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Reactome A database of biological pathways and processes Steve Jupe. Rationale – Journal information. Nature 407(6805):770-6.The Biochemistry of Apoptosis.
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ReactomeA database of biological pathways and processesSteve Jupe
Rationale – Journal information Nature 407(6805):770-6.The Biochemistry of Apoptosis. “Caspase-8 is the key initiator caspase in the death-receptor pathway. Upon ligand binding, death receptors such as CD95 (Apo-1/Fas) aggregate and form membrane-bound signalling complexes (Box 3). These complexes then recruit, through adapter proteins, several molecules of procaspase-8, resulting in a high local concentration of zymogen. The induced proximity model posits that under these crowded conditions, the low intrinsic protease activity of procaspase-8 (ref. 20) is sufficient to allow the various proenzyme molecules to mutually cleave and activate each other (Box 2). A similar mechanism of action has been proposed to mediate the activation of several other caspases, including caspase-2 and the nematode caspase CED-3 (ref. 21).” How can this be represented as computationally-accessible reactions and pathways?
Rationale - Figures A picture paints a thousand words… • but…. • Not computer readable • Omits key details • Assumes or infers Nature. 2000 Oct 12;407(6805):770-6. The biochemistry of apoptosis.
Reactome is… • A free, online, open-sourcecurated database of pathways and reactions in human biology • Authored by expert biologists, maintained by Reactome editorial staff (curators) • Mapped to cellular compartment (but not tissue or developmental stage)
Reactome is… • Extensively cross-referenced • Used to infer orthologous events in 20 non-human species • Tools for data analysis – Pathway Analysis, Expression Overlay, Species Comparison, Biomart…
BINDING DEGRADATION DISSOCIATION DEPHOSPHORYLATION PHOSPHORYLATION CLASSIC BIOCHEMICAL TRANSPORT Theory - Reactions • Pathway steps - the “units” of Reactome • Encapsulate events and states found in biology
Reaction Example 2: Transport REACT_1338.3
Other Reaction Types Dimerization Phosphorylation
Reactions Connect into Pathways CATALYST CATALYST CATALYST INPUT OUTPUT INPUT OUTPUT OUTPUT INPUT
Evidence Tracking – Inferred Reactions PMID:5555 PMID:4444 Direct evidence Direct evidence human Indirect evidence PMID:8976 mouse Indirect evidence PMID:1234 cow
Data Expansion - Link-outs From Reactome GO Molecular Function Compartment Biological process KEGG, ChEBI – small molecules UniProt – proteins Sequence dbs – Ensembl, OMIM, Entrez Gene, RefSeq, HapMap, UCSC, KEGG Gene PubMed references – literature evidence for events
Data Expansion – Projecting to Other Species Human B A A + ATP -P + ADP Mouse B A A + ATP + ADP -P Drosophila B Reaction not inferred + ATP A No orthologue - Protein not inferred
Exportable Protein-Protein Interactions • Are electronically inferred from complex and reaction data • Interaction between proteins in the same complex or reaction • Lists of interaction data from “downloads” tab • Visit the Readme document for more details
Reactome Tools • Interactive Pathway Browser • Pathway Mapping and Over-representation • Expression overlay onto pathways • Molecular Interaction overlay • Biomart
Front Page http://reactome.oicr.on.ca Navigation bar Sidebar Main text
Pathways tab – pathway hierarchy Pathway Reaction Black-box
The Pathway Browser - Pathway Diagrams Boxes are proteins, sets or complexes. Ovals are small molecules. Green boxes are proteins or sets, blue are complexes. Regulation +ve -ve Input Reaction node Catalyst Outputs Compartment Transition Binding Dissociation Omitted Uncertain
Navigating in the Pathway Browser I Home and Analyze buttons Search Click here Highlights Details here Click here to open pathway diagram...
Navigating in the Pathway Browser II Highlights Details here Click here Zoom
Pathway Analysis – Overrepresentation ‘Top-level’ Reveal next level P-val, In set/In pathway
Exercise 6 Check this!
Species Comparison II Yellow = human/rat Blue = human only Grey = not relevant Black = Complex
‘Hot’ = high ‘Cold’ = low Expression Analysis II Step through Data columns
BioMart – attributes Check to get attribute
Author Biology expert Curator Reviewer 2nd expert Where Reactome’s Data Comes From
Data Provision EXPERT CURATOR REVIEWER • Expert in the field • Recruited in various ways • jamborees, workshops etc. • Provide information on biological system • Curators can be experts