
hexadecanoate (C16:0)
hdca[i] --> hdca[y]
Transport



myocyte transport


HDCEA7tis_ac
hexadecenoate (C16:1, n-
hdcea7[a] --> hdcea7[i]
Transport



7) adipocyte transport


HDCEA9tis_ac
hexadecenoate (C16:1, n-
hdcea9[a] --> hdcea9[i]
Transport



9) adipocyte transport


HPDCEA8tis_ac
heptadecenoate (C17:1, n-
hpdcea8[a] --> hpdcea8[i]
Transport



8) adipocyte transport


ILEtis_ac
L-isoeucine transport
h[i] + ile-L[i] <==> h[a] + ile-L[a]
Transport
TC-2.A.26



in/out via proton symport,



adipocyte


NAt
sodium transport in/out
h[i] + na1[e] <==> h[e] + na1[i]
Transport
TC-2.A.36



via proton antiport (one



H+)


NAtis_mc
sodium transport in/out
na1[i] <==> na1[y]
Transport
TC-1.A.15



via the non-selective



cation channel


NH4CLt_xo
ammonium chloride
cl[i] + nh4[i] <==> cl[e] + nh4[e]
Transport



transport


NH4tis_ac
ammonia transport via
nh4[i] <==> nh4[a]
Transport



diffusion, adipocyte



cytosolic


OCDCAtis_ac
octadecanoate (C18:0)
ocdca[a] --> ocdca[i]
Transport



adipocyte transport


OCDCAtis_mc
octadecanoate (C18:0)
ocdca[i] --> ocdca[y]
Transport



myocyte transport


OCDCEA5tis_ac
octadecenoate (C18:1, n-
ocdcea5[a] --> ocdcea5[i]
Transport



5) adipocyte transport


OCDCEA7tis_ac
octadecenoate (C18:1, n-
ocdcea7[a] --> ocdcea7[i]
Transport



7) adipocyte transport


OCDCEA9tis_ac
octadecenoate (C18:1, n-
ocdcea9[a] --> ocdcea9[i]
Transport



9) adipocyte transport


OCDCEA9tis_mc
octadecenoate (C18:1, n-
ocdcea9[i] --> ocdcea9[y]
Transport



9) myocyte transport


OCDCTRA3t
Octadecatrienoate (C18:3,
ocdctra3[e] <==> ocdctra3[i]
Transport



n-3) transport


OCDCTRA3tis_ac
Octadecatrienoate (C18:3,
ocdctra3[i] <==> ocdctra3[a]
Transport



n-3) adipocyte transport


OCDCTRA6t
Octadecatrienoate (C18:3,
ocdctra6[e] <==> ocdctra6[i]
Transport



n-6) transport


OCDCTRA6tis_ac
Octadecatrienoate (C18:3,
ocdctra6[i] <==> ocdctra6[a]
Transport



n-6) adipocyte transport


OCDDEA6t
Octadecadienoate (C18:2,
ocddea6[e] <==> ocddea6[i]
Transport



n-6) transport


OCDDEA6tis_ac
Octadecadienoate (C18:2,
ocddea6[i] <==> ocddea6[a]
Transport



n-6) adipocyte transport


OCSTTEA6t
Ocosatetraenoate (C22:4,
ocsttea6[e] <==> ocsttea6[i]
Transport



n-6) transport


OCSTTEA6tis_ac
Ocosatetraenoate (C22:4,
ocsttea6[i] <==> ocsttea6[a]
Transport



n-6) adipocyte transport


PIt2_xo
phosphate transport in via
h[e] + pi[e] <==> h[i] + pi[i]
Transport



proton symport


PTDCAtis_ac
pentadecanoate (C15:0)
ptdca[a] --> ptdca[i]
Transport



adipocyte transport


PTDCAtis_mc
pentadecanoate (C15:0)
ptdca[i] --> ptdca[y]
Transport



myocyte transport


TTDCAtis_ac
tetradecanoate (C14:0)
ttdca[a] --> ttdca[i]
Transport



adipocyte transport


TTDCAtis_mc
tetradecanoate (C14:0)
ttdca[i] --> ttdcat[y]
Transport



myocyte transport


TTDCEA5tis_ac
tetradecenoate (C14:1, n-
ttdcea5[a] --> ttdcea5[i]
Transport



5) adipocyte transport


TTDCEA7tis_ac
tetradecenoate (C14:1, n-
ttdcea7[a] --> ttdcea7[i]
Transport



7) adipocyte transport


G6Pter_ac
glucose 6-phosphate
g6p[a] <==> g6p[f]
Transport,



