MetaCyc (10), UniPathway (14), MACiE (16) or Reactome (15)]; . a compound name or identiﬁer from ChEBI. The ChEBI index is used to resolve any synonyms and cross-references; . an equation describing the reaction. The Rhea search tool will attempt to parse this and return any matching reactions. If none is found, it will look for similar re- actions, i.e. with as many of the participants in the equation as possible; . an EC number, an enzyme name or a UniProtKB/ Swiss-Prot identiﬁer. The IntEnz index is used to resolve any enzyme synonyms; . a bibliographic citation, or any part of, such as an author name, title, abstract or publication identiﬁer (PubMed identiﬁer). In addition, an advanced search page allows a search to be restricted to speciﬁc ﬁelds (e.g. reaction participants, cross-references or citations) and to perform structural searches. In this latter case, the user can import or draw a 2D-structure through the JChemPaint applet (jchempaint.sourceforge.net), following which the chemical structure search algorithm OrChem (22) will perform a substructure or similarity search on the set of compounds involved in Rhea. The complete documenta- tion of the structural search is available on the ChEBI web server (http://www.ebi.ac.uk/chebi/userManualForward .do). Downloads All Rhea data is available for free download (http://www .ebi.ac.uk/rhea/download.xhtml) in three formats. These are BioPAX level 2 (23), RXN and RD (24), which facili- tate the use of data by chemoinformatics software tools. BioPAX (23) is a collaborative effort to create a data exchange format for biological pathway data. It is deﬁned in OWL and represented in RDF/XML syntax. Rhea re- actions correspond to the biochemicalReaction, transport and transportWithBiochemicalReaction BioPax classes. An example of a BioPAX export is given in the supple- mentary data section (Supplementary Figure S1). RXN is one of the chemical table (CT) ﬁle formats speciﬁed by Accelrys (formerly Symyx and MDL) (24). RXN repre- sents unidirectional processes, so the Rhea export in RXN includes only this subset of Rhea reactions. RD (reaction data) is a second CT ﬁle format, consisting of a set of records, each record deﬁning one directional reaction (in RXN format) and associated data. The 2D structures of the subset of ChEBI compounds referenced by Rhea are also available as an SDF ﬁle, a chemical format speciﬁed by Accelrys (formerly by MDL, 24). That format includes information about the atoms, bonds, connectivity and coordinates of each of the molecules of interest. Web services The Rhea resource is exposed as RESTful web services. Results following standard HTTP GET requests are sent to the client (e.g. a web browser) in one of RXN (24), Nucleic Acids Research, 2012, Vol. 40, Database issue D759 BioPAX Level 2 (23) or CMLReact formats (25), depend- ing on the HTTP Accept header or the URL of the request. The Service makes available two methods: one for general searching of reactions and another for retrieving the full entry of a reaction. The main use case of the Rhea Web Service is a client application, which invokes the search method to get a list of reaction URLs in the format it requires, and then accesses these URLs to retrieve the full reaction entries. Another use case is a client application, which acquires a Rhea identiﬁer, referenced in other services and then creates the URL specifying the format it requires to retrieve the full entry of the reaction. The service URL and the instructions on how to access the service can be found at http://www.ebi.ac.uk/rhea/rest/1.0. Software The Rhea database architecture and software tools are distributed as Open Source (at http://sourceforge.net/ projects/rhea-ebi/) allowing end-users to download and install their own local database of reactions. All software is written in Java 6. The software package includes amongst other things: . Database schema—allowing the storage and validation of data. . Domain model and data validator—providing a reaction model and ability to validate the reaction. . Rhea annotation tool—provides the ability for curators to add and modify their own reactions. . Rhea public website—allowing reaction visualization. The Rhea database runs on Oracle 11 g (http://www .oracle.com). However, minor tweaks allow it to run on open database platforms such as MySQL (www.mysql .com). The database schema is given in the supplementary data section (Supplementary Figure S2 and Supplementary Table S1). Future directions Collaborative developments with the Universal Protein Resource KnowledgeBase, UniProtKB (13), are on- going with the aim of using Rhea as a reference vocabu- lary for describing enzymatic reactions within UniProtKB protein sequence records. Rhea also aims at serving as a general resource of chemical reactions for the reconstruc- tion of genome-scale metabolic networks, as in the Microme (http://www.microme.eu) and MetaNetX (http://www.metanetx.org) initiatives. We are examining a number of curated metabolic networks in order to identify missing reactions of interest and to curate these in Rhea, with the aim of enhancing the unique content of this reaction resource. We are also developing and enhancing our submission tools to allow batch submis- sion, thereby speeding up the population of Rhea with new reactions. We will also further exploit the chemical ontology of ChEBI, where relationships between reaction participants can serve as a basis for the development of a logical reaction classiﬁcation.