1 / 33

John Mitchell

John Mitchell. Bioinformatics Chemoinformatics Computational Chemistry Theoretical Chemistry. Mitchell group – BSRC & EaStCHEM School of Chemistry Purdie Building rooms 150 &152. Lazaros Mavridis. Rosanna Alderson. Ava Sih-Yu Chen. Neetika Nath. Luna De Ferrari. James Mc Donagh.

meira
Download Presentation

John Mitchell

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. John Mitchell Bioinformatics Chemoinformatics Computational Chemistry Theoretical Chemistry

  2. Mitchell group – BSRC & EaStCHEM School of ChemistryPurdie Building rooms 150 &152 Lazaros Mavridis Rosanna Alderson Ava Sih-Yu Chen Neetika Nath Luna De Ferrari James Mc Donagh

  3. MACiE Database Mechanism,AnnotationandClassificationin Enzymes. http://www.ebi.ac.uk/thornton-srv/databases/MACiE/

  4. EC Classification Class Subclass Sub-subclass Serial number Enzyme Nomenclature and Classification

  5. The EC Classification • Reaction direction arbitrary • Cofactors and active site residues ignored • Doesn’t deal with structural and sequence information • However, it was never intended to do so • Deals with overall reaction, not mechanism

  6. A New Representation of Enzyme Reactions? • Should be complementary to, but distinct from, the EC system • Should take into account: • Reaction Mechanism • Structure • Sequence • Active Site residues • Cofactors • Need a database of enzyme mechanisms

  7. MACiE Database Mechanism,AnnotationandClassificationin Enzymes. http://www.ebi.ac.uk/thornton-srv/databases/MACiE/

  8. EC is not Everything • Different mechanisms can occur with exactly the same EC number. • MACiE has six beta-lactamases, all with different mechanisms but the same overall reaction.

  9. EC Coverage of MACiE Structures exist for: 6 EC 1.-.-.- 61 EC 1.2.-.- 204 EC 1.2.3.- 1776 EC 1.2.3.4 MACiE covers: 6 EC 1.-.-.- 57 EC 1.2.-.- 183 EC 1.2.3.- 321 EC 1.2.3.4 Representative – based on a non-homologous dataset, and chosen to represent each available EC sub-subclass.

  10. Coverage of MACiE Representative – based on a non-homologous dataset, and chosen to represent each available EC sub-subclass.

  11. Repertoire of Enzyme Catalysis G.L. Holliday et al.,J. Molec. Biol., 372, 1261-1277 (2007) G.L. Holliday et al.,J. Molec. Biol., 390, 560-577 (2009)

  12. Repertoire of Enzyme Catalysis Enzyme chemistry is largely nucleophilic

  13. Repertoire of Enzyme Catalysis

  14. Proton transfer AdN2 E1 SN2 E2 Radical reaction Tautom. Others Repertoire of Enzyme Catalysis

  15. Repertoire of Enzyme Catalysis

  16. Repertoire of Enzyme Catalysis

  17. Repertoire of Enzyme Catalysis We do see a few steps corresponding to well-known organic reactions; but these are the exception.

  18. Residue Catalytic Propensities

  19. Residue Catalytic Functions

  20. Predicting Enzyme Function … … and Mechanism L. De Ferrari et al. BMC Bioinformatics 2012, 13:61

  21. Data sources EnzML: Multi-label prediction of enzyme classes using InterPro signatures, L. De Ferrari et al. BMC Bioinformatics 2012, 13:61

  22. Data schema(1,108 Uniprot proteins)

  23. Predicting enzyme mechanism from Sequence M0243 pyridoxine 5'-phosphate synthase (EC 2.6.99.2)

  24. Predicting enzyme mechanism from Structure

  25. Enzyme Evolution Moonlighting: A starting point for evolving a new catalytic function! Main reaction Minor side reaction

  26. Investigating the apparent independent evolutionary origins of the B1 & B3 metallo- beta-lactamases at the chemical catalytic level

  27. Numbers of Mechanisms for Folds of Different Ages

  28. Protein-Ligand Affinity Prediction: Scoring Functions

  29. Prediction of Off-target Activities and Side Effects • Phospholipidosis; hERG blockade; Doping in sport; Polypharmacology

  30. ACKNOWLEDGEMENTS Cambridge Overseas Trust

More Related