# Exploring Plant Sesquiterpense Diversity by Generating Chemical Networks
## 1 Introduction  
Terpenes form a large and diverse class of natural products appearing particularly in the essential oils of many plants. They have commercial uses in medicine and as fragrances in perfumery. Synthetic derivatives of natural terpen are also used as aromas and foodadditives [1]. Ecologically, they perform key functions both in direct plant defense and in indirect mechanisms involving herbivores and their natural enemies [2]. Terpenes are produced throughout the tree of life from the \(C_{5}\) compounds isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). [PERSON] [3] formulated the\"biogenetic isoprene rule\" according to which terpen are the result of concatenating isoprene units in a \"head-to-tail\" fashion to form chains, from which then rings are formed. Prenyltransferasees condense IPP and DMAPP to geranyl pyrophosphate (GPP), famesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) as the entry points to the world of monoterpenes (\(C_{10}\)), sesquiterpenes (\(C_{15}\)), and diterpenes(\(C_{20}\)) [4]. FPP and GGPP can then be condensed further to form squalene (\(C_{30}\)) and even largermolecules [5]. These intermediates are substrates for a class of enzymes known collectively as terpene synthases (TPSs) to produce a wide variety of compounds. There are two major classes of TPS, which are distinguished by essential amino acid motifs [6; 7]. Class I TPS, which are of interest in this contribution, convert linear, all-trans, isoprenoids, geranyl (\(C_{10}\))-, famesyl (\(C_{15}\))-, or geranylgeranyl (\(C_{20}\))-diphosphate into numerous monoterpenes, sesquiterpenes, and diterpenes. They bind their substrates by the coordination of a divalent metal ion catalytic site consisting of a central cavity formed by mostly antiparallel \(\alpha\)-helices. This catalytic site has an aspartate-rich \(DDxxD/E\) motif and often another \(NSE/DTE\) motif in the C-terminal portion [8; 9; 10]. The mechanisms of sesquiterpenes synthesis involve the formation of C-C bonds, cationic intermediates, Wagner-Meerwein rearrangements, carbocation capture by water and hydride, as well as methyl- and allyl-shifts caused by conformational changes of intermediate cations [11; 12; 13]. A combinatorial reaction cascade inside the TPS combining different cyclization/rearrangement reactions yields a highly diverse set of sesquiterpenes from just a handful of simple acyclic precursors molecules. Nevertheless, there are only four dominating types of cyclization reactions initiating the complex reaction cascade: \(C_{1}\)-\(C_{10}\), \(C_{1}\)-\(C_{11}\), \(C_{1}\)-\(C_{6}\), and \(C_{1}\)-\(C_{7}\)[14]. Even though the electrophilic chemical reaction mechanisms primarily determine the diversity of the products [11], many other factors influence multiproduct sesquiterpene enzymes and their cyclization cascades, such as \(pH\), the metal cofactor [4], evolutionary forces for the functional divergence [15], plant tissue [16], and plant-plant interactions [17]. Throughout this contribution, we will refer to such a collection of factors as a _Scenario_. The complexity of the portfolio of sesquiterpenes and their synthesis pathways calls for computational models that explain the observed diversity and can be used to predict biosynthetic pathways for particular terpene compounds. Within the field of systems biology, the reconstruction and exploration of metabolic networks is grounded in determining the metabolic capabilities from the enzymes encoded in the genome and the extensive knowledge on enzymes themselves collected, e.g., in the BRENDA database [18]. Several software tools have been developed to predict pathways from annotated genome sequences and to analyze and explore them. Pathway Tools[19], for instance, is a system designed for the BioCyc database collection [20]. Complementarily, versatile tools have become available to predict the metabolism of xenobiotics, in particular, aiming at drugs.