Small protein folds at the root of an ancient metabolic network

Hagai Raanan, Saroj Poudel, Douglas H. Pike, Vikas Nanda, Paul G. Falkowski

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Life on Earth is driven by electron transfer reactions catalyzed by a suite of enzymes that comprise the superfamily of oxidoreductases (Enzyme Classification EC1). Most modern oxidoreductases are complex in their structure and chemistry and must have evolved from a small set of ancient folds. Ancient oxidoreductases from the Archean Eon between ca. 3.5 and 2.5 billion years ago have been long extinct, making it challenging to retrace evolution by sequence-based phylogeny or ancestral sequence reconstruction. However, three-dimensional topologies of proteins change more slowly than sequences. Using comparative structure and sequence profile-profile alignments, we quantify the similarity between proximal cofactor-binding folds and show that they are derived from a common ancestor. We discovered that two recurring folds were central to the origin of metabolism: ferredoxin and Rossmann-like folds. In turn, these two folds likely shared a common ancestor that, through duplication, recruitment, and diversification, evolved to facilitate electron transfer and catalysis at a very early stage in the origin of metabolism.

Original languageEnglish (US)
Pages (from-to)7193-7199
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number13
StatePublished - Mar 31 2020

All Science Journal Classification (ASJC) codes

  • General


  • Biological networks
  • Electron transfer
  • Ferredoxin
  • Flavodoxin
  • Rossmann fold

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