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Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition and inter-subunit electron transfer
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Quareshy, Mussa, Shanmugam, Muralidharan, Townsend, Eleanor, Jameson, Eleanor, Bugg, Timothy D. H., Cameron, Alexander and Chen, Yin (2021) Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition and inter-subunit electron transfer. Journal of Biological Chemistry, 296 . 100038. doi:10.1074/jbc.RA120.016019 ISSN 0021-9258.
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Official URL: https://doi.org/10.1074/jbc.RA120.016019
Abstract
Microbial metabolism of carnitine to trimethylamine (TMA) in the gut can accelerate atherosclerosis and heart disease and these TMA-producing enzymes are therefore important drug targets. Here, we report the first structures of the carnitine oxygenase CntA, an enzyme of the Rieske oxygenase family. CntA exists in a head-to-tail a3 trimeric structure. The two functional domains (the Rieske and the catalytic mononuclear iron domains) are located > 40 Å apart in the same monomer but adjacent in two neighbouring monomers. Structural determination of CntA and subsequent electron paramagnetic resonance measurements uncover the molecular basis of the so-called bridging glutamate (E205) residue in inter-subunit electron transfer. The structures of the substrate-bound CntA help to define the substrate pocket. Importantly, a tyrosine residue (Y203) is essential for ligand recognition through a π-cation interaction with the quaternary ammonium group. This interaction between an aromatic residue and quaternary amine substrates allows us to delineate a subgroup of Rieske oxygenases (group V) from the prototype ring-hydroxylating Rieske oxygenases involved in bioremediation of aromatic pollutants in the environment. Furthermore, we report the discovery of the first known CntA inhibitors and solve the structure of CntA in complex with the inhibitor, demonstrating the pivotal role of Y203 through a π-π stacking interaction with the inhibitor. Our study provides the structural and molecular basis for future discovery of drugs targeting this TMA-producing enzyme in human gut.
Item Type: | Journal Article | ||||||
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Subjects: | Q Science > QR Microbiology | ||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
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Library of Congress Subject Headings (LCSH): | Microbial metabolism, Carnitine -- Metabolism, Gastrointestinal system -- Microbiology, Microbial enzymes, Oxygenases | ||||||
Journal or Publication Title: | Journal of Biological Chemistry | ||||||
Publisher: | American Society for Biochemistry and Molecular Biology | ||||||
ISSN: | 0021-9258 | ||||||
Official Date: | 4 January 2021 | ||||||
Dates: |
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Volume: | 296 | ||||||
Article Number: | 100038 | ||||||
DOI: | 10.1074/jbc.RA120.016019 | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Reuse Statement (publisher, data, author rights): | This research was originally published in the Journal of Biological Chemistry. Quareshy, Mussa, Shanmugam, Muralidharan, Townsend, Eleanor, Jameson, Eleanor, Bugg, Timothy D. H., Cameron, Alexander and Chen, Yin (2020) Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition and inter-subunit electron transfer. Journal of Biological Chemistry. Year; Vol:pp-pp. © the American Society for Biochemistry and Molecular Biology or © the Author(s). | ||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||
Date of first compliant deposit: | 10 November 2020 | ||||||
Date of first compliant Open Access: | 10 November 2020 | ||||||
RIOXX Funder/Project Grant: |
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