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Page 1: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

The Chemistry of Protein The Chemistry of Protein CatalysisCatalysis

John Mitchell

University of St Andrews

http://www.st-andrews.ac.uk/
Page 2: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

MMechanism, AAnnotation and CClassification iin EEnzymes.http://www.ebi.ac.uk/thornton-srv/databases/MACiE/

The MACiE DatabaseThe MACiE Database

G.L. Holliday et al., Nucl. Acids Res., 35, D515-D520 (2007)

Gemma Holliday, Daniel Almonacid, Noel O’Boyle,

Janet Thornton, Peter Murray-Rust, Gail Bartlett,

James Torrance, John Mitchell

Page 3: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 4: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Enzyme Nomenclature and Enzyme Nomenclature and ClassificationClassificationEC ClassificationEC Classification

Class

Subclass

Sub-subclass

Serial number

Page 5: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

The EC ClassificationThe 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

Page 6: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

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

Page 7: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

MMechanism, AAnnotation and CClassification iin EEnzymes.http://www.ebi.ac.uk/thornton-srv/databases/MACiE/

MACiE DatabaseMACiE Database

Page 8: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 9: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 10: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Global Usage of MACiE

Page 11: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

MACiE Entries

Page 12: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Difficulties of Hierarchical Classification

• Very similar mechanisms can end up in different first level classes.

• In the case of phosphoinositide-specific phospholipases C, this is due to a slow final hydrolysis step occurring in one of the two enzymes.

Page 13: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Classifying Related Enzymes: Phosphoinositide-specific Phospholipases C

Eukaryotic (rat)

Cell Signalling

Multidomain

Catalytic TIM Barrel

EC 3.1.4.11

Hydrolase

Final hydrolysis step

Prefers bisphosphate

Acid-base mechanism

Calcium dependent

Prokaryotic (B. cereus)

Virulence factor

Single domain

Catalytic TIM Barrel

EC 4.6.1.13

Lyase

No/slow final hydrolysis

Disfavours bisphosphate

Acid-base mechanism

Not calcium dependent

Page 14: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Difficulties of Hierarchical Classification

• Different mechanisms can occur with exactly the same EC number.

• MACiE has six beta-lactamases, all with different mechanisms but the same overall reaction.

Page 15: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 16: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

MACiE Mechanisms are Sourced from the Literature

Page 17: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Coverage of MACiE

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

Page 18: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

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.-.-.-

57 EC 1.2.-.-

194 EC 1.2.3.-

1450 EC 1.2.3.4

MACiE covers:

6 EC 1.-.-.-

54 EC 1.2.-.-

165 EC 1.2.3.-

249 EC 1.2.3.4

Page 19: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

EC Coverage of MACiE

Page 20: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Repertoire of Enzyme CatalysisRepertoire 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)

Page 21: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 22: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 23: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Repertoire of Enzyme Catalysis

0

20

40

60

80

100

120

140

HeterolyticElimination

HomolyticElimination

ElectrophilicAddition

NucleophilicAddition

HomolyticAddition

ElectrophilicSubstitution

NucleophilicSubstitution

HomolyticSubstitution

Reaction Types

Num

ber

of

step

s in

MA

CiE

Intramolecular

Bimolecular

Unimolecular

Enzyme chemistry is largely nucleophilic

Page 24: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Repertoire of Enzyme Catalysis

Enzyme chemistry is largely nucleophilic

Page 25: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

0

50

100

150

200

250

300

350

400

450

Reaction Types

Num

ber

of

ste

ps in M

ACiE

ProtonProtontransfertransfer

AdAdNN22 E1E1 SSNN22 E2E2 RadicalRadicalreactionreaction

Tautom.Tautom. OthersOthers

Repertoire of Enzyme Catalysis

Page 26: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Repertoire of Enzyme Catalysis

Page 27: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Repertoire of Enzyme Catalysis

Page 28: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Repertoire of Enzyme Catalysis

Page 29: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Repertoire of Enzyme Catalysis

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

Page 30: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Repertoire of Enzyme Catalysis

Page 31: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

We divide residue roles into three categories:

Reactant: Covalently involved in the reaction step,

Spectator: Stabilisation, activation, steric roles,

Interaction: Hydrogen bonding etc.

Page 32: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 33: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Residue Catalytic Propensities

Page 34: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Residue Catalytic Functions

Page 35: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Convergent Evolution of Convergent Evolution of Enzyme FunctionEnzyme Function

D.E. Almonacid et al., PLoS Computational Biology, accepted

N.M. O’Boyle et al., J. Molec. Biol., 368, 1484-1499 (2007)

Page 36: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

We use a combination of bioinformatics & chemoinformatics to identify similarities between enzyme-catalysed reaction mechanisms

Page 37: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Similarity of Overall Reactions: Compare Bond Changes

Page 38: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Just like sequence alignment!

We can measure their similarity …

Similarity of Mechanisms: Compare Steps

Page 39: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 40: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Carrying out an analysis of pairwise similarity of reactions in MACiE ...

Page 41: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Find only a few similar pairs

Page 42: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Identify convergent evolution

Page 43: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Check MACiE for duplicates!

Page 44: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Mechanistic similarity is only weakly related to proximity in the EC classification

Page 45: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

EC in common

0 -.-.-.-

1 c.-.-.-

2 c.s.-.-

3 c.s.ss.-

Page 46: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Similarity of Analogous Reactions

• We take all possible pairs of analogous enzyme reactions from MACiE 2.3.9

• Analogous means that they carry out similar functions (EC 1.2.3.- conserved) ...

• ... and that the enzymes are not homologous

• We find 95 analogous pairs (convergent evolution).

Page 47: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 48: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 49: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 50: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

43 out of 95 pairs that are analogous according to EC have no significant reaction or mechanistic similarity

Shared EC sub-subclass and Bond Change

based reaction similarity are quite different criteria.

Page 51: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 52: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

One third of analogous pairs with significantly similar overall reactions have significantly similar mechanisms.

Page 53: The Chemistry of Protein Catalysis John Mitchell University of St Andrews
Page 54: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

For analogous pairs, we find that mechanistic similarity is less than overall similarity (almost always); these lie in the lower triangle.

Page 55: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

Conclusions for Analogous Enzymes

• Conservation of EC sub-subclass does not imply quantitative reaction similarity.

• One third of analogous pairs with significantly similar overall reactions have significantly similar mechanisms.

• Mechanistic similarity is less than overall similarity (unlike homologues).

Page 56: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

Dr Gemma Holliday

Dr Daniel Almonacid

Dr Noel O’Boyle

Prof. Janet Thornton (EBI)

Prof. Patsy Babbitt (UCSF)

Dr Peter Murray-Rust

Dr Florian Nigsch

Page 57: The Chemistry of Protein Catalysis John Mitchell University of St Andrews

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

Cambridge Overseas

Trust


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