Gradual neofunctionalization in the convergent evolution of trichomonad lactate and malate dehydrogenases

Protein Science : a Publication of the Protein Society
Phillip A SteindelDouglas L Theobald

Abstract

Lactate and malate dehydrogenases (LDH and MDH) are homologous, core metabolic enzymes common to nearly all living organisms. LDHs have evolved convergently from MDHs at least four times, achieving altered substrate specificity by a different mechanism each time. For instance, the LDH of anaerobic trichomonad parasites recently evolved independently from an ancestral trichomonad MDH by gene duplication. LDH plays a central role in trichomonad metabolism by catalyzing the reduction of pyruvate to lactate, thereby regenerating the NAD+ required for glycolysis. Using ancestral reconstruction methods, we identified the biochemical and evolutionary mechanisms responsible for this convergent event. The last common ancestor of these enzymes was a highly specific MDH, similar to modern trichomonad MDHs. In contrast, the LDH lineage evolved promiscuous activity by relaxing specificity in a gradual process of neofunctionalization involving one highly detrimental substitution at the "specificity residue" (R91L) and many additional mutations of small effect. L91 has different functional consequences in LDHs and in MDHs, indicating a prominent role for epistasis. Crystal structures of modern-day and ancestral enzymes show that the evolution...Continue Reading

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Nov 1, 2016·Molecular Biology and Evolution·Geeta N EickJoseph W Thornton
Jan 31, 2017·Scientia pharmaceutica·Mary Snow SetzerWilliam N Setzer
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Methods Mentioned

BETA
X‐ray
circular dichroism

Software Mentioned

Phy
BLAST
THESEUS
BIONJ
BAli
Cary WinUV Kinetics
XDS
PAML
Phenix
ProtParam

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