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

Gustavo Caetano-Anollés, Shin Kim Hee, Jay E. Mittenthal

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)9358-9363
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number22
StatePublished - May 29 2007


  • Enzyme activity
  • Evolution
  • Metabolism
  • Nucleotide metabolism

ASJC Scopus subject areas

  • General


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