adipocyte endoplasmic

Endoplasmic Reticular



reticular transport via



diffusion


G6Pter_mc
glucose 6-phosphate
g6p[y] <==> g6p[u]
Transport,



myocyte endoplasmic

Endoplasmic Reticular



reticular transport via



diffusion


GLCter_ac
glucose transport,
glc-D[a] <==> glc-D[f]
Transport,



endoplasmic reticulum

Endoplasmic Reticular


GLCter_mc
glucose transport,
glc-D[y] <==> glc-D[u]
Transport,



endoplasmic reticulum

Endoplasmic Reticular


CO2t_xo
CO2 transport via
co2[e] <==> co2[i]
Transport, Extracellular



diffusion


CO2tis_ac
CO2 adipocyte transport
co2[i] <==> co2[a]
Transport, Extracellular



out via diffusion


CO2tis_mc
CO2 myocyte transport
co2[i] <==> co2[y]
Transport, Extracellular



out via diffusion


CRTNt
creatinine transport
crtn[i] <==> crtn[e]
Transport, Extracellular


GLCt1_xo
glucose transport (uniport:
glc-D[e] <==> glc-D[i]
Transport, Extracellular



facilitated diffusion), intra-



organism


GLCt1is_ac
glucose transport into
glc-D[i] <==> glc-D[a]
Transport, Extracellular



adipocyte (uniport:



facilitated diffusion)


GLCt1is_mc
glucose transport into
glc-D[i] <==> glc-D[y]
Transport, Extracellular



myocyte (uniport:



facilitated diffusion)


H2Ot5_xo
H2O transport via
h2o[e] <==> h2o[i]
Transport, Extracellular



diffusion


H2Ot5is_ac
H2O transport into
h2o[i] <==> h2o[a]
Transport, Extracellular



adipocyte via diffusion


H2Ot5is_mc
H2O transport into
h2o[i] <==> h2o[y]
Transport, Extracellular



myocyte via diffusion


ILEt
L-isoeucine transport
h[e] + ile-L[e] <==> h[i] + ile-L[i]
Transport, Extracellular
TC-2.A.26



in/out via proton symport


L-LACt2_xo
L-lactate transport via
h[e] + lac-L[e] <==> h[i] + lac-L[i]
Transport, Extracellular



proton symport


L-LACt2is_mc
L-lactate reversible
h[i] + lac-L[i] <==> h[y] + lac-L[y]
Transport, Extracellular



transport into myocyte via



proton symport


O2t_xo
O2 transport via diffusion
o2[e] <==> o2[i]
Transport, Extracellular


O2tis_ac
O2 transport into
o2[i] <==> o2[a]
Transport, Extracellular



adipocyte via diffusion


O2tis_mc
O2 transport into myocyte
o2[i] <==> o2[y]
Transport, Extracellular



via diffusion


Plt2_xo [deleted
phosphate transport in via
h[e] + pi[e] --> h[i] + pi[i]
Transport, Extracellular


Aug. 26, 2004
proton symport


01:34:57 PM]


Plt6is_ac
phosphate transport in/out
h[i] + pi[i] <==> h[a] + pi[a]
Transport, Extracellular
TC-2.A.20



of adipocyte via proton



symporter


PIt6is_mc
phosphate transport in/out
h[i] + pi[i] <==> h[y] + pi[y]
Transport, Extracellular
TC-2.A.20



of myocyte via proton



symporter


3MOPtm_ac
3-Methyl-2-oxopentanoate
3mop[a] <==> 3mop[b]
Transport,



transport, diffusion,

Mitochondrial



adipocyte mitochondrial


ATP/ADPtm_ac
ATP/ADP transport,
adp[a] + atp[b] <==> adp[b] + atp[a]
Transport,



adipocyte mitochondrial

Mitochondrial


ATP/ADPtm_mc
ATP/ADP transport,
adp[y] + atp[z] <==> adp[z] + atp[y]
Transport,



myocyte mitochondrial

Mitochondrial


CITtam_ac
citrate transport, adipocyte
cit[a] + mal-L[b] <==> cit[b] + mal-
Transport,



