Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme
Open accessAbstract
Choline and trimethylamine (TMA) are small molecules that play central roles in biological processes throughout all kingdoms of life. These ubiquitous metabolites are linked through a single biochemical transformation, the conversion of choline to TMA by anaerobic microorganisms. This metabolic activity, which contributes to methanogenesis and human disease, has been known for over a century but has eluded genetic and biochemical characterization. We have identified a gene cluster responsible for anaerobic choline degradation within the genome of a sulfate-reducing bacterium and verified its function using both a genetic knockout strategy and heterologous expression in Escherichia coli . Bioinformatics and electron paramagnetic resonance (EPR) spectroscopy revealed the involvement of a C–N bond cleaving glycyl radical enzyme in TMA production, which is unprecedented chemistry for this enzyme family. Our discovery provides the predictive capabilities needed to identify choline utilization clusters in numerous bacterial genomes, underscoring the importance and prevalence of this metabolic activity within the human microbiota and the environment.
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Microbial choline TMA lyase is a glycyl radical enzyme complex of CutC and CutD encoded by adjacent genes.
“identification of a microbial choline TMA lyase was reported as a unique glycyl radical employing enzyme complex comprised of a catalytic polypeptide, CutC, and an associated activating protein, CutD, encoded by adjacent genes within a gene cluster”
From Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis (2015) · cites this paper as Craciun and Balskus, 2012
Gut microbes possess TMA lyases that cleave the C-N bond of choline/phosphatidylcholine and carnitine, releasing TMA.
“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 [75]
Two distinct microbial enzyme systems have been identified in vitro that can produce TMA from either choline or carnitine.
“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 [75]
The choline-utilizing enzyme cutC and its partner cutD form a complex that selectively uses choline and releases TMA, producing choline TMA lyase activity.
“The choline-utilizing enzyme cutC (catalytic polypeptide) and its partner cutD (regulatory polypeptide) make a complex that selectively uses choline as substrate and releases TMA (choline TMA lyase activity).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [75]
The choline-specific TMA lyase uses an unusual glycyl radical enzyme intermediate.
“Biochemical characterization of the microbial enzyme revealed a choline-specific TMA lyase that used an unusual glycyl radical enzyme intermediate.”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [75]
The cut gene cluster contains catalytic cutC and regulatory cutD, both required for anaerobic TMA production from choline.
“The microbial enzyme was found within a “choline utilization” (cut) gene cluster that contains several tightly clustered genes, including a catalytic unit (cutC) and a regulatory polypeptide (cutD), both of which were required for anaerobic TMA production from choline (75,76).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [75]
Bioinformatics and genome mining identified a gene cluster responsible for anaerobic choline degradation in Desulfovibrio desulfuricans.
“By identifying known microbial enzymes that can use the predicted cleavage product as substrate after TMA release, bioinformatics and genome mining approaches were used to identify a gene cluster responsible for anaerobic choline degradation within the genome of the choline-degrading bacterium Desulfovibrio desulfuricans (75,76).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [75]
Most nonpathogenic bacterial taxa that express genes encoding choline trimethylamine lyases are found in three of the four major phyla of the human intestinal microbiome.
“Most of the nonpathogenic bacterial taxa that express genes encoding these lyases are found in 3 of the 4 major phyla of the human intestinal microbiome.”
From Diet and the Intestinal Microbiome: Associations, Functions, and Implications for Health and Disease (2014) · cites this paper as [60]
The bacterial gene family responsible for converting choline into trimethylamine is called choline trimethylamine lyases.
“Researchers have identified the bacterial gene family responsible for the conversion of choline into TMA; these are called choline TMA lyases60.”
From Diet and the Intestinal Microbiome: Associations, Functions, and Implications for Health and Disease (2014) · cites this paper as [60]
CutC and CutD are essential for converting choline to TMA.
“Deletion of the CutC gene in Desulfovibrio alaskensis G20 and heterologous expression of the CutC and CutD genes from D. alaskensis G20 in Escherichia coli confirmed that these genes are essential for the conversion of choline to TMA (32).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [32]
The choline-to-TMA pathway involves radical C-N bond cleavage of choline to produce TMA and acetaldehyde.
“The pathway involves a radical C-N bond cleavage of choline to generate TMA and acetaldehyde (32).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [32]
A choline-utilization gene cluster responsible for anaerobic conversion of choline to TMA was identified in Desulfovibrio desulfuricans.
“A choline-utilization gene cluster (Cut) responsible for anaerobic conversion of choline to TMA was identified in the sulfate-reducing bacterium Desulfovibrio desulfuricans (32,112).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [32]
No known mammalian enzymes can cleave the C-N bond of choline.
“there are no known mammalian enzymes that can cleave the C-N bond of choline54.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [54]
The choline-degrading sulfate-reducing bacterium Desulfovibrio desulfuricans uses a pathway involving radical C-N bond cleavage of choline to generate TMA and acetaldehyde.
“Subsequent experiments with the choline-degrading sulfate-reducing bacterium Desulfovibrio desulfuricans (i) revealed a pathway that involves a radical C–N bond cleavage of choline to generate TMA and acetaldehyde and (ii) identified a gene cluster encoding this activity (22).”
The choline utilization gene cluster includes cutC, cutD, and genes encoding proteins involved in assembly of microcompartments.
“This cluster includes cutC, which encodes a glycyl radical enzyme with choline trimethylamine-lyase activity; cutD, which encodes a glycyl radical-activating protein; and genes encoding proteins involved in the assembly of microcompartments which may sequester the acetaldehyde generated as a by-product during TMA production (22, 23).”
