The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index.
Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota
Open accessAbstract
Significance: Metabolism of l -carnitine, a compound abundant in human diet, to trimethylamine by human microbiota has been shown to promote atherosclerosis and subsequent development of heart disease. However, the underpinning molecular and biochemical mechanisms remain unknown. In this study, we reveal that a previously unidentified Rieske-type protein is responsible for carnitine transformation to trimethylamine from human microbiota. Knowledge gained in our study provides the opportunity not only to explore Rieske protein inhibitors in preventing trimethylamine formation in animal studies and clinical trials, but also for its use as a functional genetic marker to better understand human microbiota and their dynamics in our health and disease in future epidemiological studies and dietary interventions.
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In the citing paper
“While mammals do not have the enzyme, gut microbes have TMA lyases, which can cleave the C-N bond of these nutrients, releasing the TMA moiety as a waste product.”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [77]
In the citing paper
“Thus far, 2 distinct microbial enzyme systems have been identified in vitro that can produce TMA from either choline or carnitine as substrate (75,77).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [77]
In the citing paper
“Similarly, a microbial oxygenase (CntA) complexes with the microbial reductase (CntB) to form an active complex that selectively uses carnitine as substrate and forms TMA (carnitine TMA lyase activity).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [77]
In the citing paper
“Characterization of recombinant isolated CntA/B showed they formed a 2-component Rieske-type oxygenase/reductase complex (77).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [77]
In the citing paper
“In other studies that used a similar bioinformatics approach with Acinetobacter baumannii as the model, an alternative microbial enzyme cluster (catalytic and regulatory protein CntA and CntB) specific for carnitine TMA lyase activity was also recently reported (77).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [77]
In the citing paper
“Carnitine oxidoreductase is the main enzyme responsible for the conversion of L-carnitine into TMA [20]”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [20]
In the citing paper
“Two genes, CntA and CntB, encode a two-subunit oxidoreductase (A encodes the carnitine oxidase, and B encodes a reductase) for L-carnitine conversion to TMA (confirmed by a series of knockout and heterologous expression experiments) (137).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [137]
In the citing paper
“TMA is also produced by carnitine oxygenase, a Rieske-type protein, using carnitine found in red meat as a substrate (Zhu et al., 2014).”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Zhu et al., 2014
In the citing paper
“Two major TMA-synthesis pathways have been described with a specific glycyl radical enzyme, the choline TMA-lyase (CutC) and its activator CutD [6], that takes choline as a substrate and a two-component Rieske-type oxygenase/reductase (CntA/B) [7], which acts on carnitine and its derivative gamma-butyrobetaine, as the key enzymes.”
From Uncovering the trimethylamine-producing bacteria of the human gut microbiota (2017) · cites this paper as [7]
In the citing paper
“In this study, we, hence, considered YeaW as belonging to the CntA cluster of enzymes as originally proposed by Zhu and colleagues [7].”
From Uncovering the trimethylamine-producing bacteria of the human gut microbiota (2017) · cites this paper as [7]
In the citing paper
“All sequences (with one exception) display a conserved “bridging” glutamate instead of aspartate (E205D), which was previously suggested as a signature for that enzyme [7].”
From Uncovering the trimethylamine-producing bacteria of the human gut microbiota (2017) · cites this paper as [7]
In the citing paper
“The established databases present a comprehensive update of previous cutC [9] and cntA [7] gene sequence collections adding a multitude of new gene sequences.”
From Uncovering the trimethylamine-producing bacteria of the human gut microbiota (2017) · cites this paper as [7]
In the citing paper
“TMA formation via cntA represents a distinctive branch of TMA synthesis”
From Uncovering the trimethylamine-producing bacteria of the human gut microbiota (2017) · cites this paper as [7]
In the citing paper
“Thus, specific conditions that select against the latter bacteria might be compensated by an increase of taxa encoding CntA [7]”
From Uncovering the trimethylamine-producing bacteria of the human gut microbiota (2017) · cites this paper as [7]
In the citing paper
“ecophysiologic features of its key player, E. coli, are substantially different to those of the major cutC-exhibiting taxa”
From Uncovering the trimethylamine-producing bacteria of the human gut microbiota (2017) · cites this paper as [7]
In the citing paper
“Human and animal studies suggest that several families of bacteria are involved in TMA/TMAO production, namely, Deferribacteraceae, Anaeroplasmataceae, Prevotellaceae [3] and Enterobacteriaceae [18,19].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [19]
In the citing paper
“However, the patients did have decreased risk for rehospitalization.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [224]
In the citing paper
“the authors did not see long-term benefits in mortality224.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [224]
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Metadata
- Authors
- Zhu, Y., Jameson, E., Crosatti, M., Schäfer, H., Rajakumar, K., Bugg, T. D. H., & Chen, Y.
- Affiliations
- School of Life Sciences and
- University of Leicester (GB)
- University of Warwick (GB)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-03-03
- Volume
- 111
- Issue
- 11
- Pages
- 4268-4273
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3964110
- OpenAlex
- W2000670099
- Cited by
- 372
- References
- 58
- Citations by year
- 2026: 22 · 2025: 35 · 2024: 46 · 2023: 36 · 2022: 44 · 2021: 47 · 2020: 36 · 2019: 22 · 2018: 29 · 2017: 14 · 2016: 16 · 2015: 17 · 2014: 7
- FWCI
- 7.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Royal Society
- Natural Environment Research Council (NE/I027061/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial metabolism and enzyme function
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Keywords
- carnitine metabolism, trimethylamine, human gut microbiome, Acinetobacter baumannii, heterologous expression, trimethylamine N-oxide, cardiovascular disease, flavin-containing monooxygenase, gene clusters
- MeSH terms
- Carnitine, Chromatography, Ion Exchange, Escherichia coli, Humans, Methylamines, Oxidoreductases, Oxygenases, Spectrophotometry, Ultraviolet, Mutagenesis, Site-Directed, Computational Biology, Acinetobacter baumannii, Microbiota
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