mitochondrial
L[a]
Mitochondrial


CITtam_mc
citrate transport, myocyte
cit[y] + mal-L[z] <==> cit[z] + mal-
Transport,



mitochondrial
L[y]
Mitochondrial


CO2tm_ac
CO2 transport (diffusion),
co2[a] <==> co2[b]
Transport,



adipocyte mitochondrial

Mitochondrial


CO2tm_mc
CO2 transport (diffusion),
co2[y] <==> co2[z]
Transport,



myocyte mitochondrial

Mitochondrial


CRNCARtm_mc
carnithine-acetylcarnithine
acrn[y] + crn[z] --> acrn[z] + crn[y]
Transport,



carrier, myocyte

Mitochondrial



mitochondrial


CRNODETm_mc
carnitine 9-cis-
coa[z] + odecrn9[y] <==> crn[y] + odecoa9[z]
Transport,



octadecenoyltransferase

Mitochondrial



II, myocyte


CRNPTDTm_mc
carnitine
coa[z] + pdcrn[y] <==> crn[y] + pdcoa[z]
Transport,



pentadecanoyltransferase

Mitochondrial



II, myocyte


DHAP1tm_ac
dihydroxyacetone
dhap[a] <==> dhap[b]
Transport,



phosphate transport,

Mitochondrial



adipocyte mitochondrial


DHAP1tm_mc
dihydroxyacetone
dhap[y] <==> dhap[z]
Transport,



phosphate transport,

Mitochondrial



myocyte mitochondrial


GACm_ac
glutamate aspartate
asp-L[b] + glu-L[a] + h[a] --> asp-
Transport,



carrier, adipocyte
L[a] + glu-L[b] + h[b]
Mitochondrial



cytosolic/mitochondrial


GACm_mc
glutamate aspartate
asp-L[z] + glu-L[y] + h[y] --> asp-
Transport,



carrier, myocyte
L[y] + glu-L[z] + h[z]
Mitochondrial



cytosolic/mitochondrial


GL3Ptm_mc
glycerol-3-phosphate
glyc3p[y] <==> glyc3p[z]
Transport,



transport, myocyte

Mitochondrial



mitochondrial


GTPt3m_ac
GTP/GDP transporter,
gdp[b] + gtp[a] + h[a] --> gdp[a] + gtp[b] + h[b]
Transport,



adipocyte mitochondrial

Mitochondrial


GTPt3m_mc
GTP/GDP transporter,
gdp[z] + gtp[y] + h[y] --> gdp[y] + gtp[z] + h[z]
Transport,



myocyte mitochondrial

Mitochondrial


H2Otm_ac
H2O transport, adipocyte
h2o[a] <==> h2o[b]
Transport,



mitochondrial

Mitochondrial


H2Otm_mc
H2O transport, myocyte
h2o[y] <==> h2o[z]
Transport,



mitochondrial

Mitochondrial


MALAKGtm_ac
malate-alphaketoglutarate
akg[b] + mal-L[a] --> akg[a] + mal-
Transport,



transporter, adipocyte
L[b]
Mitochondrial



mitochondria


MALAKGtm_mc
malate-alphaketoglutarate
akg[z] + mal-L[y] --> akg[y] + mal-
Transport,



transporter, myocyte
L[z]
Mitochondrial



mitochondria


O2trm_ac
O2 transport into
o2[a] <==> o2[b]
Transport,



adipocyte mitochondria

Mitochondrial



(diffusion)


O2trm_mc
O2 transport into myocyte
o2[y] <==> o2[z]
Transport,



mitochondria (diffusion)

Mitochondrial


Pltm_ac
phosphate transporter,
h[a] + pi[a] <==> h[b] + pi[b]
Transport,



adipocyte mitochondrial

Mitochondrial


Pltm_mc
phosphate transporter,
h[y] + pi[y] <==> h[z] + pi[z]
Transport,



myocyte mitochondrial

Mitochondrial


PPAtm_ac
propionate transport in/out
h[a] + ppa[a] <==> h[b] + ppa[b]
Transport,
TC-2.A.20



via proton symport,

Mitochondrial



adipocyte


PYRtm_ac
pyruvate transport,
h[a] + pyr[a] <==> h[b] + pyr[b]
Transport,



adipocyte mitochondrial

Mitochondrial


PYRtm_mc
pyruvate transport,
h[y] + pyr[y] <==> h[z] + pyr[z]
Transport,



myocyte mitochondrial

Mitochondrial


CRNCARtp_mc
carnithine-acetylcarnithine
acrn[y] + crn[w] <==> acrn[w] + crn[y]
Transport, Peroxisomal



