Trimethylamine N-oxide

Last updated
Trimethylamine N-oxide
Trimethylaminoxid.svg
Trimethylamine-N-oxide-3D-balls.png
Names
Preferred IUPAC name
N,N-Dimethylmethanamine N-oxide
Other names
Trimethylamine oxide, TMAO, TMANO
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.013.341 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C3H9NO/c1-4(2,3)5/h1-3H3 Yes check.svgY
    Key: UYPYRKYUKCHHIB-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C3H9NO/c1-4(2,3)5/h1-3H3
    Key: UYPYRKYUKCHHIB-UHFFFAOYAU
  • C[N+](C)(C)[O-]
Properties
C3H9NO
Molar mass 75.11
Appearancecolorless solid
Melting point 220 to 222 °C (428 to 432 °F; 493 to 495 K) (dihydrate: 96 °C)
good
5.4 D
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

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.

Contents

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, at a recorded depth of 8,076 m (26,496 ft). [1] [2]

In animals, TMAO is a product of the oxidation of trimethylamine, a common metabolite of trimethyl quaternary ammonium compounds, like choline, trimethylglycine, and L-carnitine. [3] High TMAO concentrations are associated with an increased risk of all-cause mortality and cardiovascular disease. [4] [5] [6]

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. [1] [2] [7] [8] [9]

TMAO decomposes to trimethylamine (TMA), which is the main odorant that is characteristic of degrading seafood.

TMAO in diet

TMAO levels increase with consumption of animal protein such as eggs, red meat, shellfish and total fish consumption. [10] [11] Plant-based diets such as vegan, vegetarian and the Mediterranean diet lower TMAO levels. [11] [12]

Chemistry

TMAO can be synthesized from trimethylamine by treatment with hydrogen peroxide: [13]

H2O2 + (CH3)3N → H2O + (CH3)3NO

The dihydrate is dehydrated by azeotropic distillation from dimethylformamide. [14]

Laboratory applications

Trimethylamine oxide is used in protein folding experiments to counteract the unfolding effects of urea. [15]

In the organometallic chemistry reaction of nucleophilic abstraction, Me3NO is employed as a decarbonylation agent according to the following stoichiometry:

M(CO)n + Me3NO + L → M(CO)n−1L + Me3N + CO2

This reaction is used to decomplex organic ligands from metals, e.g. from (diene)Fe(CO)3. [13]

It is used in certain oxidation reactions, e.g. the conversion of alkyl iodides to the corresponding aldehyde. [16]

Effects on protein stability

The effects of TMAO on the backbone and charged residues of peptides are found to stabilize compact conformations, [17] 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. [18]

Disorders

Trimethylaminuria

Trimethylaminuria is a rare defect in the production of the enzyme flavin-containing monooxygenase 3 (FMO3). [19] [20] 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

High TMAO concentrations are associated with an increased risk of cardiovascular disease and all-cause mortality. [4] [21]

Hypertension

High TMAO concentrations are associated with an increased risk of hypertension. [22] [23]

Stroke

High TMAO concentrations are associated with an increased risk of stroke. [24]

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. [25]

See also

Related Research Articles

<span class="mw-page-title-main">Choline</span> Chemical compound and essential nutrient

Choline ( KOH-leen) is an essential nutrient for humans and many other animals, which was formerly classified as a B vitamin (vitamin B4). It is a structural part of phospholipids and a methyl donor in metabolic one-carbon chemistry. The compound is related to trimethylglycine in the latter respect. It is a cation with the chemical formula [(CH3)3NCH2CH2OH]+. Choline forms various salts, for example choline chloride and choline bitartrate.

<span class="mw-page-title-main">Phenethylamine</span> Organic compound, a stimulant in humans

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

Linoleic acid (LA) is an organic compound with the formula HOOC(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are cis. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 cis-9,12. A linoleate is a salt or ester of this acid.

<span class="mw-page-title-main">Vegetarian nutrition</span> Nutritional and human health aspects of vegetarian diets

Vegetarian nutrition is the set of health-related challenges and advantages of vegetarian diets.

<span class="mw-page-title-main">Trimethylamine</span> Chemical compound responsible for rotten fish odor

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 on contact. At lower concentrations, it has a "fishy" odor, the odor associated with rotting fish.

