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Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota
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Zhu, Yijun , Jameson, Eleanor, Cosatti, Marialuisa , Schäfer, Hendrik, Rajakumar, Kumar , Bugg, Tim and Chen, Yin (2014) Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proceedings of the National Academy of Sciences of the United States of America, 111 (11). pp. 4268-4273. doi:10.1073/pnas.1316569111 ISSN 0027-8424.
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WRAP_0676431-lf-300114-zhu_2014.pdf - Accepted Version - Requires a PDF viewer. Download (2333Kb) | Preview |
Official URL: http://dx.doi.org/10.1073/pnas.1316569111
Abstract
Dietary intake of L-carnitine can promote cardiovascular diseases in humans through microbial production of trimethylamine (TMA) and its subsequent oxidation to trimethylamine N-oxide (TMAO) by hepatic flavin-containing monooxygenases. Although our microbiota are responsible for TMA formation from carnitine, the underpinning molecular and biochemical mechanisms remain unclear. In this study, using bioinformatics approaches, we first identified a two-component Rieske-type oxygenase/reductase (CntAB) and associated gene cluster proposed to be involved in carnitine metabolism in representative genomes of the human microbiota. CntA belongs to a group of previously uncharacterized Rieske-type proteins and has an unusual "bridging" glutamate but not the aspartate residue, which is believed to facilitate inter-subunit electron transfer between the Rieske centre and the catalytic mononuclear iron centre. Using Acinetobacter baumannii as the model, we then demonstrate that cntAB is essential in carnitine degradation to TMA. Heterologous overexpression of cntAB enables Escherichia coli to produce TMA, confirming that these genes are sufficient in TMA formation. Site-directed mutagenesis experiments have confirmed that this unusual "bridging glutamate" residue in CntA is essential in catalysis and neither mutant (E205D, E205A) is able to produce TMA. Together, our study reveals the molecular and biochemical mechanisms underpinning carnitine metabolism to TMA in human microbiota and assigns the role of this novel group of Rieske-type proteins in microbial carnitine metabolism.
Item Type: | Journal Article | ||||||
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Alternative Title: | |||||||
Subjects: | Q Science > QP Physiology | ||||||
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): | Carnitine -- Metabolism, Cardiovascular system -- Diseases -- Etiology | ||||||
Journal or Publication Title: | Proceedings of the National Academy of Sciences of the United States of America | ||||||
Publisher: | National Academy of Sciences | ||||||
ISSN: | 0027-8424 | ||||||
Official Date: | 18 March 2014 | ||||||
Dates: |
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Volume: | 111 | ||||||
Number: | 11 | ||||||
Page Range: | pp. 4268-4273 | ||||||
DOI: | 10.1073/pnas.1316569111 | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||
Date of first compliant deposit: | 26 December 2015 | ||||||
Date of first compliant Open Access: | 26 December 2015 | ||||||
Funder: | Royal Society (Great Britain), Natural Environment Research Council (Great Britain) (NERC) | ||||||
Grant number: | RG2011/R1 (RS), NE/I027061/1 (NERC) |
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