the evolution and structural anatomy of small molecule metabolism pathways in escherichia coli
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The evolution and structural anatomy of small molecule metabolism pathways in Escherichia coli. Of Pathways and Proteins Stuart Rison and Sarah Teichmann. Questions. How are homologous proteins (enzymes) distributed in E. coli metabolism?

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the evolution and structural anatomy of small molecule metabolism pathways in escherichia coli

The evolution and structural anatomy of small molecule metabolism pathways in Escherichia coli.

Of Pathways and Proteins

Stuart Rison and Sarah Teichmann

questions
Questions
  • How are homologous proteins (enzymes) distributed in E. coli metabolism?
  • How does this distribution fit with theories of pathway evolution?
pathway evolution
Pathway evolution
  • Norman Horowitz, 1945: ‘On the evolution of biochemical syntheses’, Proc. Nat. Acc. Sci. 31:153-157.

“Retrograde evolution”

  • Roy Jensen, 1976: ‘Enzyme recruitment in evolution of new function’, Ann. Rev. Microbiol 30:409-425.

“Patchwork evolution”

jensen 1976 substrate ambiguity
Jensen, 1976: Substrate ambiguity
  • ‘Original pool’ of unregulated and enzymatically versatile proteins
  • Enzymes recruited from the pool
  • Ad hoc pathways
  • Gene duplication and specialisation leads to regulated, specific and efficient pathways
why e coli
An extensively studied model organism

Complete genome available

Most Small Molecule Metabolism pathways well known and empirically characterised

A manageable size

Good associated databases

Why E. coli?
strategy
Strategy
  • Identify all SMM proteins and the pathway(s) in which they belong
  • Detect homologous proteins by structure or sequence
  • Combine these data to analyse homologous protein distribution in SMM
methods

SCOP

Methods

E. coli

IMPALA

EcoCyc

HMM

Y-BLAST

+

=

Structural Anatomy

Y-BLAST

(>75aa)

Evolutionary

Relationships

Pathways

Proteins

domain assignments
Domain assignments

566 SMM proteins

124 unassigned

proteins

442 proteins assigned

to 1+ families (78%)

169 PDB-D families

31 ‘sequence’ domain

families

200 domain families

glycogen catabolism
Glycogen Catabolism

Domains

Glycosyltransferases

Chemistry and

close substrate

Chemistry and

substrate

a-amylase, C-term

Internal duplication

Isozymes

b-glucosyltransferase

Phosphoglucomutase

glycogen phosphorylase

a-amylase, 3.2.1.1

a-amylase, 3.2.1.1

malS

amyA

glgP

phosphoglucomutase, 5.4.2.2

malodextrin phosphorylase

malP

pgm

malodextrin glucosidase

amylomaltase, 2.4.1.25

malZ

malQ

duplications across pathways
Duplications Across Pathways
  • 110 out of 200 families occur in more than one pathway
  • Can exhibit conservation of chemistry, shared cofactor or minor substrate similarity
  • 36 families have close conservation of EC number (Chemistry conserved)
  • 74 families conserve 1 or no EC number; 11 are cofactor-binding families (cofactor, minor substrate)
duplications within and across pathways
Duplications within and across Pathways
  • 710 domains in 200 families
  • 510 domains have arisen by duplication
  • 232 duplications within pathways to 278 duplications across pathways

(Assumption: duplication within pathways wherever possible.)

conclusion structural anatomy
Conclusion: Structural Anatomy
  • 710 domains in 442 proteins of the 566 proteins in E. coli SMM pathways
  • 200 families (3.5 members/family)
  • Most sizeable families are distributed in several pathways
conclusion recruitment and conservation
Conclusion: Recruitment and Conservation
  • Duplications have taken place between and within pathways to roughly the same degree
  • Duplications occur within most longer pathways:
    • Isozymes, internal duplications and co-factor binding most common
    • Chemistry common
    • Conservation of substrate binding with modified chemistry is rare
conclusions pathway evolution
Conclusions: Pathway evolution
  • Data support a “patchwork evolution” model
  • Little evidence of “retrograde evolution”
conclusions hum
Conclusions: hum…
  • Recruitment, duplication and evolution of enzymes are constantly taking place so we are always observing a dynamic system
  • Likely to be other evolutionary mechanisms and combinations thereof
future
Future
  • Identification and analysis of novel pathway duplication events
  • Focus on order in pathways:
    • Stepwise analysis
    • Doublet/triplet analysis
  • Analysis domain combination in SMM
acknowledgements
Acknowledgements
  • Sarah A. Teichmann, Dept. Biochemistry, University College London
  • Janet M. Thornton, David Lee, Dept. Crystallography, Birkbeck College and Dept. Biochemistry, University College London
  • Monica Riley, Alida Pelegrini-Toole, Marine Biology Laboratory, Woods Hole, USA
  • Cyrus Chothia, Julian Gough, MRC Laboratory of Molecular Biology, Cambridge, UK
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