<span class="mw-page-title-main">Trimethylaminuria</span> Medical condition

Trimethylaminuria (TMAU), also known as fish odor syndrome or fish malodor syndrome, is a rare metabolic disorder that causes a defect in the normal production of an enzyme named flavin-containing monooxygenase 3 (FMO3). When FMO3 is not working correctly or if not enough enzyme is produced, the body loses the ability to properly convert the fishy-smelling chemical trimethylamine (TMA) from precursor compounds in food digestion into trimethylamine oxide (TMAO), through a process called N-oxidation.

<span class="mw-page-title-main">Synephrine</span> Chemical compound

Synephrine, or, more specifically, p-synephrine, is an alkaloid, occurring naturally in some plants and animals, and also in approved drugs products as its m-substituted analog known as neo-synephrine. p-Synephrine and m-synephrine are known for their longer acting adrenergic effects compared to epinephrine and norepinephrine. This substance is present at very low concentrations in common foodstuffs such as orange juice and other orange products, both of the "sweet" and "bitter" variety. The preparations used in traditional Chinese medicine (TCM), also known as Zhi Shi (枳实), are the immature and dried whole oranges from Citrus aurantium. Extracts of the same material or purified synephrine are also marketed in the US, sometimes in combination with caffeine, as a weight-loss-promoting dietary supplement for oral consumption. While the traditional preparations have been in use for millennia as a component of TCM-formulas, synephrine itself is not an approved over the counter drug. As a pharmaceutical, m-synephrine (phenylephrine) is still used as a sympathomimetic, mostly by injection for the treatment of emergencies such as shock, and rarely orally for the treatment of bronchial problems associated with asthma and hay-fever.

<span class="mw-page-title-main">Asymmetric dimethylarginine</span> Chemical compound

Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally essential amino acid. ADMA interferes with L-arginine in the production of nitric oxide (NO), a key chemical involved in normal endothelial function and, by extension, cardiovascular health.

<span class="mw-page-title-main">Lipoprotein(a)</span> Low-density lipoprotein containing apolipoprotein(a)

Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.

<span class="mw-page-title-main">Refined grains</span> Cereal containing endosperm, but not bran nor germ

Refined grains have been significantly modified from their natural composition, in contrast to whole grains. The modification process generally involves the mechanical removal of bran and germ, either through grinding or selective sifting.

<span class="mw-page-title-main">Salt substitute</span> Low-sodium table salt alternative

A salt substitute, also known as low-sodium salt, is a low-sodium alternative to edible salt marketed to reduce the risk of high blood pressure and cardiovascular disease associated with a high intake of sodium chloride while maintaining a similar taste.

<span class="mw-page-title-main">Flavin-containing monooxygenase 3</span> Protein-coding gene in the species Homo sapiens

Flavin-containing monooxygenase 3 (FMO3), also known as dimethylaniline monooxygenase [N-oxide-forming] 3 and trimethylamine monooxygenase, is a flavoprotein enzyme (EC 1.14.13.148) that in humans is encoded by the FMO3 gene. This enzyme catalyzes the following chemical reaction, among others:

Osmolytes are low-molecular-weight organic compounds that influence the properties of biological fluids. Osmolytes are a class of organic molecules that play a significant role in regulating osmotic pressure and maintaining cellular homeostasis in various organisms, particularly in response to environmental stressors. Their primary role is to maintain the integrity of cells by affecting the viscosity, melting point, and ionic strength of the aqueous solution. When a cell swells due to external osmotic pressure, membrane channels open and allow efflux of osmolytes carrying water, restoring normal cell volume.

Trimethylamine N-oxide reductase is a microbial enzyme that can reduce trimethylamine N-oxide (TMAO) into trimethylamine (TMA), as part of the electron transport chain. The enzyme has been purified from E. coli and the photosynthetic bacteria Roseobacter denitrificans.

<span class="mw-page-title-main">Animal source foods</span>

Animal source foods (ASF) include many food items that come from an animal source such as fish, meat, dairy, eggs and honey. Many individuals consume little ASF or even none for long periods of time by either personal choice or necessity, as ASF may not be accessible or available to these people.

