Updates in Rhea--a manually curated resource of biochemical reactions

Abstract

Rhea (http://www.ebi.ac.uk/rhea) is a comprehensive and non-redundant resource of expert-curated biochemical reactions described using species from the ChEBI (Chemical Entities of Biological Interest) ontology of small molecules. Rhea has been designed for the functional annotation of enzymes and the description of genome-scale metabolic networks, providing stoichiometrically balanced enzyme-catalyzed reactions (covering the IUBMB Enzyme Nomenclature list and additional reactions), transport reactions and spontaneously occurring reactions. Rhea reactions are extensively curated with links to source literature and are mapped to other publicly available enzyme and pathway databases such as Reactome, BioCyc, KEGG and UniPathway, through manual curation and computational methods. Here we describe developments in Rhea since our last report in the 2012 database issue of Nucleic Acids Research. These include significant growth in the number of Rhea reactions and the inclusion of reactions involving complex macromolecules such as proteins, nucleic acids and other polymers that lie outside the scope of ChEBI. Together these developments will significantly increase the utility of Rhea as a tool for the description, analysis and reconciliation of genome-scale metabolic models.

Figure 1.

Interactions between Rhea and other resources. Rhea provides cross-references to chemical entities of ChEBI (2), to biochemical reactions of EcoCyc (19), MetaCyc (20), KEGG (18), MACiE (16), Reactome (17) and UniPathway (21), to EC numbers of IntEnz (10) and to protein sequences of UniProtKB (15). The Gene Ontology (GO) is closely aligned with ChEBI , and GO molecular functions describing enzymatic reactions cross-reference Rhea (29). Rhea is one of the reaction repositories employed by MicroScope (9), an integrated resource for the curation and comparative analysis of genomic and metabolic data of microbes. Rhea also provides metabolic reactions for a number of other resources including the EBI Enzyme Portal (5), the reference layer of the MetaboLights resource (6), the metabolic model analysis and reconciliation platform of MetaNetX.org (7,8), EC-BLAST (11) and Metabolic tinker (12).

Figure 2.

Rhea generics. (A) RHEA:12071 represents the priming of acyl carrier protein (ACP) by ACP synthase, where a phosphopantetheine group from coenzyme A (CoA) is attached to a conserved serine residue of ACP to form the activated holo-[ACP] and to release adenosine 3′,5′ bisphosphate (CHEBI:58343). Apo-[ACP] is modeled by a single l-serine residue (GENERIC:9690) and holo-[ACP] by an O-(pantetheine-4′-phosphoryl)-l-serine residue (GENERIC:9685). (B) RHEA:41791 represents the initiation of fatty acid synthesis on holo-[ACP] in which an acetyl group is transferred from acetyl CoA (CHEBI:57288) to the O-(pantetheine-4′-phosphoryl)-l-serine residue of the holo-[ACP] (GENERIC:9685), forming acetyl-[ACP] (GENERIC:9621) that includes an O-(S-acetylpantetheine-4′-phosphoryl)-l-serine residue (CHEBI:78446). (C) RHEA:42399 illustrates the use of Rhea generics composed of multiple residues. The substrate is Rhea GENERIC:10246, which includes both a CMP residue (CHEBI:82748) at position 32 and a GMP residue (CHEBI:74269) at position 34. The corresponding product is Rhea GENERIC:10247, which carries the corresponding 2′-O-methylcytidine 5′-phosphate residue (CHEBI:74495) and 2′-O-methylguanosine 5′-phosphate residue (CHEBI:74445) at the same positions.

Figure 3.

Rhea polymers. RHEA:17800 is a polymerization reaction where the glucosyl moiety of GDP-α-d-glucose (CHEBI:62230) is added to (1,4-β-d-glucosyl)_n (POLYMER:10033) through a β-1→4 linkage to produce (1,4-β-d-glucosyl)_n+1 (POLYMER:10034).