SII-SWORD/CoKE huggingface dataset:
4-oxalocrotonate tautomerase (4-OT)
Type: Family

This entry represents 4-Oxalocrotonate tautomerase (4-OT, also known as 2-hydroxymuconate tautomerase) from bacteria and some archaeal species. It is an enzyme that converts 2-hydroxymuconate to the α-β-unsaturated ketone, 2-oxo-3-hexenedioate . This enzyme forms part of a bacterial metabolic pathway that oxidatively catabolizes toluene, o-xylene, 3-ethyltoluene, and 1,2,4-trimethylbenzene into intermediates of the citric acid cycle. With a monomer size of just 62 amino acid residues, the 4-Oxalocrotonate tautomerase is one of the smallest enzyme subunits known . However, in solution, the enzyme forms a hexamer of six identical subunits, so the active site may be formed by amino acid residues from several subunits . This enzyme is also unusual in that it uses a proline residue at the amino terminus as an active site residue.
Small ribosomal subunit protein uS5, N-terminal, conserved site (Ribosomal_uS5_N_CS)
Type: Conserved_site

Ribosomal protein uS5 is one of the proteins from the small ribosomal subunit, and is a protein of 166 to 254 amino-acid residues. In Escherichia coli, S5 is known to be important in the assembly and function of the 30S ribosomal subunit. Mutations in S5 have been shown to increase translational error frequencies. It belongs to a family of ribosomal proteins which, on the basis of sequence similarities , groups bacterial, cyanelle, red algal chloroplast, archaeal and fungal mitochondrial S5; mammalian, Caenorhabditis elegans, Drosophila and plant S2; and yeast S4 (SUP44).

This entry represents a conserved glycine-rich region found at the N-terminal of the ribosomal protein uS5.
Glycerate kinase, flavodoxin-like fold (Glyc_kinase_flavodox-like_fold)
Type: Homologous_superfamily

Proteins in this entry include glycerate kinase 2 (

), which catalyses the phosphorylation of (R)-glycerate to 3-phospho-(R)-glycerate in the presence of ATP. These proteins consist of two different α/β domains: domain 1 has a flavodoxin-like fold, while domain 2 has a restriction enzyme-like fold (domain 2 is inserted into domain 1).

This superfamily represents domain 1 with a flavodoxin-like fold.
Nickel-dependent hydrogenase, large subunit, nickel binding site (Ni-dep_hyd_lsu_Ni_BS)
Type: Binding_site

Hydrogenases are enzymes that catalyse the reversible oxidation of hydrogen and are important in anaerobic metabolism. There are various types of metal-containing hydrogenases and can be broadly divided into three groups: Fe ('iron only') hydrogenases; Ni-Fe hydrogenases; and Ni-Fe-Se hydrogenases .

The [NiFe] and [NiFeSe] hydrogenases are heterodimer that consist of a small subunit (S) that contains a signal peptide and a large subunit (L). All the known large subunits seem to be evolutionary related ; they contain two Cys-x-x-Cys motifs; one at their N-terminal end; the other at their C-terminal end. These four cysteines are involved in the binding of nickel . In the [NiFeSe] hydrogenases the first cysteine of the C-terminal motif is a selenocysteine which has experimentally been shown to be a nickel ligand .
Transferrin family, iron binding site (Transferrin_Fe_BS)
Type: Binding_site

Transferrins are a family of eukaryotic iron-binding glycoproteins that share the common function of controlling the level of free iron in biological fluids . The transferrin family currently includes:

Blood serotransferrin (siderophilin).

Milk lactotransferrin (lactoferrin).

Egg white ovotransferrin (conalbumin).

Membrane-associated melanotransferrin.

Inhibitor of carbonic anhydrase.

Transferrins are proteins of 650 to 700 residues which have evolved from the duplication of a domain of around 340 residues. Each of the duplicated domains binds one atom of iron. Each iron atom is bound by four conserved residues: an aspartic acid, two tyrosines, and a histidine . All of the cysteines in both domains are involved in intradomain disulphide bonds.
Glycerate kinase, restriction-enzyme-like fold (Glycerate_kinase_RE-like)
Type: Homologous_superfamily

Glycerate kinase 2 (

) catalyses the phosphorylation of (R)-glycerate to 3-phospho-(R)-glycerate in the presence of ATP. These proteins consist of two different α/β domains: domain 1 has a flavodoxin-like fold, while domain 2 has a restriction enzyme-like fold (domain 2 is inserted into domain 1).
ATP phosphoribosyltransferase, conserved site (ATP_PRibTrfase_CS)
Type: Conserved_site

ATP phosphoribosyltransferase (

) is the enzyme that catalyzes the first step in the biosynthesis of histidine in bacteria, fungi and plants as shown below. It is a member of the larger phosphoribosyltransferase superfamily of enzymes which catalyse the condensation of 5-phospho-alpha-D-ribose 1-diphosphate with nitrogenous bases in the presence of divalent metal ions .

