Trimethylamine ''N''-oxide (TMAO) is an

organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

with the formula . It is in the class of

amine oxide In chemistry, an amine oxide, also known as an amine ''N''-oxide or simply ''N''-oxide, is a chemical compound that has the chemical formula . It contains a nitrogen-oxygen coordinate covalent bond with three additional hydrogen and/or substitue ...

s. Although the anhydrous compound is known, trimethylamine ''N''-oxide is usually encountered as the

dihydrate In chemistry, a hydrate is a substance that contains water or its constituent elements. The chemical state of the water varies widely between different classes of hydrates, some of which were so labeled before their chemical structure was understo ...

. 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 fish species, '' Pseudoliparis swirei'', which was found in the

Mariana Trench The Mariana Trench is an oceanic trench located in the western Pacific Ocean, about east of the Mariana Islands; it is the deep sea, deepest oceanic trench on Earth. It is crescent-shaped and measures about in length and in width. The maxi ...

, at a recorded depth of . In animals, TMAO is a product of the oxidation of

trimethylamine Trimethylamine (TMA) is an organic compound with the formula N(CH3)3. It is a trimethylated derivative of ammonia. TMA is widely used in industry. At higher concentrations it has an ammonia-like odor, and can cause necrosis of mucous membranes ...

, a common

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

of trimethyl quaternary ammonium compounds, like

choline Choline is a cation with the chemical formula . Choline forms various Salt (chemistry), salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membrane ...

, trimethylglycine, and L-carnitine. High TMAO concentrations are associated with an increased risk of all-cause mortality and cardiovascular disease.

Marine animals

Trimethylamine ''N''-oxide is an osmolyte found in molluscs, crustaceans, and all marine fishes and bony 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

(TMA), which is the main

odorant An aroma compound, also known as an odorant, aroma, fragrance, flavoring or flavor, is a chemical compound that has a smell or odor. For an individual chemical or class of chemical compounds to impart a smell or fragrance, it must be sufficien ...

that is characteristic of degrading seafood.

TMAO in diet

TMAO levels increase with consumption of

animal Animals are multicellular, eukaryotic organisms in the Biology, biological Kingdom (biology), kingdom Animalia (). With few exceptions, animals heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, ...

protein such as eggs,

red meat In gastronomy, red meat is commonly red when raw (and a dark color after it is cooked), in contrast to white meat, which is pale in color before (and after) cooking. In culinary terms, only flesh from mammals or fowl (not fish) is classified ...

, shellfish and total

fish A fish (: fish or fishes) is an aquatic animal, aquatic, Anamniotes, anamniotic, gill-bearing vertebrate animal with swimming fish fin, fins and craniate, a hard skull, but lacking limb (anatomy), limbs with digit (anatomy), digits. Fish can ...

consumption.

Plant-based diet A plant-based diet is a diet consisting mostly or entirely of plant-based foods. It encompasses a wide range of dietary patterns that contain low amounts of animal products and high amounts of fiber-rich plant products such as vegetables ...

s such as vegan, vegetarian and the

Mediterranean diet The Mediterranean diet is a concept first proposed in 1975 by the American biologist Ancel Keys and chemist Margaret Keys. The diet took inspiration from the eating habits and traditional food typical of Crete, much of the rest of Greece, and s ...

lower TMAO levels.

Chemistry

TMAO can be synthesized from

by treatment with

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...

: : The dihydrate is dehydrated by azeotropic distillation from

dimethylformamide Dimethylformamide, DMF is an organic compound with the chemical formula . Its structure is . Commonly abbreviated as DMF (although this initialism is sometimes used for 2,5-dimethylfuran, dimethylfuran, or dimethyl fumarate), this colourless liqui ...

Laboratory applications

Trimethylamine oxide is used in

protein folding Protein folding is the physical process by which a protein, after Protein biosynthesis, synthesis by a ribosome as a linear chain of Amino acid, amino acids, changes from an unstable random coil into a more ordered protein tertiary structure, t ...

experiments to counteract the unfolding effects of

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

. In the

organometallic chemistry Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and so ...

reaction of nucleophilic abstraction, is employed as a

decarbonylation In chemistry, decarbonylation is a type of organic reaction that involves the loss of carbon monoxide (CO). It is often an undesirable reaction, since it represents a degradation. In the chemistry of metal carbonyls, decarbonylation describes a ...

agent according to the following

stoichiometry Stoichiometry () is the relationships between the masses of reactants and Product (chemistry), products before, during, and following chemical reactions. Stoichiometry is based on the law of conservation of mass; the total mass of reactants must ...

: : where M is a metal. This reaction is used to decomplex organic

ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...

from metals, e.g. from . It is used in certain oxidation reactions, e.g. the conversion of alkyl iodides to the corresponding

aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...

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.

Disorders

Trimethylaminuria

Trimethylaminuria is a rare defect in the production of the enzyme

flavin-containing monooxygenase 3 Flavin-containing monooxygenase 3 (FMO3), also known as dimethylaniline monooxygenase -oxide-forming3 and trimethylamine monooxygenase, is a flavoprotein enzyme () that in humans is encoded by the ''FMO3'' gene. This enzyme catalyzes the foll ...

(''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.

Health effects

Mortality

High circulating TMAO concentrations are associated with an increased risk of all-cause mortality.

Cardiovascular disease

High circulating TMAO concentrations are associated with an increased risk of cardiovascular events and

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

s in particular.

Hypertension

High circulating TMAO concentrations are associated with an increased risk of

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

Potential toxicity

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.

References

{{Reflist, 30em Amine oxides Lipid disorders Nutrition Oxidizing agents Quaternary ammonium compounds Microbiomes Methyl compounds