carrier, myocyte



peroxixome

## Claims

1. A computer readable medium or media having stored thereon computer-implemented instructions causing a processor to generate an output describing a physiological function of a first cell and a second cell that interact with one another via an intercellular space by performing steps comprising:
(a) providing a first stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of first reactions within a first naturally occurring biochemical network within the first cell, each of said reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the first stoichiometric matrix relates said substrate and said product;
(b) providing a second stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of second reactions within a second naturally occurring biochemical network within the second cell, each of said reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the second stoichiometric matrix relates said substrate and said product;
(c) providing a third stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of intercellular reactions relating to an interaction between said first and second cells via a third naturally occurring biochemical network within the intercellular space, each of said intercellular reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the third stoichiometric matrix relates said substrate and said product;
(d) providing a constraint set for said plurality of reactions for said first, second, and third stoichiometric matrices, the constraint set specifying an upper or lower boundary of flux through each of the reactions described in the first, second, and third stoichiometric matrices;
(e) defining an objective function to be a linear combination of fluxes through the reactions described in the first, second, and third stoichiometric matrices that relates to a physiological function of said first and second cells;
(f) determining at least one flux distribution for said plurality of first, second, and intercellular reactions across said first cell, said second cell, and said intercellular space by (i) identifying a plurality of flux vectors that each satisfies the first, second, and third stoichiometric matrices and satisfies the constraint set and (ii) identifying at least one linear combination of the identified flux vectors that minimizes or maximizes the objective function, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells; and
(g) providing output to a user of said at least one flux distribution determined in step (f).

2. The computer readable medium or media of claim 1, further comprising instructions causing the processor to provide one or more fourth stoichiometric matrices, each fourth stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of reactions within one or more third cells within a multicellular organism, each of said reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the one or more fourth stoichiometric matrices relates said substrate and said product.

3. The computer readable medium or media of claim 2, wherein said one or more fourth stoichiometric matrices comprises a plurality of stoichiometric matrices.

4. The computer readable medium or media of claim 3, wherein said plurality of stoichiometric matrices comprise a stoichiometric matrix for a plurality of different cells.

5. The computer readable medium or media of claim 2, wherein said plurality of stoichiometric matrices comprise a stoichiometric matrix for a plurality of different cell types.

6. The computer readable medium or media of claim 4 or 5, wherein said one or more third cells comprise at least 4 cells, 5 cells, 6 cells, 7 cells, 8 cells, 9 cells, 10 cells, 100cells, 1000 cells, 5000 cells, 10,000 cells or more.

7. The computer readable medium or media of claim 1, wherein said first and second cells comprise eukaryotic cells.

8. The computer readable medium or media of claim 1, wherein said first and second cells comprise prokaryotic cells.

9. The computer readable medium or media of claim 7, wherein said first and second eukaryotic cells comprise cells of the same tissue or organ.

10. The computer readable medium or media of claim 7, wherein said first and second eukaryotic cells comprise cells of different tissues or organs.

11. The computer readable medium or media of claim 1, wherein at least one of said reactions is annotated to indicate an associated gene.

12. The computer readable medium or media of claim 11, further comprising a gene database having information characterizing said associated gene.

13. The computer readable medium or media of claim 1, wherein at least one reaction within said plurality of first reactions, said plurality of second reactions, or said plurality of intercellular reactions is a regulated reaction.

14. The computer readable medium or media of claim 13, wherein said constraint set includes a variable constraint for said regulated reaction.

15. The computer readable medium or media of claim 1, wherein said plurality of intercellular reactions comprise one or more reactions performed in the hematopoietic system, urine, connective tissue, contractile system, lymphatic system, respiratory system or renal system.

16. The computer readable medium or media of claim 15, wherein said intercellular reactions comprise a reactant or reactions selected from the group consisting of a bicarbonate buffer system, an ammonia buffer system, a hormone, a signaling molecule, a vitamin, a mineral or a combination thereof.

