title: 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.
authors: Bioinformatics Center, Institute for Chemical Research, Kyoto University , Uji, Kyoto 611-0011, Japan.
authors: Ai
authors: A
authors: Muto
authors: Masaaki
authors: M
authors: Kotera
authors: Toshiaki
authors: T
authors: Tokimatsu
authors: Zenichi
authors: Z
authors: Nakagawa
authors: Susumu
authors: S
authors: Goto
authors: Minoru
authors: M
authors: Kanehisa
mesh_terms: D001711:Biotransformation; D002952:Citric Acid Cycle / Q000235:genetics; D017124:Conserved Sequence; D030541:Databases, Genetic; D004798:Enzymes / Q000737:chemistry; D005227:Fatty Acids / Q000138:chemical synthesis; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D005810:Multigene Family; D010084:Oxidation-Reduction
chemical_list: D004798:Enzymes; D005227:Fatty Acids
references: J Theor Biol. 1974 Mar;44(1):145-60
references: 4207200
references: Annu Rev Microbiol. 1996;50:553-90
references: 8905091
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D593-7
references: 18776214
references: J Comput Biol. 1999 Fall-Winter;6(3-4):343-60
references: 10582571
references: Plant J. 2011 Apr;66(1):66-79
references: 21443624
references: Genetics. 1999 Aug;152(4):1299-305
references: 10430560
references: Bioinformatics. 2002 Feb;18(2):351-61
references: 11847093
references: Science. 2002 Aug 30;297(5586):1551-5
references: 12202830
references: Proc Natl Acad Sci U S A. 1945 Jun;31(6):153-7
references: 16578152
references: J Am Chem Soc. 2003 Oct 1;125(39):11853-65
references: 14505407
references: J Bacteriol. 2000 May;182(10):2753-60
references: 10781543
references: Annu Rev Microbiol. 1976;30:409-25
references: 791073
references: Biochem J. 1999 Oct 1;343 Pt 1:115-24
references: 10493919
references: J Comput Biol. 2011 Mar;18(3):219-35
references: 21385030
references: Trends Biochem Sci. 2004 Dec;29(12):641-7
references: 15544950
references: Bioinformatics. 2005 Aug 15;21(16):3401-8
references: 15985496
references: Nucleic Acids Res. 2000 Oct 15;28(20):4021-8
references: 11024183
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D109-14
references: 22080510
references: Genome Res. 1998 Mar;8(3):203-10
references: 9521924
references: J Bacteriol. 2012 Jan;194(2):544
references: 22207748
references: Bioinformatics. 2007 Aug 1;23(15):1978-85
references: 17540683
references: Arch Microbiol. 2005 Jan;183(1):27-36
references: 15551059
references: J Am Chem Soc. 2004 Dec 22;126(50):16487-98
references: 15600352
references: BMC Bioinformatics. 2006 Mar 13;7:130
references: 16533389
references: Nat Chem Biol. 2009 Sep;5(9):673-9
references: 19620981
references: Genetica. 1999;106(1-2):159-70
references: 10710722
references: Proc Int Conf Intell Syst Mol Biol. 2000;8:376-83
references: 10977098