Trimethylamine N-oxide (TMAO) is an organic compound with the formula (CH3)3NO. It is in the class of amine oxides. Although the anhydrous compound is known, trimethylamine N-oxide is usually encountered as the dihydrate. It is a product of the oxidation of trimethylamine, a common metabolite in animals. Both the anhydrous and hydrated materials are white, water-soluble solids.
|Preferred IUPAC name
trimethylamine oxide, TMAO, TMANO
3D model (JSmol)
CompTox Dashboard (EPA)
|Melting point||220 to 222 °C (428 to 432 °F; 493 to 495 K) (dihydrate: 96 °C)|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
Occurrence in natureEdit
Trimethylamine N-oxide is an osmolyte found in molluscs, crustaceans, and fishes such as sharks and rays. It is considered as a protein stabilizer that may serve to counteract urea, the major osmolyte of sharks, skates and rays. It is also higher in deep-sea fishes and crustaceans, where it may counteract the protein-destabilizing effects of pressure. TMAO decomposes to trimethylamine (TMA), which is the main odorant that is characteristic of degrading seafood.
Trimethylaminuria is a rare defect in the production of the enzyme flavin-containing monooxygenase 3 (FMO3). Those suffering from trimethylaminuria are unable to convert choline-derived trimethylamine into trimethylamine oxide. Trimethylamine then accumulates and is released in the person's sweat, urine, and breath, giving off a strong fishy odor.
The order Clostridiales, the genus Ruminococcus, and the taxon Lachnospiraceae are positively associated with TMA and TMAO levels. In contrast, proportions of S24-7, an abundant family from Bacteroidetes, are inversely associated with TMA and TMAO levels.
A study published in 2013, assessing 513 adults with a history of major adverse cardiovascular events, an average age of 68, and 69% of whom previously or currently smoke, may indicate that high levels of TMAO in the blood are associated with an increased risk of additional cardiovascular events. The concentration of TMAO in the blood increases after consuming foods containing carnitine or lecithin if the bacteria that convert those substances to TMAO are present in the gut. High concentrations of carnitine are found in red meat, some energy drinks, and some dietary supplements. Some types of normal gut bacteria (e.g. species of Acinetobacter) in the human microbiome convert dietary carnitine to TMAO. TMAO alters cholesterol metabolism in the intestines, in the liver, and in artery walls. In the presence of TMAO, there is increased deposition of cholesterol in, and decreased removal of cholesterol from peripheral cells such as those in artery walls. Lecithin is found in soy, eggs, as an ingredient in processed food, is sold as a dietary supplement, is used as an emulsifier, and is used to prevent sticking (for example in non-stick cooking spray).
The link between cardiovascular diseases and TMAO is disputed by other researchers. Clouatre et al. argue that choline sources and dietary L-carnitine do not contribute to a significant elevation of blood TMAO, and the main TMAO source in the diet is fish.
Another source of TMAO is dietary phosphatidylcholine, again by way of bacterial action in the gut. Phosphatidyl choline is present at high concentration in egg yolks and some meats.
It has been suggested that TMAO may be involved in the regulation of arterial blood pressure and etiology of hypertension and thrombosis (blood clots) in atherosclerotic disease. A 2017 meta-analysis found higher circulating TMAO was associated with 23% higher risk of cardiovascular events and a 55% higher risk of mortality.
Strikingly, none of the above-mentioned clinical studies evaluated the plasma level of TMA (TMAO precursor) in addition to TMAO. Notably, toxic effect of TMA were described in several clinical and experimental papers in the early 20th century , and very recent studies show deleterious effect of TMA on the circulatory system , , . Furthermore, due to the obvious toxicity and, at the same time, widespread use in industry, various exposure limit guidelines with a detailed description of toxicity are available such as “Recommendation from the Scientific Committee on Occupational Exposure Limits” by the European Union Commission . Therefore, it seems that it is TMA but not TMAO that may be a marker and mediator of cardiovascular risk.
Vegan and vegetarian diets appear to select against gut flora that metabolize carnitine (in favor of other gut flora more coordinated with their food supply). This apparent difference in their microbiome is associated with substantially reduced gut bacteria capable of converting carnitine to trimethylamine, which is later metabolized in the liver to TMAO.
3,3-Dimethyl-1-butanol (DMB), a structural analog of choline, inhibits microbial TMA formation in mice and in human feces, thereby reducing plasma TMAO levels after choline or carnitine supplementation. It is found in some balsamic vinegars, red wines, and some cold-pressed extra virgin olive oils and grape seed oils.
Effects of TMAO on protein stabilityEdit
The effects of TMAO on the backbone and charged residues of peptides are found to stabilize compact conformations, whereas effects of TMAO on nonpolar residues lead to peptide swelling. This suggests competing mechanisms of TMAO on proteins, which accounts for hydrophobic swelling, backbone collapse, and stabilization of charge-charge interactions. These mechanisms are observed in Trp cage.
Organic chemistry of TMAOEdit
TMAO can be synthesized from trimethylamine by treatment with hydrogen peroxide:
- H2O2 + (CH3)3N → H2O + (CH3)3NO
- M(CO)n + Me3NO + L → M(CO)n-1L + Me3N + CO2
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• A structural analog of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (e.g., intestinal contents, human feces) and reduce TMAO levels in mice fed a high-choline or L-carnitine diet.
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The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events
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Recent findings showed that resveratrol reduces levels of trimethylamine-N-oxide (TMAO), known to be a contributory factor in the development of atherosclerosis (Chen et al., 2016). This was partially mediated through down-regulating the enterohepatic farnesoid X receptor-fibroblast growth factor (FXR) axis, and indicates that gut microbiota may become an interesting target for pharmacological and nutritional precision medicine interventions to decrease the risk of developing metabolic diseases.
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