The reactome pathway knowledgebase

Abstract

The Reactome Knowledgebase (https://reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations in a single consistent data model, an extended version of a classic metabolic map. Reactome functions both as an archive of biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. To extend our ability to annotate human disease processes, we have implemented a new drug class and have used it initially to annotate drugs relevant to cardiovascular disease. Our annotation model depends on external domain experts to identify new areas for annotation and to review new content. New web pages facilitate recruitment of community experts and allow those who have contributed to Reactome to identify their contributions and link them to their ORCID records. To improve visualization of our content, we have implemented a new tool to automatically lay out the components of individual reactions with multiple options for downloading the reaction diagrams and associated data, and a new display of our event hierarchy that will facilitate visual interpretation of pathway analysis results.

Figure 1.

Annotating drugs: antithrombotic activity of Factor Xa inhibitors. (A) The Reactome annotation of apixaban associates it with reference information in the ChEBI (1) and IUPHAR (2) databases, with a disease process, pulmonary embolism, from the Disease Ontology (3), with a cellular component, ‘extracellular region’ from GO (4), and with literature references from PubMed (5). Each of these entries is associated with a Reactome identifier; following the link on the Reactome page takes the user to the web page for that entry in the reference database. (B) Apixiban is grouped with four other similarly annotated small molecules (1), betrixaban, endoxaban, reviroxaban and eribaxan, to form the set of Factor Xa inhibitors. (C) The shared molecular function of this set of molecules (1) is represented by annotating their binding (2) to the complex of Factors Va and Xa (3) to form an inactive complex (4), thereby negatively regulating (5) the cleavage (6) of Factor 2 (7). In our iconography, entities with a drug role are shown with their usual icon shapes but shaded purple and with an ‘Rx’ tag in the lower right corner of the icon.

Figure 2.

Soliciting community input for new annotations. The new ‘external contribution’ web page is accessible via the community tab (1) at the top of the Reactome homepage. It displays a list of newly annotated, internally reviewed events for which we are seeking external reviews (2). Clicking on the help@reactome.org link next to an event of interest (3) opens an e-mail message (4) pre-populated with the event’s details with slots to accommodate personal details. Clicking on the event itself in the table opens a Google Document that contains a text description of the event.

Figure 3.

Associating expert authors’ and reviewers’ ORCID IDs with Reactome events. (A). A search (1) on a person’s name returns a list (2) of all events (pathways and reactions) with which that person is associated as author or reviewer. Details of an individual event can be exported in BibTex (www.bibtex.org) format (3). Clicking on the ‘Are you [person]?’ text at the top of the event list opens a window in which the person can enter his or her ORCID ID and password (4). These credentials are verified and the web page that lists the events is displayed (B) with buttons (5) that enable the person to claim authored and reviewed pathways and reactions.

Figure 4.

Automated reaction layout. When the details of a reaction are displayed, e.g., as the result of a search, a graphical representation of the individual reaction is generated that identifies its inputs (1), outputs (2), type (here, chemical transformation) (3), catalyst (4) and subcellular location or locations (5). The reaction image and its associated data can be exported in a variety of formats (6). Clicking on the image or the text below it takes the user to a view of the reaction in its pathway context (7).

Figure 5.

Pathway browser views of the ‘Metabolism’ superpathway and its children. (A). Standard ‘fireworks’ format. (B). Voronoi diagram (‘ReacFoam’) format.