1. 1 SRI International Bioinformatics Large-Scale Metabolic Network Alignment: MetaCyc and KEGG Tomer Altman Bioinformatics Research Group SRI International taltman@ai.sri.com

2. 2 SRI International Bioinformatics Problem Motivation There are an increasing number of ‘encyclopedic’ metabolic networks, or reaction databases KEGG and MetaCyc, plus Rhea, BRENDA, and GO A natural question to ask is, “what is similar / different between them?” There has been some linking of MetaCyc compounds to KEGG, but none for reactions

3. 3 SRI International Bioinformatics Challenges with Mapping Objects Multiple aspects to compare (name, chemical structure, reaction substrates, external identifiers) Inexact naming Inexact structures (different specificity of stereocenters) Inexact description of reactions (classes vs. instances, proton-balancing) How to combine the evidence in a logical fashion

4. 4 SRI International Bioinformatics Evidence / Prediction Data Structure Prediction type Predictor name MetaCyc Object Frame ID KEGG Object identifier Iteration number Parameters used

5. 5 SRI International Bioinformatics Compound Evidence Curated MetaCyc links to KEGG Name matching PubChem identifier mapping (used for ChEBI as well) Molecular Fingerprint Tanimoto Similarity Coefficient InChI string comparison Exact Sub-Structure Match (no stereochemistry) ‘All-but-one’ inference

6. 6 SRI International Bioinformatics Compound Prediction Detail: ‘All-but- one’ Most of the compounds between these two reactions are the same Class vs. instance, and naming issues lead to unknown match between “acceptor” and “oxidized electron acceptor”

7. 7 SRI International Bioinformatics Reaction Evidence EC Numbers UniProt Accession Numbers Name matches (gleaned from associated objects) Exact equation match Inexact equation match (cosine similarity)

8. 8 SRI International Bioinformatics Reaction Prediction Detail: UniProt Mapping Use UniProt Accession numbers to map the enzymes in MetaCyc and KEGG to one another Use UniRef 90 or 100 to map “the same protein” when not exact same Accession Number

9. 9 SRI International Bioinformatics From Evidence to Prediction Rule #1: Evidence is partitioned into exact and inexact quality types Rule #2: Evidence is partitioned (orthogonally) into qualitative and quantitative types Rule #3: A high-quality prediction will consist of qualitative and quantitative evidence in favor Rule #4: We try exact quality types first, then inexact Rule #5: No contradictory predictions Rule #6: Iterate until no new predictions This is the general idea, but implementation has some domain-based heuristics thrown in, such as with EC numbers

10. 10 SRI International Bioinformatics Statistics 3269 MetaCyc reactions with links to KEGG (~75%) 4004 MetaCyc compounds with links to KEGG (>50%)

11. 11 SRI International Bioinformatics Future Work Greatest Common Subgraph Compound Matching Sensitivity / Specificity characterization of all evidence types Analysis of unmatched content of KEGG and MetaCyc for algorithm improvement and focused curation (inexact reaction matching and novel reaction import) Hierarchical clustering of compounds and reactions A general tool that can be used for any two given metabolic networks Recasting algorithm in a machine learning framework

12. 12 SRI International Bioinformatics Acknowledgements Peter Karp Douglas Brutlag Dan Davison Anamika Kothari Joseph Dale MetaCyc.org

13. 13 SRI International Bioinformatics … One more thing! Pathway Tools API (beta) http://www.ai.sri.com/~taltman/ptools-api/ptools_api.html