The origin of modern metabolic networks inferred from phylogenomic analysis of protein architecture

Proc Natl Acad Sci U S A. 2007 May 29;104(22):9358-63. doi: 10.1073/pnas.0701214104. Epub 2007 May 21.


Metabolism represents a complex collection of enzymatic reactions and transport processes that convert metabolites into molecules capable of supporting cellular life. Here we explore the origins and evolution of modern metabolism. Using phylogenomic information linked to the structure of metabolic enzymes, we sort out recruitment processes and discover that most enzymatic activities were associated with the nine most ancient and widely distributed protein fold architectures. An analysis of newly discovered functions showed enzymatic diversification occurred early, during the onset of the modern protein world. Most importantly, phylogenetic reconstruction exercises and other evidence suggest strongly that metabolism originated in enzymes with the P-loop hydrolase fold in nucleotide metabolism, probably in pathways linked to the purine metabolic subnetwork. Consequently, the first enzymatic takeover of an ancient biochemistry or prebiotic chemistry was related to the synthesis of nucleotides for the RNA world.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Evolution, Molecular
  • Genomics*
  • Metabolic Networks and Pathways*
  • Nucleotides / genetics
  • Phylogeny*
  • Proteins / chemistry
  • Proteins / genetics*
  • Proteins / metabolism*


  • Nucleotides
  • Proteins