Nucleic Acids Research, 2012, Vol. 40, Database issue D755 Figure 1. Chemical compound issues. (A) The same chemical compound can be described using different names in textual representations of reactions in the IUBMB classiﬁcation. (B) A chemical compound may exist in different forms that can interchange spontaneously, such as keto and enol tautomers, and reactions may include each of these forms. To illustrate this, RHEA:22580 describes a reaction involving a keto tautomeric form while RHEA:27873 describes a separate reaction involving an enolic form of the same compound. The keto-enol tautomerization reaction RHEA:31295 allows the two reactions to be linked if necessary. Escherichia coli (menaquinone-8, MK-8), seven isoprene units in certain species of the genus Bacillus and nine in species of Streptococcus. Each of these reactions has a precise description within Rhea, which speciﬁes the number of repeat units within the menaquinone. In addition to providing speciﬁc descriptions of known instances of generic reactions, Rhea also provides trans- port reactions and spontaneous reactions that lack a cor- responding textual deﬁnition in the IUBMB classiﬁcation. These reactions are designed to facilitate the use of Rhea as a reference resource for genome-scale metabolic network reconstruction, where precise deﬁnitions of sub- strate and product speciﬁcity, and the inclusion of spon- taneous and transport reactions, are essential steps in building a functional genome-scale model for metabolism (5–7). More generally, the use of explicit reaction descrip- tions facilitates the precise identiﬁcation, mapping and comparison of compounds and reactions between differ- ent resources and different metabolic models (8). This can be difﬁcult to achieve using the systematic unambiguous chemical nomenclature of IUPAC (International Union of Pure and Applied Chemistry), as biologists often prefer common names to IUPAC standardized labels (which can be relatively complex). The inconsistent use of common names and standardized nomenclature can lead to ambiguity in reaction and compound descriptions that requires manual curation to resolve, as illustrated in Figure 1A, where a single compound is referred to vari- ously as cholate and 3a,12a-dihydroxy-7-oxo-5b- cholanate within two reaction descriptions. A further source of ambiguity arises from the use of generic compound labels that are intended to describe more than one chemical species, such as NAD(P)/NAD(P)H, which is often used in oxidoreduction reactions that use NAD+/NADH or NADP+/NADPH redox couples. Rhea provides an explicit description of each of the correspond- ing reactions, allowing unambiguous assignment of reac- tions including NAD+/NADH or NADP+/NADPH. A third example of ambiguity may occur when considering reactions involving keto-enol tautomers. Rhea provides spontaneous tautomerization reactions that can be used to link reactions involving tautomeric forms of the same compound, such as RHEA:31295 which connects reac- tions involving (2E)-2-hydroxypenta-2,4-dienoate (enol form) and 2-oxopent-4-enoate (keto form) (Figure 1B). Although Rhea attempts to reduce or eliminate ambi- guity in reaction descriptions wherever possible, some al- lowance is made for incomplete knowledge of reaction chemistry. Rhea provides incomplete reactions where not all the reactants are known, and where the reactions are not necessarily balanced. These reactions are clearly identiﬁed by their ‘preliminary’ status. Reaction representation in Rhea Rhea provides explicit representations of biochemical re- actions using chemical species from the ChEBI ontology (1). ChEBI includes information on chemical formula and charge, as well as nomenclature and 2D-structural infor- mation in various chemical formats. The latter informa- tion is used by Rhea for reaction search, display,