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Cited by 107Enzyme Structure and FunctionEnzyme Catalysis and ImmobilizationChemical Reaction Mechanisms

Mapping the reaction coordinates of enzymatic defluorination

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Chan, Peter W. Y., Yakunin, Alexander F., Edwards, Elizabeth A., Pai, Emil F.·2011·Journal of the American Chemical Society
DOI 10.1021/ja200277dPMC PMC3101105
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Abstract

The carbon-fluorine bond is the strongest covalent bond in organic chemistry, yet fluoroacetate dehalogenases can readily hydrolyze this bond under mild physiological conditions. Elucidating the molecular basis of this rare biocatalytic activity will provide the fundamental chemical insights into how this formidable feat is achieved. Here, we present a series of high-resolution (1.15-1.80 Å) crystal structures of a fluoroacetate dehalogenase, capturing snapshots along the defluorination reaction: the free enzyme, enzyme-fluoroacetate Michaelis complex, glycolyl-enzyme covalent intermediate, and enzyme-product complex. We demonstrate that enzymatic defluorination requires a halide pocket that not only supplies three hydrogen bonds to stabilize the fluoride ion but also is finely tailored for the smaller fluorine halogen atom to establish selectivity toward fluorinated substrates. We have further uncovered dynamics near the active site which may play pivotal roles in enzymatic defluorination. These findings may ultimately lead to the development of novel defluorinases that will enable the biotransformation of more complex fluorinated organic compounds, which in turn will assist the synthesis, detoxification, biodegradation, disposal, recycling, and regulatory strategies for the growing markets of organofluorines across major industrial sectors.

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  • Crystal structures, mutagenesis and molecular dynamics/molecular mechanics studies have shed light on mechanistic insights and structural features for defluorination and highlighted the role of catalytic amino acids (such as the Asp-His-Asp triad).

    “Crystal structures, mutagenesis (Chan et al., 2011; Jitsumori et al., 2009) and molecular dynamics/molecular mechanics (Li et al., 2016) studies have shed light on mechanistic insights and structural features for defluorination and highlighted the role of catalytic amino acids (such as the Asp-His-Asp triad).”

    From A review of microbial degradation of per- and polyfluoroalkyl substances (PFAS): Biotransformation routes and enzymes (2023) · cites this paper as Chan et al., 2011

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Cited by

Sorted by citations

Authors
Chan, P. W. Y., Yakunin, A. F., Edwards, E. A., & Pai, E. F.
Affiliations
University Health Network (CA)
Corresponding author
Pai, Emil F.
ORCID
Venue
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Published
2011-04-21
Volume
133
Issue
19
Pages
7461-7468
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
DOI
10.1021/ja200277d
PMC
PMC3101105
OpenAlex
W1979780018
Cited by
107
References
1
Citations by year
2026: 13 · 2025: 14 · 2024: 15 · 2023: 5 · 2022: 5 · 2021: 11 · 2020: 8 · 2019: 11 · 2018: 4 · 2017: 6 · 2016: 3 · 2015: 3 · 2013: 2 · 2012: 6
FWCI
1.41
Type
journal article
Language
en
Open access
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Center for Research Resources (P41RR007707, RR007707)
Topics
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
Keywords
fluoroacetate dehalogenase, carbon-fluorine bond cleavage, reaction coordinate, enzyme-substrate complex, active site dynamics, substrate specificity
MeSH terms
Fluorine, Hydrogen Bonding, Hydrolases, Models, Molecular, Molecular Structure, Crystallography, X-Ray, Catalytic Domain, Biocatalysis

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