John Mitchell Bioinformatics Chemoinformatics Computational Chemistry Theoretical Chemistry.

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Presentation transcript:

John Mitchell Bioinformatics Chemoinformatics Computational Chemistry Theoretical Chemistry

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

MACiE Mechanism, Annotation and Classification in Enzymes. MACiE Database

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

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

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

MACiE Mechanism, Annotation and Classification in Enzymes. MACiE Database

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.

EC Coverage of MACiE Representative – based on a non-homologous dataset, and chosen to represent each available EC sub-subclass. Structures exist for: 6 EC EC EC EC MACiE covers: 6 EC EC EC EC

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

Repertoire of Enzyme Catalysis G.L. Holliday et al., J. Molec. Biol., 372, (2007) G.L. Holliday et al., J. Molec. Biol., 390, (2009)

Repertoire of Enzyme Catalysis Enzyme chemistry is largely nucleophilic

Repertoire of Enzyme Catalysis

Protontransfer Ad N 2 E1 SN2SN2SN2SN2E2 RadicalreactionTautom.Others Repertoire of Enzyme Catalysis

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

Residue Catalytic Propensities

Residue Catalytic Functions

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

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

25 Data schema (1,108 Uniprot proteins)

26 Predicting enzyme mechanism from Sequence M0243 pyridoxine 5'-phosphate synthase (EC ) M0243 pyridoxine 5'-phosphate synthase (EC )

Predicting enzyme mechanism from Structure

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

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

Numbers of Mechanisms for Folds of Different Ages

Protein-Ligand Affinity Prediction: Scoring Functions

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

ACKNOWLEDGEMENTS Cambridge Overseas Trust