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SAR_EMBL_EBI_EC_BLAST_NOV_2013_Industry_workshop

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SAR_EMBL_EBI_EC_BLAST_NOV_2013_Industry_workshop

  1. 1. EC-BLAST: A Novel Tool for Finding Chemically Similar Reactions Dr. Syed Asad Rahman asad@ebi.ac.uk Thornton Group Computational Tools for Chemical Biology Nov-2013
  2. 2. Sequence to Function Evolution Seq. to Structure Structure to Function
  3. 3. How to classify and compare enzymes? • Find similar enzymes which can perform similar task (Superfamily) • Design de-novo enzymes and small molecule pathway analysis • Optimise enzymes of commercial importance • Drug and mode of action/ cross reactivity • Assignment/Clustering of EC numbers based on the quantitative measure
  4. 4. Ontology based Classification Method • IUBMB Enzyme Commission • 6 Primary classes with 4 levels of sub-classification • EC 1(Oxidoreductases), EC 2 (Transferases), EC 3 (Hydrolases), EC 4 (Lyases), EC 5 (Isomerases), EC 6 (Ligases) • 6.1.1.1 (ligase) • EC 6.1 Forming Carbon-Oxygen Bonds • EC 6.1.1 Ligases Forming Aminoacyl-tRNA and Related Compounds • EC 6.1.1.1 tyrosine—tRNA ligase
  5. 5. ECBLAST S. A. Rahman et. al., EC-BLAST: A Tool to Automatically Search and Compare Enzyme Reactions, Nature Methods (accepted) http://www.ebi.ac.uk/thornton-srv/software/rbl/
  6. 6. Algorithm
  7. 7. EC Clusters: Bond and Reaction Centre Similarity
  8. 8. Enzyme Similarity in the Metabolic • Teichmann SA et. al. Pathways (2001, PubMed ID: 11518524), • Rison RC et. al. (2002, PubMed ID: 12054833). Comparison of Reaction Centre (RC) similarity in the E-coli core metabolic pathway 1.00 Tanimoto Scores 0.75 0.50 0.25 0.00 EC-BLAST top score Pathway Neighbours Random Reactions Reaction Centre Similarity
  9. 9. Phosphatidylinositol phosphodiesterase (CATH: 3.20.20.190) (PI)
  10. 10. Linking Sequence Domains and Chemical Attributes • Find all the sequence domains using Pfam/CATH • Find all the chemical attributes interacting with those domains from EC-BLAST DB • Report the chemical features and common substructure Chemical  Domains  Sequence EC: 6.2.1.* Pfam: PF00501-AMP-binding UniProt: Q6FLU2 Core Fragment
  11. 11. Future • • • • • • Integrated database with Rhea and BRENDA reactions ~ 15,000 Reactions linked to UniProt, Pfam etc Link Chemistry to Sequence Toxicity Web service Collaborations
  12. 12. Acknowledgements • • • • • • Gemma L. Holliday Gilleain Torrence Franz Fenninger Lorenzo Baldacci Dame Prof. Janet M. Thornton Nicholas Furnham Sergio Martinez Cuesta • Nimish Gopal, Sophie Williams and Saket Choudhary • Funded by
  13. 13. http://www.ebi.ac.uk/thornton-srv/software/rbl Dr. Syed Asad Rahman asad@ebi.ac.uk Computational Tools for Chemical Biology Workshop
  14. 14. Warm up exercise • Reaction similarity search using EC 6.1.1.1 • Look at the similarity scores and the top 10 hits. • EC number and linked information (Pfam, PDB etc) by clicking on them
  15. 15. Exercise 1 • Search for “penicillin G” using molecule search option in the EC-BLAST
  16. 16. Exercise 1- Step 1 • Find Reactions with “penicillin G”
  17. 17. Exercise 2 in 3 Steps 1. Select the top hit and return to the main screen 2. Then perform EC-BLAST using one of the reaction similarity measures.
  18. 18. Step 1- Select the top hit
  19. 19. Step 2- Perform EC-BLAST
  20. 20. Step 3- Top 10 Hits
  21. 21. Exercise 3: Top 3 hits using Reaction Structure Similarity (KEGG ID R04868)

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