Modular Architecture of Metabolic Pathways Revealed by Conserved Sequences of Reactions

Abstract

The metabolic network is both a network of chemical reactions and a network of enzymes that catalyze reactions. Toward better understanding of this duality in the evolution of the metabolic network, we developed a method to extract conserved sequences of reactions called reaction modules from the analysis of chemical compound structure transformation patterns in all known metabolic pathways stored in the KEGG PATHWAY database. The extracted reaction modules are repeatedly used as if they are building blocks of the metabolic network and contain chemical logic of organic reactions. Furthermore, the reaction modules often correspond to traditional pathway modules defined as sets of enzymes in the KEGG MODULE database and sometimes to operon-like gene clusters in prokaryotic genomes. We identified well-conserved, possibly ancient, reaction modules involving 2-oxocarboxylic acids. The chain extension module that appears as the tricarboxylic acid (TCA) reaction sequence in the TCA cycle is now shown to be used in other pathways together with different types of modification modules. We also identified reaction modules and their connection patterns for aromatic ring cleavages in microbial biodegradation pathways, which are most characteristic in terms of both distinct reaction sequences and distinct gene clusters. The modular architecture of biodegradation modules will have a potential for predicting degradation pathways of xenobiotic compounds. The collection of these and many other reaction modules is made available as part of the KEGG database.

KEGG: new perspectives on genomes, pathways, diseases and drugs

“…First, the RPAIR database for reactant pairs (7) was discontinued, but its main content for defining reaction classes (8) remains to be available as pairs of COMPOUND entries. Second, the DGENES database (7) for eukaryotic draft genomes was merged into the GENES database.…”

PIERO ontology for analysis of biochemical transformations: Effective implementation of reaction information in the IUBMB enzyme list

“…10 The relationships between biochemical substructures and the corresponding names were retrieved from the BiSSCat database 11 using KEGG Chemical Functionand-Substructures (KCF-S). 12 These data were converted to the Resource Description Framework (RDF), where the relationships were described by the triad of subjects, predicates, and objects.…”

Automated interpretation of metabolic capacity from genome and metagenome sequences

“…The reactions of citrate synthase (R00351) and homocitrate synthase (R00271) are simplified in the reaction map formulas excluding water and CoA, and sometimes acetyl-CoA as well. Figure 4 shows additional processing of reaction data in KEGG [8]. The reaction formula is decomposed into a set of reactant pairs, one-to-one relationships of substrateproduct pairs, by considering the reaction type and the flow of atoms.…”

“…Using the reaction class information, a systematic survey was performed both computationally and manually to extract conserved reaction sequence patterns, represented by RC number sequences, from all known metabolic pathways in KEGG [8]. As already mentioned, reaction modules (also called RC modules) tend to correspond to KEGG modules (also called KO modules) despite the fact that they are separately defined from different properties.…”

“…However, it is more complex because of the existence of subtypes caused by the fact that reaction class is too finely classified. Reaction modules are defined by considering the similarity grouping of RC entries [8], for example, RC00067, RC01205, and RC00470 are the same in this grouping.…”