1. Structural Biology and Molecular Biophysics
  2. Evolutionary Biology
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An atomic-resolution view of neofunctionalization in the evolution of apicomplexan lactate dehydrogenases

  1. Jeffrey I Boucher
  2. Joseph R Jacobowitz
  3. Brian C Beckett
  4. Scott Classen
  5. Douglas L Theobald  Is a corresponding author
  1. Brandeis University, United States
  2. Lawrence Berkeley National Laboratory, United States
Research Article
  • Cited 44
  • Views 3,439
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Cite this article as: eLife 2014;3:e02304 doi: 10.7554/eLife.02304

Abstract

Malate and lactate dehydrogenases (MDH and LDH) are homologous, core metabolic enzymes that share a fold and catalytic mechanism yet possess strict specificity for their substrates. In the Apicomplexa, convergent evolution of an unusual LDH from MDH resulted in a difference in substrate preference exceeding 12 orders of magnitude. The molecular and evolutionary mechanisms responsible for this extraordinary functional shift are currently unknown. Using ancestral sequence reconstruction, we find that the evolution of pyruvate specificity in apicomplexan LDHs arose through a classic neofunctionalization mechanism characterized by long-range epistasis, a promiscuous intermediate, and relatively few gain-of-function mutations of large effect. Residues far from the active site determine specificity, as shown by the crystal structures of three ancestral proteins that bracket the key gene duplication event. This work provides an unprecedented atomic-resolution view of evolutionary trajectories resulting in the de novo creation of a nascent enzymatic function.

Article and author information

Author details

  1. Jeffrey I Boucher

    Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Joseph R Jacobowitz

    Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Brian C Beckett

    Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Scott Classen

    Lawrence Berkeley National Laboratory, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Douglas L Theobald

    Brandeis University, Waltham, United States
    For correspondence
    dtheobald@brandeis.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Michael Levitt, Stanford University, United States

Publication history

  1. Received: January 19, 2014
  2. Accepted: June 23, 2014
  3. Accepted Manuscript published: June 25, 2014 (version 1)
  4. Version of Record published: July 29, 2014 (version 2)

Copyright

© 2014, Boucher et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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