Upload
meira
View
51
Download
0
Tags:
Embed Size (px)
DESCRIPTION
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. - PowerPoint PPT Presentation
Citation preview
John Mitchell
BioinformaticsChemoinformatics
Computational ChemistryTheoretical Chemistry
2
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
Mechanism, Annotation and Classification in Enzymes.http://www.ebi.ac.uk/thornton-srv/databases/MACiE/
MACiE Database
Enzyme Nomenclature and Classification
EC Classification
Class
Subclass
Sub-subclass
Serial number
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
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
Mechanism, Annotation and Classification in Enzymes.http://www.ebi.ac.uk/thornton-srv/databases/MACiE/
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 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
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, 1261-1277 (2007)G.L. Holliday et al., J. Molec. Biol., 390, 560-577 (2009)
Repertoire of Enzyme Catalysis
Enzyme chemistry is largely nucleophilic
Repertoire of Enzyme Catalysis
0
50
100
150
200
250
300
350
400
450
Reaction Types
Num
ber o
f ste
ps in
MAC
iE
Protontransfer
AdN2 E1 SN2 E2 Radicalreaction
Tautom. Others
Repertoire of Enzyme Catalysis
Repertoire of Enzyme Catalysis
Repertoire of Enzyme Catalysis
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 pyridoxine5'-phosphatesynthase
(EC 2.6.99.2)
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
2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 80
200
400
600
800
1000
1200
Nitrogen-Oxygen Distance Dis-tribution
DIstance/ Angstroms
Num
ber o
bser
ved
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