17. The computer readable medium or media of claim 1, wherein said first or second cell is selected from a mammary gland cell, hepatocyte, white fat cell, brown fat cell, liver lipocyte, red skeletal muscle cell, white skeletal muscle cell, intermediate skeletal muscle cell, smooth muscle cell, red blood cell, adipocyte, monocyte, reticulocyte, fibroblast, neuronal cell epithelial cell or a cell set forth in Table 5.

18. The computer readable medium or media of claim 1, wherein said physiological function is selected from metabolite yield, ATP yield, biomass demand, growth, triacylglycerol storage, muscle contraction, milk secretion and oxygen transport capacity.

19. The computer readable medium or media of claim 1, wherein at least one reactant within said plurality of first reactions, said plurality of second reactions, or said plurality of intercellular reactions or at least one reaction within said plurality of first reactions, said plurality of second reactions, or said plurality of intercellular reactions is annotated with an assignment to a subsystem or compartment.

20. The computer readable medium or media of claim 19, wherein a first substrate or product in said plurality of reactions is assigned to a first compartment and a second substrate or product in said plurality of reactions is assigned to a second compartment.

21. The computer readable medium or media of claim 12, wherein a plurality of reactions is annotated to indicate a plurality of associated genes and wherein said gene database comprises information characterizing said plurality of associated genes.

22. A computer readable medium or media having stored thereon computer-implemented instructions causing a processor to generate an output describing a physiological function of a plurality of first cells and a plurality of second cells that interact with one another via an intercellular space by performing steps comprising:
(a) providing a plurality of first stoichiometric matrices having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of first reactions within a plurality of first naturally occurring biochemical networks within the plurality of first cells within a multicellular organism, each of said first reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the stoichiometric matrix relates said substrate and said product;
(b) providing a plurality of second stoichiometric matrices having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of second reactions within a plurality of second naturally occurring biochemical networks within the plurality of second cells within said multicellular organism, each of said second reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the stoichiometric matrix relates said substrate and said product;
(c) providing a plurality of third stoichiometric matrices having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of intercellular reactions relating to interactions between the plurality of first and second cells within said multicellular organism via a plurality of third naturally occurring biochemical networks within the intercellular space, each of said intercellular reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the stoichiometric matrix relates said substrate and said product;
(d) providing a constraint set for said plurality of reactions for said pluralities of first, second and third stoichiometric matrices, the constraint set specifying an upper or lower boundary of flux through each of the reactions described in the pluralities of first, second, and third stoichiometric matrices;
(e) defining an objective function to be a linear combination of fluxes through the reactions described in the pluralities of first, second, and third stoichiometric matrices that relates to a physiological function of said multicellular organism;
(f) determining at least one flux distribution for said pluralities of first, second, and intercellular reactions across said plurality of first cells, said plurality of second cells and said plurality of intercellular spaces by (i) identifying a plurality of flux vectors that each satisfies the pluralities of first, second, and third stoichiometric matrices and satisfies the constraint set and (ii) identifying at least one linear combination of the identified flux vectors within said multicellular organism that minimizes or maximizes the objective function, wherein said at least one flux distribution is predictive of a physiological function of said multicellular organism; and
(g) providing output to a user of said at least one flux distribution determined in step (f).

23. The computer readable medium or media of claim 22, further comprising a plurality of fourth stoichiometric matrices, each of said plurality of fourth stoichiometric matrices having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of reactions within a plurality of third cells within a multicellular organism, each of said reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the plurality of fourth stoichiometric matrices relates said substrate and said product.

24. The computer readable medium or media of claim 23, wherein said plurality of first through fourth stoichiometric matrices comprise stoichiometric matrices for a plurality of different cells.

25. The computer readable medium or media of claim 23, wherein said plurality of first through fourth stoichiometric matrices comprise stoichiometric matrices for a plurality of different cell types.

26. The computer readable medium or media of claim 24 or 25, wherein said one or more third cells comprise at least 4 cells, 5 cells, 6 cells, 7 cells, 8 cells, 9 cells, 10 cells, 100 cells, 1000 cells, 5000 cells, 10,000 cells or more.

