Evolution of a catalytic mechanism

Alissa Rauwerdink, Mark Lunzer, Titu Devamani, Bryan Jones, Joanna Mooney, Zhi Jun Zhang, Jian He Xu, Romas J. Kazlauskas, Antony M. Dean

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


The means by which superfamilies of specialized enzymes arise by gene duplication and functional divergence are poorly understood. The escape from adaptive conflict hypothesis, which posits multiple copies of a gene encoding a primitive inefficient and highly promiscuous generalist ancestor, receives support from experiments showing that resurrected ancestral enzymes are indeed more substrate-promiscuous than their modern descendants. Here, we provide evidence in support of an alternative model, the innovation- Amplification-divergence hypothesis, which posits a single-copied ancestor as efficient and specific as any modern enzyme. We argue that the catalytic mechanisms of plant esterases and descendent acetone cyanohydrin lyases are incompatible with each other (e.g., the reactive substrate carbonyl must bind in opposite orientations in the active site). We then show that resurrected ancestral plant esterases are as catalytically specific as modern esterases, that the ancestor of modern acetone cyanohydrin lyases was itself only very weakly promiscuous, and that improvements in lyase activity came at the expense of esterase activity. These observations support the innovation- Amplification-divergence hypothesis, in which an ancestor gains a weak promiscuous activity that is improved by selection at the expense of the ancestral activity, and not the escape from adaptive conflict in which an inefficient generalist ancestral enzyme steadily loses promiscuity throughout the transition to a highly active specialized modern enzyme.

Original languageEnglish (US)
Pages (from-to)971-979
Number of pages9
JournalMolecular biology and evolution
Issue number4
StatePublished - Apr 1 2016

Bibliographical note

Funding Information:
This work was supported by the National Institute of Health (NIH) grant 5R01GM102205 and National Science Foundation (NSF) grant 1152804 to A.M.D. and R.J.K.

Publisher Copyright:
© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved.


  • Amplification
  • Catalysis
  • Divergence
  • Escape from adaptive conflict
  • Gene duplication and divergence
  • Innovation
  • Transition state stabilization


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