The reactome pathway knowledgebase 2022

Abstract

The Reactome Knowledgebase (https://reactome.org), an Elixir core resource, provides manually curated molecular details across a broad range of physiological and pathological biological processes in humans, including both hereditary and acquired disease processes. The processes are annotated as an ordered network of molecular transformations in a single consistent data model. Reactome thus functions both as a digital archive of manually curated human biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. Recent curation work has expanded our annotations of normal and disease-associated signaling processes and of the drugs that target them, in particular infections caused by the SARS-CoV-1 and SARS-CoV-2 coronaviruses and the host response to infection. New tools support better simultaneous analysis of high-throughput data from multiple sources and the placement of understudied ('dark') proteins from analyzed datasets in the context of Reactome's manually curated pathways.

Figure 1.

Drugs that potentially target SARS-CoV-2. (A) The pathway ‘Potential therapeutics for SARS’ (R-HSA-9679191, https://reactome.org/content/detail/R-HSA-9679191) is a systematic catalog of drug binding reactions; the binding of dexamethasone and other NR3C1 (glucocorticoid receptor) agonists to a complex including NR3C1 protein (R-HSA-9678925, https://reactome.org/content/detail/R-HSA-9678925), outlined in red is enlarged in (B), which also shows the full list of small-molecule NR3C1 agonists annotated in Reactome. The effect of this binding on the HSP90 chaperone complex (R-HSA-9690534, https://reactome.org/content/detail/R-HSA-9690534) is shown in (C).

Figure 2.

Comparative analysis of the biological effect of three compounds in atopic dermatitis using ReactomeGSA. The efficacy of Secukinumab, an IL17 inhibitor (GSE137430, transcriptomics) (17), Ustekinumab, an IL23/IL12 inhibitor (GSE140684, microarray) (18), and a JAK/SYK inhibitor (GSE133385, microarray) (19) was each compared with placebo. (A) Correlation analysis shows there is no shared biological effect between the drugs (example Secukinumab versus Ustekinumab). (B) As expected, only the JAK/SYK inhibitor led to a significant down-regulation of inflammatory pathways, consistent with the efficacy (and FDA approval) of only this class of the tested drugs in atopic dermatitis. (C) Comparison of different timepoints of a longitudinal study. The time series analysis of the JAK/SYK inhibitor effect shows earlier down-regulation of MHC signaling, followed by broad down-regulation of T-cell related inflammation.

Figure 3.

The IDG portal incorporates new features to help users visualize potential functions of understudied (‘dark’) proteins in the context of Reactome pathways. The screenshot shows some of these features, including level of knowledge of each displayed protein as a drug target (i.e. Tclin, target of drugs with known mechanism of action, Tchem, target of drugs (no mechanism), Tbio, well-characterized protein not known to be targeted by any drug, Tdark, poorly characterized protein not known to be targeted by any drug, http://juniper.health.unm.edu/tcrd/, overlaying pairwise relationships from different resources (e.g. BioGrid, BioPlex and StringDB), and a new network view.