Microbial choline utilization gene clusters responsible for TMA production have been detected in 20 members of the human gut microbiome, including Firmicutes, Proteobacteria, and Actinobacteria but not Bacteroidetes.
“The microbial choline utilization (cut) gene clusters responsible for the production of TMA have been detected in 20 members of the human gut microbiome, including representatives of the major Firmicutes, Proteobacteria, and Actinobacteria (but not Bacteroidetes) phyla126.”
From The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism (2016) · cites this paper as [126]
Choline-containing compounds are metabolized by microbial glycyl radical enzymes to trimethylamine, which is absorbed and oxidized by hepatic flavin monooxygenases to TMAO.
“In the colon, choline-containing compounds undergo metabolism by microbial glycyl radical enzymes126 to form the intermediate gas trimethylamine (TMA; Fig. 4). In turn, TMA is absorbed and oxidized by hepatic flavin monooxygenases, forming TMA N-oxide (TMAO)”
From The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism (2016) · cites this paper as [126]
A large clinical cohort found an association between cardiovascular disease risk and microbial metabolites of choline-containing compounds.
“analysis of a large clinical cohort recently found an association between risk of cardiovascular disease and microbial metabolites of choline-containing compounds”
From The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism (2016) · cites this paper as [126]
Because choline utilization capability is unevenly distributed across the gut microbiome, inter-individual differences in gut microbial community composition could serve as biomarkers for the strength of the diet-cardiovascular outcome linkage.
“Because choline utilization capability is unevenly distributed across the gut microbiome, inter-individual differences in gut microbial community composition could potentially serve as biomarkers for the strength of linkage between diet and cardiovascular outcomes.”
From The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism (2016) · cites this paper as [126]
Two major TMA-synthesis pathways have been described: CutC/CutD takes choline as substrate, and CntA/B acts on carnitine and gamma-butyrobetaine.
“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 [6]
The major microbial choline trimethylamine lyase is thought to be encoded by the microbial cutC/D genes.
“The major microbial choline TMA lyase is thought to be encoded by the microbial cutC/D genes (choline utilization gene cluster genes C (catalytic) and D)12.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [12]
Human and animal studies suggest that several families of bacteria are involved in TMA/TMAO production, namely Deferribacteraceae, Anaeroplasmataceae, Prevotellaceae and Enterobacteriaceae.
“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 [18]
Desulfovibrio desulfuricans has a gene cluster including cutD involved in radical C-N bond cleavage of choline leading to generation of TMA.
“Recently, experiments with the choline-degrading sulfate reducing bacterium Desulfovibrio desulfuricans identified a gene cluster (including cutD) involved in radical C–N bond cleavage of choline leading to generation of TMA [18].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [18]
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Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics
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Microbial impact on cholesterol and bile acid metabolism: current status and future prospects
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Self-citationMetabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption
Romano, K. A., Martinez-del Campo, A., Kasahara, K., Chittim, C. L., Vivas, E. I., Amador-Noguez, D., Balskus, E. P., & Rey, F. E. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.07.021 · Cited by 224 · see citing works
Self-citationMicrobial-derived metabolites as a risk factor of age-related cognitive decline and dementia
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Characterization of Choline Trimethylamine-Lyase Expands the Chemistry of Glycyl Radical Enzymes
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“138 Cell Reports 20, 136–148, July 5, 2017 commensal bacteria, and metabolized into TMAO, dimethylamine (DMA), and monomethylamine (MMA) in the liver (Figure 2D) (al-Waiz et al., 1992; Craciun and Balskus, 2012; Dolphin et al., 1997).”
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Gut microbiota, fatty liver disease, and hepatocellular carcinoma
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Dietary Regulation of Gut-Brain Axis in Alzheimer’s Disease: Importance of Microbiota Metabolites
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Alzheimer’s disease and gut microbiota: does trimethylamine N-oxide (TMAO) play a role?
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Targeting the human gut microbiome with small-molecule inhibitors
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Self-citationConverging on a mechanism for choline degradation
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- Authors
- Craciun, S., & Balskus, E. P.
- Affiliations
- Harvard University (US)
- ORCID
- Balskus, Emily P.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-11-14
- Volume
- 109
- Issue
- 52
- Pages
- 21307-21312
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3535645
- OpenAlex
- W2043900297
- Cited by
- 701
- References
- 41
- Citations by year
- 2026: 59 · 2025: 61 · 2024: 39 · 2023: 59 · 2022: 67 · 2021: 83 · 2020: 66 · 2019: 36 · 2018: 60 · 2017: 39 · 2016: 47 · 2015: 36 · 2014: 38 · 2013: 9 · 2012: 1
- FWCI
- 10.79
- 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)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Harvard University
- University of Oklahoma
- Universidade Nova de Lisboa
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial metabolism and enzyme function
- Physical Sciences › Engineering › Building and Construction › Anaerobic Digestion and Biogas Production
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Keywords
- glycyl radical enzymes, C–N bond cleavage, anaerobic metabolism, gene clusters, sulfate-reducing bacteria, methanogenesis, human microbiota, heterologous expression, electron spin resonance
- MeSH terms
- Anaerobiosis, Choline, Electron Spin Resonance Spectroscopy, Free Radicals, Genes, Bacterial, Multigene Family, Glycine, Humans, Lyases, Methylamines, Mutation, Computational Biology, Desulfovibrio desulfuricans, Genetic Association Studies
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