John Mitchell
description
Transcript of John Mitchell
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John Mitchell
BioinformaticsChemoinformatics
Computational ChemistryTheoretical Chemistry
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Mitchell group – BSRC & EaStCHEM School of ChemistryPurdie Building rooms 150 &152
Lazaros Mavridis Ava Sih-Yu Chen Rosanna Alderson
Neetika Nath James Mc Donagh Luna De Ferrari
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Mechanism, Annotation and Classification in Enzymes.http://www.ebi.ac.uk/thornton-srv/databases/MACiE/
MACiE Database
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Enzyme Nomenclature and Classification
EC Classification
Class
Subclass
Sub-subclass
Serial number
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The EC Classification
Reaction direction arbitraryCofactors and active site residues ignoredDoesn’t deal with structural and sequence
informationHowever, it was never intended to do so
Deals with overall reaction, not mechanism
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A New Representation of Enzyme Reactions?
Should be complementary to, but distinct from, the EC system
Should take into account:Reaction Mechanism
StructureSequenceActive Site residuesCofactors
Need a database of enzyme mechanisms
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Mechanism, Annotation and Classification in Enzymes.http://www.ebi.ac.uk/thornton-srv/databases/MACiE/
MACiE Database
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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.
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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 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
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Coverage of MACiE
Representative – based on a non-homologous dataset,and chosen to represent each available EC sub-subclass.
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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)
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Repertoire of Enzyme Catalysis
Enzyme chemistry is largely nucleophilic
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Repertoire of Enzyme Catalysis
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Reaction Types
Num
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MAC
iE
Protontransfer
AdN2 E1 SN2 E2 Radicalreaction
Tautom. Others
Repertoire of Enzyme Catalysis
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Repertoire of Enzyme Catalysis
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Repertoire of Enzyme Catalysis
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Repertoire of Enzyme Catalysis
We do see a few steps corresponding to well-known organic reactions; but these are the exception.
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Residue Catalytic Propensities
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Residue Catalytic Functions
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Predicting Enzyme Function …… and Mechanism
L. De Ferrari et al. BMC Bioinformatics 2012, 13:61
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Data sources
EnzML: Multi-label prediction of enzyme classes using InterPro signatures,L. De Ferrari et al. BMC Bioinformatics 2012, 13:61
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Data schema
(1,108 Uniprot proteins)
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Predicting enzyme mechanism from Sequence
M0243 pyridoxine5'-phosphatesynthase
(EC 2.6.99.2)
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Predicting enzyme mechanism from Structure
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Moonlighting: A starting point for evolving
a new catalytic function!
Main reaction Minor side reaction
Enzyme Evolution
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Investigating the apparent independent evolutionary origins of the B1 & B3 metallo- beta-lactamases at the chemical catalytic level
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Numbers of Mechanisms for Folds of Different Ages
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Nitrogen-Oxygen Distance Dis-tribution
DIstance/ Angstroms
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Protein-Ligand Affinity Prediction: Scoring Functions
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Prediction of Off-target Activities and Side Effects• Phospholipidosis; hERG blockade; Doping in sport; Polypharmacology
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ACKNOWLEDGEMENTS
Cambridge Overseas
Trust