Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme
Yang, Gloria ; Anderson, Dave W ; Baier, Florian ; Dohmen, Elias ; Hong, Nansook ; Carr, Paul D ; Kamerlin, Shina Caroline Lynn LU
; Jackson, Colin J
; Bornberg-Bauer, Erich
and Tokuriki, Nobuhiko
(2019)
In Nature Chemical Biology
15(11).
p.1120-1128
- 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... (More)
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.
(Less)
- author
- Yang, Gloria
; Anderson, Dave W
; Baier, Florian
; Dohmen, Elias
; Hong, Nansook
; Carr, Paul D
; Kamerlin, Shina Caroline Lynn
LU
; Jackson, Colin J
; Bornberg-Bauer, Erich
and Tokuriki, Nobuhiko
- publishing date
- 2019-11
- type
- Contribution to journal
- publication status
- published
- keywords
- Epistasis, Genetic, Hydrolases/metabolism, Methyl Parathion/metabolism, Xenobiotics/metabolism
- in
- Nature Chemical Biology
- volume
- 15
- issue
- 11
- pages
- 9 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85073657282
- pmid:31636435
- ISSN
- 1552-4469
- DOI
- 10.1038/s41589-019-0386-3
- language
- English
- LU publication?
- no
- id
- 6d936a51-e671-4d2b-ba68-b36071440a99
- date added to LUP
- 2025-01-11 21:14:36
- date last changed
- 2025-07-27 19:38:25
@article{6d936a51-e671-4d2b-ba68-b36071440a99,
abstract = {{<p>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.</p>}},
author = {{Yang, Gloria and Anderson, Dave W and Baier, Florian and Dohmen, Elias and Hong, Nansook and Carr, Paul D and Kamerlin, Shina Caroline Lynn and Jackson, Colin J and Bornberg-Bauer, Erich and Tokuriki, Nobuhiko}},
issn = {{1552-4469}},
keywords = {{Epistasis, Genetic; Hydrolases/metabolism; Methyl Parathion/metabolism; Xenobiotics/metabolism}},
language = {{eng}},
number = {{11}},
pages = {{1120--1128}},
publisher = {{Nature Publishing Group}},
series = {{Nature Chemical Biology}},
title = {{Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme}},
url = {{http://dx.doi.org/10.1038/s41589-019-0386-3}},
doi = {{10.1038/s41589-019-0386-3}},
volume = {{15}},
year = {{2019}},
}