Cyclooxygenases are enzymes that take part in a complex biosynthetic cascade that results in the conversion of polyunsaturated fatty acids to prostaglandins and thromboxane(s). Their main role is to catalyze the transformation of arachidonic acid into the intermediate prostaglandin H2, which is the precursor of a variety of prostanoids with diverse and potent biological actions. Cyclooxygenases have two main isoforms that are called COX-1 and COX-2. COX-1 is responsible for the synthesis of prostaglandin and thromboxane in many types of cells, including the gastro-intestinal tract and blood platelets. COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells and in the central nervous system. Prostaglandin synthesis in these sites is a key factor in the development of inflammation and hyperalgesia. COX-2 inhibitors have analgesic and anti-inflammatory activity by blocking the transformation of arachidonic acid into prostaglandin H2 selectively.

<span class="mw-page-title-main">Lacto-ovo vegetarianism</span> Vegetarian diet allowing eggs and dairy

Lacto-ovo vegetarianism or ovo-lacto vegetarianism is a type of vegetarianism which forbids animal flesh but allows the consumption of animal products such as dairy and eggs. Unlike pescetarianism, it does not include fish or other seafood. A typical ovo-lacto vegetarian diet may include fruits, vegetables, grains, legumes, meat substitutes, nuts, seeds, soy, cheese, milk, yogurt and eggs.

<span class="mw-page-title-main">Phenolic content in tea</span> Natural plant compounds

The phenolic content in tea refers to the phenols and polyphenols, natural plant compounds which are found in tea. These chemical compounds affect the flavor and mouthfeel of tea. Polyphenols in tea include catechins, theaflavins, tannins, and flavonoids.

<span class="mw-page-title-main">Flavin-containing monooxygenase</span> Class of enzymes

The flavin-containing monooxygenase (FMO) protein family specializes in the oxidation of xeno-substrates in order to facilitate the excretion of these compounds from living organisms. These enzymes can oxidize a wide array of heteroatoms, particularly soft nucleophiles, such as amines, sulfides, and phosphites. This reaction requires an oxygen, an NADPH cofactor, and an FAD prosthetic group. FMOs share several structural features, such as a NADPH binding domain, FAD binding domain, and a conserved arginine residue present in the active site. Recently, FMO enzymes have received a great deal of attention from the pharmaceutical industry both as a drug target for various diseases and as a means to metabolize pro-drug compounds into active pharmaceuticals. These monooxygenases are often misclassified because they share activity profiles similar to those of cytochrome P450 (CYP450), which is the major contributor to oxidative xenobiotic metabolism. However, a key difference between the two enzymes lies in how they proceed to oxidize their respective substrates; CYP enzymes make use of an oxygenated heme prosthetic group, while the FMO family utilizes FAD to oxidize its substrates.

<span class="mw-page-title-main">Corn sauce</span>

Corn sauce or fermented corn sauce is produced by fermentation using corn starch as the primary substrate. It is used as a food condiment and ingredient, both in paste and in powder form. Corn sauce, like soy sauce, has a characteristic savory taste. It is used to flavor dishes including soups, broths, and gravies.

