Yang G, Anderson DW, Baier F, Dohmen E, Hong N, Carr PD, Kamerlin SCL, Jackson C, Bornberg-Bauer E, Tokuriki N
Higher-order epistatic networks underlie the evolutionary fitness landscape of a xenobiotic-degrading enzyme
Nature Chem Bio, 2018

[Login to Download]


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), a xenobiotic
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 a complex interaction
network, defined in part by higher-order epistasis, determined the adaptive pathways that were
available. By also characterizing the adaptive landscapes in terms of their functional activity
towards three other OP substrates, we reveal that subtle differences in substrate substituents
drastically alter the enzyme’s epistatic network by changing its intramolecular interactions. Our
work suggests that the mutations function collectively to enable substrate recognition via subtle
structural repositioning.