ATP + 5-phospho-alpha-D-ribose 1-diphosphate = 1-(5-phospho-D-ribosyl)-ATP + diphosphate

Histidine biosynthesis is an energetically expensive process and ATP phosphoribosyltransferase activity is subject to control at several levels. Transcriptional regulation is based primarily on nutrient conditions and determines the amount of enzyme present in the cell, while feedback inihibition rapidly modulates activity in response to cellular conditions. The enzyme has been shown to be inhibited by 1-(5-phospho-D-ribosyl)-ATP, histidine, ppGpp (a signal associated with adverse environmental conditions) and ADP and AMP (which reflect the overall energy status of the cell). As this pathway of histidine biosynthesis is present only in prokayrotes, plants and fungi, this enzyme is a promising target for the development of novel antimicrobial compounds and herbicides.

ATP phosphoribosyltransferase is found in two distinct forms: a long form containing two catalytic domains and a C-terminal regulatory domain, and a short form in which the regulatory domain is missing. The long form is catalytically competent, but in organisms with the short form, a histidyl-tRNA synthetase paralogue, HisZ, is required for enzyme activity .
This entry represents the catalytic region of this enzyme.

The structures of the long form enzymes from Escherichia coli (

) and Mycobacterium tuberculosis (

) have been determined . The enzyme itself exists in equilibrium between an active dimeric form, an inactive hexameric form and higher aggregates. Interconversion between the various forms is largely reversible and is influenced by the binding of the natural substrates and inhibitors of the enzyme. The two catalytic domains are linked by a two-stranded β-sheet and togther form a "periplasmic binding protein fold". A crevice between these domains contains the active site. The C-terminal domain is not directly involved in catalysis but appears to be involved the formation of hexamers, induced by the binding of inhibitors such as histidine to the enzyme, thus regulating activity.

This entry represents the conserved site of ATP phosphoribosyltransferase enzymes.
Small ribosomal subunit protein eS4, N-terminal, conserved site (Ribosomal_eS4_N_CS)
Type: Conserved_site

A number of eukaryotic and archaeal ribosomal proteins can be grouped on the basis of sequence similarities. One of these families includes
small ribosomal subunit protein eS4 from archaea and eukaryotes. Small ribosomal subunit protein eS4A from yeast is also known as S7/YS6; archaeal members are also known as S4e; and mammalian and plant cytoplasmic proteins were previously known as S4 . Two highly similar isoforms of mammalian S4 exist, one coded by a gene on chromosome Y, and the other on chromosome X.

This entry represents the conserved site of the ribosomal protein eS4 that is found at the N-terminal region and includes some charged residues.
Ubiquitin specific protease, conserved site (USP_CS)
Type: Conserved_site

Protein ubiquitination is a reversible posttranslational modification that affects a large number of cellular processes, including protein degradation, trafficking, cell signalling, and the DNA damage response. Ubiquitination is reversible, and dedicated deubiquitinases exist that hydrolyse isopeptide bonds. Ubiquitin-specific proteases (USPs)

are the largest family of deubiquitinating enzymes. USP domains consist of a common conserved catalytic core that is interspersed at five points with insertions, some of which are as large as the catalytic domain itself. The insertions can fold into independent domains that can be involved in the regulation of deubiquitinase activity. As commonly found in signalling proteins, many USP deubiquitinases have a modular architecture and not only contain a catalytic domain but also additional protein-protein interaction and localisation domains. Most USP domains cleave the isopeptide linkage between two ubiquitin molecules and hence contain (at least) two ubiquitin-binding sites, one for the distal ubiquitin, the C terminus of which is linked to the Lys residue on the proximal ubiquitin in a second, proximal binding site . The USP domain forms the peptidase family C19 .

