Trimethylamine N-oxide

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. Both the anhydrous and hydrated materials are white, water-soluble solids.
TMAO is found in the tissues of marine crustaceans and marine fish, where it prevents water pressure from distorting proteins and thus killing the animal. The concentration of TMAO increases with the depth at which the animal lives; TMAO is found in high concentrations in the deepest-living described species, "Pseudoliparis swirei", which was found in the Mariana Trench, at a recorded depth of .
TMAO is a product of the oxidation of trimethylamine, a common metabolite in animals. TMAO is biosynthesized from trimethylamine, which is derived from choline.
Marine animals.
Trimethylamine "N"-oxide is an osmolyte found in molluscs, crustaceans, and all marine fishes. It is a protein stabilizer that serves to counteract the protein-destabilizing effects of pressure. In general, the bodies of animals living at great depths are adapted to high pressure environments by having pressure-resistant biomolecules and small organic molecules present in their cells, known as piezolytes, of which TMAO is the most abundant. These piezolytes give the proteins the flexibility they need to function properly under great pressure.
TMAO decomposes to trimethylamine (TMA), which is the main odorant that is characteristic of degrading seafood.
Chemistry.
TMAO can be synthesized from trimethylamine by treatment with hydrogen peroxide:
The dihydrate is dehydrated by azeotropic distillation from dimethylformamide.
Laboratory applications.
Trimethylamine oxide is used in protein folding experiments to counteract the unfolding effects of urea.
In the organometallic chemistry reaction of nucleophilic abstraction, Me3NO is employed as a decarbonylation agent according to the following stoichiometry:
This reaction is used to decomplex organic ligands from metals, e.g. from (diene)Fe(CO)3.
It is used in certain oxidation reactions, e.g. the conversion of alkyl iodides to the corresponding aldehyde.
Effects on protein stability.
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.
Microbiotic associations.
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.
Disorders.
Trimethylaminuria.
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.
Cardiovascular disease.
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.
Background.
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).
Controversy.
The link between cardiovascular diseases and TMAO is disputed. Clouatre et al. argue that choline sources and dietary L-carnitine do not contribute to a significant elevation of blood TMAO. However, the study used to raise this dispute was sponsored by Lonza, Inc., who manufactures and sells an L-Carnitine supplement, so their dispute should be considered biased. Instead the main source of TMAO 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. The strongest evidence to contradict the apparent causal relationship between TMAO and cardiovascular disease comes from a Mendelian randomization study that failed to detect a significant association between circulating TMAO levels and mycardial infarction or coronary artery disease.
Hypertension and thrombosis.
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.
Notably, toxic effects of TMA were described in several clinical and experimental papers in the mid 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.