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.

Figure 1

Fingerprint representation of the RDM pattern. Two reaction class entries RC00106 and RC01192 are shown for the reactant pairs of pyruvate and acetolactate (upper) and oxobutanoate and 2-aceto-2-hydroxybutanoate (lower). The RDM notation for these reaction class entries is converted to the fingerprint representation, which reveals that they are the same in the fingerprint representation despite the difference in the M atom (circled) in the RDM notation.

Figure 2

Architecture of reaction modules consisting of 2-oxocarboxylic acid chain extension and modification, generating (A) basic amino acids and (B) branched-chain amino acids. Vertical arrows indicate the extension modules RM001. Horizontal arrows indicate the modification modules RM002, RM032, and RM033 together with the reductive amination step (RC00006 and RC00036).

Figure 3

Aromatic ring cleavage modules in microbial degradation pathways. Aromatic rings are cleaved in the following three steps. The first step is an occasional preprocessing step (RM003) converting a methyl group into a carboxylic group on the aromatic ring. The second step is the main step of dihydroxylation, which is classified into three types (RM006, RM004, and RM005) depending on how two hydroxyl groups are added on the aromatic ring. The third step is either ortho-cleavage (RM008) or meta-cleavage (RM009) followed by characteristic reaction patterns leading to TCA cycle intermediates.