D754–D760 Nucleic Acids Research, 2012, Vol. 40, Database issue doi:10.1093/nar/gkr1126 Published online 1 December 2011 Rhea—a manually curated resource of biochemical reactions Rafael Alca´ ntara1,*, Kristian B. Axelsen 2 , Anne Morgat2,3, Eugeni Belda 4 , Elisabeth Coudert2, Alan Bridge 2 , Hong Cao 1 , Paula de Matos 1 , Marcus Ennis1, Steve Turner1, Gareth Owen 1 , Lydie Bougueleret2, Ioannis Xenarios2,5 and Christoph Steinbeck1 1Chemoinformatics and Metabolism Team, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK, 2Swiss-Prot Group, SIB Swiss Institute of Bioinformatics, CMU, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland, 3Equipe BAMBOO, INRIA Grenoble Rhoˆ ne-Alpes, 655 avenue de l’Europe, F-38330 Montbonnot Saint-Martin, France, 4Genoscope—LABGeM, CEA, 2 Rue Gaston Cre´ mieux, CP 5706, F-91057 Evry, France and 5Vital-IT, Swiss Institute of Bioinformatics, Quartier Sorge, Baˆ timent Ge´ nopode, CH-1015 Lausanne, Switzerland Received August 18, 2011; Revised November 4, 2011; Accepted November 8, 2011 ABSTRACT Rhea (http://www.ebi.ac.uk/rhea) is a comprehen- sive resource of expert-curated biochemical reactions. Rhea provides a non-redundant set of chemical transformations for use in a broad spectrum of applications, including metabolic network reconstruction and pathway inference. Rhea includes enzyme-catalyzed reactions (covering the IUBMB Enzyme Nomenclature list), transport reactions and spontaneously occurring re- actions. Rhea reactions are described using chemical species from the Chemical Entities of Biological Interest ontology (ChEBI) and are stoi- chiometrically balanced for mass and charge. They are extensively manually curated with links to source literature and other public resources on me- tabolism including enzyme and pathway databases. This cross-referencing facilitates the mapping and reconciliation of common reactions and compounds between distinct resources, which is a common first step in the reconstruction of genome scale metabol- ic networks and models. RHEA AIMS AND SCOPE Rhea is a freely available and comprehensive resource of expert-curated biochemical reactions. It has been designed to provide a non-redundant set of chemical transformations for applications such as the functional annotation of enzymes, pathway inference and metabolic network recon- struction. Rhea provides explicit representations of biochem- ical reactions using chemical species from the Chemical Entities of Biological Interest ontology (ChEBI) (1) that include structural information and curated links to a host of other resources. Rhea reaction descriptions cover the ofﬁcial list of enzyme catalyzed reactions deﬁned by the Nomenclature Committee of the IUBMB (NC-IUBMB) (http://www.chem.qmul.ac.uk/iubmb/enzyme/) (2,3). This extends where possible to the provision of explicit descrip- tions for speciﬁc instances of generic reactions that are catalyzed by enzymes with broad substrate speciﬁcity (as well as reactions that are only referred to within the free text comments of IUBMB entries). One example of such a generic reaction is that catalyzed by alcohol dehydrogenase (EC 1.1.1.1), which is described in the following way within the IUBMB classiﬁcation: An alcohol + NAD+ ¼ an aldehyde or ketone + NADH Within Rhea, a generic reaction description is provided that corresponds to this textual description, along with speciﬁc reactions for all known substrate/product pairs. A similar approach is used to describe reactions involving polymers with varying numbers of repeated units, such as isoprenoid quinones, which participate in the reaction catalyzed by malate dehydrogenase (EC 1.1.5.4): ðSÞ -malate +a menaquinone ¼ oxaloacetate +a menaquinol This reaction involves a menaquinone with a variable number of isoprene units (4): eight isoprene units in *To whom correspondence should be addressed. Tel: +44 0 1223 494414; Fax: +44 0 1223 494468; Email: rafael.alcantara@ebi.ac.uk The authors wish it to be known that, in their opinion, the ﬁrst three authors should be regarded as joint First Authors. The Author(s) 2011. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.