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Cited by 25Plant biochemistry and biosynthesisPlant Gene Expression AnalysisPhysical Organic Chemistry and Reaction Kinetics

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Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY

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Kim, Colin Y., Mitchell, Andrew J., Kastner, David W., Albright, Claire E., Gutierrez, Michael A., Glinkerman, Christopher M., Kulik, Heather J., Weng, Jing-Ke·2023·Nature Communications
DOI 10.1038/s41467-023-36299-1PMC PMC9898226

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Abstract

Plants contain rapidly evolving specialized enzymes that support the biosynthesis of functionally diverse natural products. In coumarin biosynthesis, a BAHD acyltransferase-family enzyme COSY was recently discovered to accelerate coumarin formation as the only known BAHD enzyme to catalyze an intramolecular acyl transfer reaction. Here we investigate the structural and mechanistic basis for COSY’s coumarin synthase activity. Our structural analyses reveal an unconventional active-site configuration adapted to COSY’s specialized activity. Through mutagenesis studies and deuterium exchange experiments, we identify a unique proton exchange mechanism at the α-carbon of the o -hydroxylated trans -hydroxycinnamoyl-CoA substrates during the catalytic cycle of COSY. Quantum mechanical cluster modeling and molecular dynamics further support this key mechanism for lowering the activation energy of the rate-limiting trans -to- cis isomerization step in coumarin production. This study unveils an unconventional catalytic mechanism mediated by a BAHD-family enzyme, and sheds light on COSY’s evolutionary origin and its recruitment to coumarin biosynthesis in eudicots.

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Metadata

Authors
Kim, C. Y., Mitchell, A. J., Kastner, D. W., Albright, C. E., Gutierrez, M. A., Glinkerman, C. M., Kulik, H. J., & Weng, J.-K.
Affiliations
  • Whitehead Institute for Biomedical Research (US)
  • Massachusetts Institute of Technology (US)
Corresponding author
Weng, Jing-Ke
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-02-03
Volume
14
Issue
1
Pages
597-597
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-36299-1
PMC
PMC9898226
OpenAlex
W4319078070
Cited by
25
References
1
Citations by year
2026: 7 · 2025: 5 · 2024: 8 · 2023: 4
FWCI
2.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Science Foundation (1745302)
  • Burroughs Wellcome Fund
  • W. M. Keck Foundation
  • Family Larsson‐Rosenquist Foundation
  • Arnold and Mabel Beckman Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant Gene Expression Analysis
  • Physical Sciences › Chemistry › Organic Chemistry › Physical Organic Chemistry and Reaction Kinetics
Keywords
COSY, coumarin biosynthesis, BAHD acyltransferase, trans-cis isomerization, lactonization, active site configuration, hydrogen-deuterium exchange, enzyme mechanism, eudicots
MeSH terms
Acyltransferases, Coumarins, Isomerism, Plants, Protons

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