Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme
Date
2019
Authors
Yang, Gloria
Anderson, Dave W.
Baier, Florian
Dohmen , Elias
Hong, Nansook
Carr, Paul D
Kamerlin, Shina CL
Jackson, Colin
Bornberg-Bauer, Erich
Tokuriki, Nobuhiko
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Nature Publishing Group
Abstract
Characterizing the adaptive landscapes that encompass the emergence of novel enzyme functions can provide molecular
insights into both enzymatic and evolutionary mechanisms. Here, we combine ancestral protein reconstruction with biochemical,
structural and mutational analyses to characterize the functional evolution of methyl-parathion hydrolase (MPH), an
organophosphate-degrading enzyme. We identify five mutations that are necessary and sufficient for the evolution of MPH
from an ancestral dihydrocoumarin hydrolase. In-depth analyses of the adaptive landscapes encompassing this evolutionary
transition revealed that the mutations form a complex interaction network, defined in part by higher-order epistasis, that constrained
the adaptive pathways available. By also characterizing the adaptive landscapes in terms of their functional activities
towards three additional organophosphate substrates, we reveal that subtle differences in the polarity of the substrate substituents
drastically alter the network of epistatic interactions. Our work suggests that the mutations function collectively to
enable substrate recognition via subtle structural repositioning.
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Nature Chemical Biology
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Journal article
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2037-12-31
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