27. A computer implemented method for predicting a physiological function of a first cell and second cell that interact with one another via an intercellular space in a multicellular organism, comprising:
(a) providing on a computer a first stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of first reactions within a first naturally occurring biochemical network within the first cell, each of said reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the first stoichiometric matrix relates said substrate and said product;
(b) providing on a computer a second stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of second reactions within a second naturally occurring biochemical network within the second cell, each of said reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the second stoichiometric matrix relates said substrate and said product;
(c) providing on a computer a third stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of intercellular reactions relating to an interaction between said first and second cells via a third naturally occurring biochemical network within the intercellular space, each of said intercellular reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the third stoichiometric matrix relates said substrate and said product;
(d) providing a constraint set for said plurality of reactions for said first, second and third stoichiometric matrices, the constraint set specifying an upper or lower boundary of flux through each of the reactions described in the first, second, and third stoichiometric matrices;
(e) defining an objective function to be a linear combination of fluxes through the reactions described in the first, second, and third stoichiometric matrices that relates to a physiological function of said first and second cells;
(f) determining at least one flux distribution for said plurality of first, second, and intercellular reactions across said first cell, said second cell and said intercellular space by (i) identifying a plurality of flux vectors that each satisfies the first, second, and third stoichiometric matrices and satisfies the constraint set and (ii) identifying at least one linear combination of the identified flux vectors that minimizes or maximizes the objective function, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells; and
(g) providing output to a user of said at least one flux distribution determined in step (f).

28. The method of claim 27, further comprising one or more fourth stoichiometric matrices, each fourth stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of reactions within one or more third cells within a multicellular organism, each of said reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, wherein a stoichiometric coefficient of the one or more fourth stoichiometric matrices relates said substrate and said product.

29. The method of claim 28, wherein said one or more fourth stoichiometric matrices comprises a plurality of stoichiometric matrices.

30. The method of claim 29, wherein said plurality of stoichiometric matrices comprise a stoichiometric matrix for a plurality of different cells.

31. The method of claim 29, wherein said plurality of stoichiometric matrices comprise a stoichiometric matrix for a plurality of different cell types.

32. The method of claim 30 or 31, wherein said one or more third cells comprise at least 4 cells, 5 cells, 6 cells, 7 cells, 8 cells, 9 cells, 10 cells, 100 cells, 1000 cells, 5000 cells, 10,000 cells or more.

33. The method of claim 27, wherein said first and second cells comprise eukaryotic cells.

34. The method of claim 27, wherein said first and second cells comprise prokaryotic cells.

35. The method of claim 33, wherein said first and second eukaryotic cells comprise cells of the same tissue or organ.

36. The method of claim 33, wherein said first and second eukaryotic cells comprise cells of different tissues or organs.

37. The method of claim 27, wherein at least one of said reactions is annotated to indicate an associated gene.

38. The method of claim 27, further comprising a gene database having information characterizing said associated gene.

39. The method of claim 27, wherein at least one of said reactions is a regulated reaction.

40. The method of claim 39, wherein said constraint set includes a variable constraint for said regulated reaction.

41. The method of claim 27, wherein said at least one intercellular reaction comprises one or more reactions performed in the hematopoietic system, urine, connective tissue, contractile system, lymphatic system, respiratory system or renal system.

42. The method of claim 41, wherein said intercellular reactions comprise a reactant or reactions selected from the group consisting of a bicarbonate buffer system, an ammonia buffer system, a hormone, a signaling molecule, a vitamin, a mineral or a combination thereof.

43. The method of claim 27, wherein said first or second cell is selected from a mammary gland cell, hepatocyte, white fat cell, brown fat cell, liver lipocyte, red skeletal muscle cell, white skeletal muscle cell, intermediate skeletal muscle cell, smooth muscle cell, red blood cell, adipocyte, monocyte, reticulocyte, fibroblast, neuronal cell epithelial cell or a cell set forth in Table 5.

44. The method of claim 27, wherein said physiological function is selected from metabolite yield, ATP yield, biomass demand, growth, triacylglycerol storage, muscle contraction, milk secretion and oxygen transport capacity.

45. The method of claim 27, wherein at least one reactant within said plurality of first reactions, said plurality of second reactions, or said plurality of intercellular reactions or at least one reaction within said plurality of first reactions, said plurality of second reactions, or said plurality of intercellular reactions is annotated with an assignment to a subsystem or compartment.

46. The method of claim 45, wherein a first substrate or product in said plurality of reactions is assigned to a first compartment and a second substrate or product in said plurality of reactions is assigned to a second compartment.

47. The method of claim 38, wherein a plurality of reactions is annotated to indicate a plurality of associated genes and wherein said gene database comprises information characterizing said plurality of associated genes.