Homology Among (betaalpha)(8) Barrels: Implications for the Evolution of Metabolic Pathways

J Mol Biol. 2000 Nov 3;303(4):627-41. doi: 10.1006/jmbi.2000.4152.


We provide statistically reliable sequence evidence indicating that at least 12 of 23 SCOP (betaalpha)(8) (TIM) barrel superfamilies share a common origin. This includes all but one of the known and predicted TIM barrels found in central metabolism. The statistical evidence is complemented by an examination of the details of protein structure, with certain structural locations favouring catalytic residues even though the nature of their molecular function may change. The combined analysis of sequence, structure and function also enables us to propose a phylogeny of TIM barrels. Based on these data, we are able to examine differing theories of pathway and enzyme evolution, by mapping known TIM barrel folds to the pathways of central metabolism. The results favour widespread recruitment of enzymes between pathways, rather than a "backwards evolution" model, and support the idea that modern proteins may have arisen from common ancestors that bound key metabolites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde-Lyases / chemistry
  • Aldehyde-Lyases / metabolism
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Computational Biology
  • Databases as Topic
  • Enzymes / chemistry*
  • Enzymes / metabolism*
  • Evolution, Molecular*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Multigene Family
  • Phosphates / metabolism
  • Phosphopyruvate Hydratase / chemistry
  • Phosphopyruvate Hydratase / metabolism
  • Phylogeny
  • Protein Structure, Secondary
  • Protein Structure, Tertiary*
  • Pyruvate Kinase / chemistry
  • Pyruvate Kinase / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid


  • Enzymes
  • Phosphates
  • Pyruvate Kinase
  • Aldehyde-Lyases
  • Phosphopyruvate Hydratase