Nucleic Acids Research, 2006, Vol. 34, Database issue D511–D516 doi:10.1093/nar/gkj128 MetaCyc: a multiorganism database of metabolic pathways and enzymes Ron Caspi, Hartmut Foerster1, Carol A. Fulcher, Rebecca Hopkinson, John Ingraham2, 1 Pallavi Kaipa, Markus Krummenacker, Suzanne Paley, John Pick, Seung Y. Rhee , 5 Christophe Tissier1, Peifen Zhang1 and Peter D. Karp* SRI International, 333 Ravenswood, Menlo Park, CA 94025, USA, 1Department of Plant biology, Carnegie Institution, 260 Panama Street, Stanford, CA 94305, USA and 2Section of Microbiology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA Received September 15, 2005; Revised and Accepted October 21, 2005 10 ABSTRACT MetaCyc is a database of metabolic pathways and enzymes located at http://MetaCyc.org/. Its goal is to serve as a metabolic encyclopedia, containing a collection of non-redundant pathways central to 15 small molecule metabolism, which have been reported in the experimental literature. Most of the pathways in MetaCyc occur in microorganisms and plants, although animal pathways are also repre- sented. MetaCyc contains metabolic pathways, 20 enzymatic reactions, enzymes, chemical compounds, genes and review-level comments. Enzyme infor- mation includes substrate specificity, kinetic pro- perties, activators, inhibitors, cofactor requirements and links to sequence and structure databases. 25 Data are curated from the primary literature by curat- ors with expertise in biochemistry and molecular biology. MetaCyc serves as a readily accessible comprehensive resource on microbial and plant pathways for genome analysis, basic research, edu- 30 cation, metabolic engineering and systems biology. Querying, visualization and curation of the database is supported by SRI’s Pathway Tools software. The PathoLogic component of Pathway Tools is used in conjunction with MetaCyc to predict the meta- 35 bolic network of an organism from its annotated genome. SRI and the European Bioinformatics Institute employed this tool to create pathway/ genome databases (PGDBs) for 165 organisms, available at the BioCyc.org website. These PGDBs 40 also include predicted operons and pathway hole fillers. INTRODUCTION MetaCyc is a reference database of small molecule metabol- ism that contains experimentally veriﬁed pathway and enzyme information curated from t4h5e scientiﬁc literature (1). A meta- bolic pathway in MetaCyc consists of reactions, enzymes, metabolites, information on feedback regulation and genes that encode the enzymes for each species (Figure 1). The current version of MetaCyc (9.5) contains 621 pathways from >500 species (Table s50 1 and 2) ranging from microbes to plants and humans, with >90% of the information curated from >7300 research articles. MetaCyc can be searched and browsed using a web browser. Pathways are dynamically generated from the database and graphically displayed with hyperlinks to various pa g55es detailing reactions, enzymes, genes and compounds from MetaCyc, as well as external databases such as Swiss-Prot and PubMed. It, therefore, serves as a readily accessible source of up-to-date, literature-curated information on metabolic pathways and enzymes to research- ers for use in basic resea6r0ch and genome analysis, and to students and teachers for educational purposes. In addition, MetaCyc, in conjunction with the Pathway Tools software (2), can be used to predict metabolic networks from a list of annot- ated sequences resulting from genome or transcript sequencing (3–5). Those predicted ne65tworks can provide a knowledge framework onto which reaction ﬂux models can be built. A number of major improvements made in the last 2 years are described in this article. There has been a signiﬁcant increase in the content of the database, covering both primary metabolism and less comm70on pathways, such as microbial degradation of environmental pollutants and plant secondary metabolism. Other improvements include reorganization and expansion of both the pathway and cellular component ontologies, and enhancement of the Web pages providing background information ab75 out MetaCyc, such as the user’s guide at URL http://metacyc.org/MetaCycUserGuide.shtml. *To whom correspondence should be addressed. Tel: +1 650 859 4358; Fax: +1 650 859 3735; Email: pkarp@ai.sri.com The Author 2006. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. 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