The USP catalytic core can be divided into six conserved boxes that are present in all USP domains. Box 1 contains the catalytic Cys residue, box 5 contains the catalytic His, and box 6 contains the catalytic Asp/Asn residue. All boxes show several additional conserved features and residues. Boxes 3 and 4 contain a Cys-X-X-Cys motif each, which have been shown to constitute a functional zinc-binding motif. Potentially, zinc-binding facilitates folding of the USP core, helping the interaction of sequence motifs some few hundred residues apart. USP domains share a common conserved fold. The USP domain resembles an open hand containing Thumb, Palm and Fingers subdomains. The catalytic triad resides between the Thumb (Cys) and Palm subdomains (His/Asp) .

This entry represents two conserved sites for the USP domain. The first one is around the catalytic cysteine in box 1, and the second around the catalytic histidine in box 5.
Beta-ketoacyl synthase, active site (Ketoacyl_synth_AS)
Type: Active_site

This entry represents the active site of beta-ketoacyl synthases from bacteria and eukaryotes.

Fatty acid synthases (FASs) and polyketide synthases (PKSs) are closely related and have a common evolutionary history. FASs and PKSs share a similar enzymatic domain structure in which acyl transferase (AT), ketosynthase (KS) and an acyl carrier protein (ACP) form the core structure for condensation of acyl units, and are essential for both PKSs and FASs .

Beta-ketoacyl-ACP synthase (EC 2.3.1.41) (KAS, also known as 3-oxoacyl synthase or ketoacyl synthase, KS) is the enzyme that catalyses the condensation of malonyl-ACP with the growing fatty acid chain. The condensation reaction is a two step process: the acyl component of an activated acyl primer is transferred to a cysteine residue of the enzyme and
is then condensed with an activated malonyl donor with the concomitant release
of carbon dioxide.

KASs fall into five families separated by their characteristic primary structures, each having members with the same catalytic residues, mechanisms, and tertiary structures. KS3, a very large family, is composed of bacterial and eukaryotic 3-ketoacyl-ACP synthases I and II, often found in multidomain fatty acid and polyketide synthases .
Serine carboxypeptidase, serine active site (Ser_caboxypep_ser_AS)
Type: Active_site

All known carboxypeptidases are either metallo carboxypeptidases or serine carboxypeptidases (

and

). The catalytic activity of the serine carboxypeptidases, like that of the trypsin family serine proteases, is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which is itself hydrogen-bonded to a serine . Proteins known to be serine carboxypeptidases include:

Barley and wheat serine carboxypeptidases I, II, and III .

Yeast carboxypeptidase Y (YSCY) (gene PRC1), a vacuolar protease involved in degrading small peptides.

Yeast KEX1 protease, involved in killer toxin and alpha-factor precursor processing.

Fission yeast sxa2, a probable carboxypeptidase involved in degrading or processing mating pheromones .

Penicillium janthinellum carboxypeptidase S1 .

Aspergullus niger carboxypeptidase pepF.

Aspergullus satoi carboxypeptidase cpdS.

Vertebrate protective protein / cathepsin A , a lysosomal protein which is not only a carboxypeptidase but also essential for the activity of both beta-galactosidase and neuraminidase.

Mosquito vitellogenic carboxypeptidase (VCP) .

Naegleria fowleri virulence-related protein Nf314 .

Yeast hypothetical protein YBR139w.

Caenorhabditis elegans hypothetical proteins C08H9.1, F13D12.6, F32A5.3, F41C3.5 and K10B2.2.

In higher plants and fungi serine carboxypeptidases are found in the cell vacuoles. In animal cells serine carboxypeptidases are found lysosomes .

The sequences surrounding the active site histidine residue are highly conserved in all these serine carboxypeptidases.
Tryptophan synthase, alpha chain, active site (Trp_synthase_alpha_AS)
Type: Active_site

Tryptophan synthase (

) catalyses the last step in the biosynthesis of tryptophan: the conversion of indoleglycerol phosphate and serine, to tryptophan and glyceraldehyde 3-phosphate .

Tryptophan synthetase has two functional domains: the alpha chain for the aldol cleavage of indoleglycerol phosphate to indole and glyceraldehyde 3-phosphate and the beta chain (

) for the synthesis of tryptophan from indole and serine. In bacteria and plants , each domain is found on a separate subunit (alpha and beta chains), while in fungi the two domains are fused together on a single multifunctional protein. In Escherichia coli, the 2 subunits, A and B, are encoded by the trpA and trpB genes respectively. In fungi the two domains are fused together in a single multifunctional protein, in the order: (NH2-A-B-COOH) . The two domains of the Neurospora crassa polypeptide are linked by a connector of 54-amino acid residues that has less than 25% identity to the 45-residue connector of the Saccharomyces cerevisiae (Baker's yeast) polypeptide. Two acidic residues are believed to serve as proton donors/acceptors in the enzyme's catalytic mechanism.

This entry represents a motif based around active site residues of the alpha chain. This motif contains three conserved acidic residues, where the first and the third acidic residues are believed to serve as proton donors/acceptors in the enzyme's catalytic mechanism .
Electron transfer flavoprotein subunit alpha, conserved site (ETF_asu_C_CS)
Type: Conserved_site

This entry represents the conserved site of the C-terminal domain of the alpha subunit of both Group I and Group II electron transfer flavoproteins.

Electron transfer flavoproteins (ETFs) serve as specific electron acceptors for primary dehydrogenases, transferring the electrons to terminal respiratory systems. They can be functionally classified into constitutive, "housekeeping" ETFs, mainly involved in the oxidation of fatty acids (Group I), and ETFs produced by some prokaryotes under specific growth conditions, receiving electrons only from the oxidation of specific substrates (Group II) .

ETFs are heterodimeric proteins composed of an alpha and beta subunit, and contain an FAD cofactor and AMP . ETF consists of three domains: domains I and II are formed by the N- and C-terminal portions of the alpha subunit, respectively, while domain III is formed by the beta subunit. Domains I and III share an almost identical α-β-α sandwich fold, while domain II forms an α-β-α sandwich similar to that of bacterial flavodoxins. FAD is bound in a cleft between domains II and III, while domain III binds the AMP molecule. Interactions between domains I and III stabilise the protein, forming a shallow bowl where domain II resides.
Haem oxygenase conserved site (Haem_oxygenase_CS)
Type: Conserved_site

Haem oxygenase (

) (HO) is the microsomal enzyme that, in animals, carries out the oxidation of haem, it cleaves the haem ring at the alpha-methene bridge to form biliverdin and carbon monoxide . Biliverdin is subsequently converted to bilirubin by biliverdin reductase. In mammals there are three isozymes of haem oxygenase: HO-1 to HO-3. The first two isozymes differ in their tissue expression and their inducibility: HO-1 is highly inducible by its substrate haem and by various non-haem substances, while HO-2 is non-inducible. It has been suggested that HO-2 could be implicated in the production of carbon monoxide in the brain where it is said to act as a neurotransmitter. In the genome of the chloroplast of red algae as well as in cyanobacteria, there is a haem oxygenase (gene pbsA) that is the key enzyme in the synthesis of the chromophoric part of the photosynthetic antennae . A haem oxygenase is also present in the bacteria Corynebacterium diphtheriae (gene hmuO), where it is involved in the acquisition of iron from the host haem . There is, in the central section of these enzymes, a well-conserved region centred on a histidine residue.
Glycoside hydrolase family 11, active site 1 (GH11_AS_1)
Type: Active_site

The microbial degradation of cellulose and xylans requires several types of enzymes such as endoglucanases (

), cellobiohydrolases (

) (exoglucanases), or xylanases (

) . Fungi and bacteria produces a spectrum of cellulolytic enzymes (cellulases) and xylanases which, on the basis of sequence similarities, can be classified into families. One of these families is known as the cellulase family G or as the glycosyl hydrolases family 11 .

The GH11 domain folds into a jelly-roll shape likened to a partially closed right hand. Several anti-parallel β-strands bend almost 90deg to produce a substrate-binding groove characteristic of the GH11 domain active sites. Two catalytic Glu residues face each other from opposite sides of the groove. The hydrolysis reaction is believed to follow a double- displacement mechanism, with one Glu residue acting as a general acid/base catalyst and the other as a nucleophile.

This entry represents a conserved region found in these enzymes that is centred on glutamic acid residues. The other conserved region is represented in

. In Bacillus pumilis xylanase, this site is necessary for catalytic activity .
Pyruvate kinase, active site (Pyrv_Knase_AS)
Type: Active_site

Pyruvate kinase (

) (PK) catalyses the final step in glycolysis , the conversion of phosphoenolpyruvate to pyruvate with concomitant phosphorylation of ADP to ATP:

ADP + phosphoenolpyruvate = ATP + pyruvate

The enzyme, which is found in all living organisms, requires both magnesium and potassium ions for its activity. In vertebrates, there are four tissue-specific isozymes: L (liver), R (red cells), M1 (muscle, heart and brain), and M2 (early foetal tissue). In plants, PK exists as cytoplasmic and plastid isozymes, while most bacteria and lower eukaryotes have one form, except in certain bacteria, such as Escherichia coli, that have two isozymes. All isozymes appear to be tetramers of identical subunits of ~500 residues.

PK helps control the rate of glycolysis, along with phosphofructokinase (

) and hexokinase (

). PK possesses allosteric sites for numerous effectors, yet the isozymes respond differently, in keeping with their different tissue distributions . The activity of L-type (liver) PK is increased by fructose-1,6-bisphosphate (F1,6BP) and lowered by ATP and alanine (gluconeogenic precursor), therefore when glucose levels are high, glycolysis is promoted, and when levels are low, gluconeogenesis is promoted. L-type PK is also hormonally regulated, being activated by insulin and inhibited by glucagon, which covalently modifies the PK enzyme. M1-type (muscle, brain) PK is inhibited by ATP, but F1,6BP and alanine have no effect, which correlates with the function of muscle and brain, as opposed to the liver.

The structure of several pyruvate kinases from various organisms have been determined . The protein comprises three-four domains: a small N-terminal helical domain (absent in bacterial PK), a β/α-barrel domain, a β-barrel domain (inserted within the β/α-barrel domain), and a 3-layer α/β/α sandwich domain.

This entry represents an active site that includes a lysine residue which seems to be the acid/base catalyst responsible for the interconversion of pyruvate and enolpyruvate, and a glutamic acid residue implicated in the binding of the magnesium ion.
Alcohol dehydrogenase, iron-type, conserved site (ADH_Fe_CS)
Type: Conserved_site

Alcohol dehydrogenase (

) (ADH) catalyses the reversible oxidation of ethanol to acetaldehyde with the concomitant reduction of NAD. Currently three, structurally and catalytically, different types of alcohol dehydrogenases are known:

Zinc-containing 'long-chain' alcohol dehydrogenases.

Insect-type, or 'short-chain' alcohol dehydrogenases.

Iron-containing alcohol dehydrogenases.

Iron-containing ADH's have been found in yeast (gene ADH4) , as well as in Zymomonas mobilis (gene adhB) . These two iron-containing ADH's are closely related to the following enzymes:

Escherichia coli lactaldehyde reductase (also known as propanediol oxidoreductase) (

) (gene fucO) , an enzyme involved in the metabolism of fucose and which also seems to contain ferrous ion(s).

Clostridium acetobutylicum NADPH- and NADH-dependent butanol dehydrogenases (

) (genes adh1, bdhA and bdhB) , an enzyme which has activity using butanol and ethanol as substrates.

E. coli aldehyde-alcohol dehydrogenase (AdhE) , an iron-dependent enzyme which harbor three different activities: alcohol dehydrogenase, acetaldehyde dehydrogenase (acetylating) (

) and pyruvate-formate-lyase deactivase.

Bacterial glycerol dehydrogenase (

) (gene gldA or dhaD) .

Clostridium kluyveri NAD-dependent 4-hydroxybutyrate dehydrogenase (4hbd) (

).

Citrobacter freundii and Klebsiella pneumoniae 1,3-propanediol dehydrogenase (

) (gene dhaT).

Bacillus methanolicus NAD-dependent methanol dehydrogenase (

) .

E. coli and Salmonella typhimurium ethanolamine utilization protein eutG.

E. coli hypothetical protein yiaY.
Sodium/solute symporter, conserved site (Na/solute_symporter_CS)
Type: Conserved_site

Sodium/substrate symport (or co-transport) is a widespread mechanism of solute transport across cytoplasmic membranes of pro-and eukaryotic cells. Thereby the energy stored in an inwardly directed electrochemical sodium gradient (sodium motive force, SMF) is used to drive solute accumulation against a concentration gradient. The SMF is generated by primary sodium pumps (e.g. sodium/potassium ATPases, sodium translocating respiratory chain complexes) or via the action of sodium/proton antiporters. Sodium/substrate transporters are grouped in different families based on sequence similarities .

One of these families, known as the sodium:solute symporter family (SSSF), contains over a hundred members of pro-and eukaryotic origin . The average hydropathy plot for SSSF proteins predicts 11 to 15 putative transmembrane domains (TMs) in α-helical conformation. A secondary structure model of PutP from Escherichia coli suggests the protein contains 13 TMs with the N terminus located on the periplasmic side of the membrane and the C terminus facing the cytoplasm. The results support the idea of a common topological motif for members of the SSSF. Transporters with a C-terminal extension are proposed to have an additional 14th TM.