References

  1. 1 2 Linley, T.D., M.E. Gerringer, P.H. Yancey, J.C. Drazen, C.L. Weinstock, A.J. Jamieson (2016). "Fishes of the hadal zone including new species, in situ observations and depth records of Liparidae". Deep Sea Research Part I: Oceanographic Research Papers. 114: 99–110. Bibcode:2016DSRI..114...99L. doi: 10.1016/j.dsr.2016.05.003 .
  2. 1 2 Gerringer, M.E., T.D. Linley, P.H. Yancey, A.J. Jamieson, E. Goetze, J.C. Drazen (2016). "Pseudoliparis swirei sp. nov.: A newly-discovered hadal snailfish (Scorpaeniformes: Liparidae) from the Mariana Trench". Zootaxa. 4358 (1): 161–177. doi: 10.11646/zootaxa.4358.1.7 . PMID   29245485.
  3. ↑ Baker, J.R., Chaykin, S. (1 April 1962). "The biosynthesis of trimethylamine-N-oxide". J. Biol. Chem. 237 (4): 1309–13. doi: 10.1016/S0021-9258(18)60325-4 . PMID   13864146.
  4. 1 2 Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A, Trimarco B, Esposito G, Perrino C. (2017). "Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis". European Heart Journal. 38 (39): 2948–2956. doi: 10.1093/eurheartj/ehx342 . PMID   29020409.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ↑ Li D, Lu Y, Yuan S, Cai X, He Y, Chen J, Wu Q, He D, Fang A, Bo Y, Song P, Bogaert D, Tsilidis K, Larsson SC, Yu H, Zhu H, Theodoratou E, Zhu Y, Li X. (2022). "Gut microbiota-derived metabolite trimethylamine-N-oxide and multiple health outcomes: an umbrella review and updated meta-analysis". Am J Clin Nutr. 116 (1): 230–243. doi:10.1093/ajcn/nqac074. PMID   35348578.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ↑ Dean YE, Rouzan SS, Loayza Pintado JJ, Talat NE, Mohamed ARH, Verma S, Anwar Kamdi Z, Gir D, Helmy A, Helmy Z, Afzal A, Mady T, Hazimeh Y, Aiash H. (2023). "Serum trimethylamine N-oxide levels among coronary artery disease and acute coronary syndrome patients: a systematic review and meta-analysis". Annals of Medicine and Surgery. 85 (12): 6123–6133. doi:10.1097/MS9.0000000000001426. PMID   38098555.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ↑ Yancey, P. (2005). "Organic osmolytes as compatible, metabolic, and counteracting cytoprotectants in high osmolarity and other stresses". J. Exp. Biol. 208 (15): 2819–2830. doi: 10.1242/jeb.01730 . PMID   16043587.
  8. ↑ Velasquez M, Ramezani A, Manal A, Raj D (8 November 2016). "Trimethylamine N-Oxide: The good, the bad and the unknown". Toxins. 8 (11): 326. doi: 10.3390/toxins8110326 . PMC   5127123 . PMID   27834801.
  9. ↑ "What does it take to live at the bottom of the ocean?". BBC Earth. 2016. Archived from the original on 13 May 2016. Retrieved 19 May 2016.
  10. ↑ Yang JJ, Shu XO, Herrington DM, Moore SC, Meyer KA, Ose J, Menni C, Palmer ND, Eliassen H, Harada S, Tzoulaki I, Zhu H, Albanes D, Wang TJ, Zheng W, Cai H, Ulrich CM, Guasch-Ferré M, Karaman I, Fornage M, Cai Q, Matthews CE, Wagenknecht LE, Elliott P, Gerszten RE, Yu D. (2021). "Circulating trimethylamine N-oxide in association with diet and cardiometabolic biomarkers: an international pooled analysis". The American Journal of Clinical Nutrition. 113 (5): 1145–1156. doi:10.1093/ajcn/nqaa430. hdl: 10044/1/86226 . PMC   8106754 . PMID   33826706.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. 1 2 Lombardo M, Aulisa G, Marcon D, Rizzo G. (2022). "The Influence of Animal- or Plant-Based Diets on Blood and Urine Trimethylamine-N-Oxide (TMAO) Levels in Humans". Curr Nutr Rep. 11 (1): 56–68. doi:10.1007/s13668-021-00387-9. PMID   34990005.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ↑ Evans M, Dai L, Avesani CM, Kublickiene K, Stenvinkel P. (2023). "The dietary source of trimethylamine N-oxide and clinical outcomes: an unexpected liaison". Clin Kidney J. 16 (11): 1804–1812. doi:10.1093/ckj/sfad095. PMID   37915930.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. 1 2 A. J. Pearson "Trimethylamine N-Oxide" in Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, 2001: New York. doi : 10.1002/047084289X.rt268
  14. ↑ Soderquist, J. A., Anderson, C. L. (1986). "Crystalline anhydrous trimethylamine N-oxide". Tetrahedron Lett. 27 (34): 3961–3962. doi:10.1016/S0040-4039(00)84884-4.
  15. ↑ Zou, Q., Bennion BJ, Daggett V, Murphy KP (2002). "The Molecular Mechanism of Stabilization of Proteins by TMAO and Its Ability to Counteract the Effects of Urea". J. Am. Chem. Soc. 124 (7): 1192–1202. doi:10.1021/ja004206b. PMID   11841287.
  16. ↑ Volker Franzen (1973). "Octanal". Organic Syntheses ; Collected Volumes, vol. 5, p. 872.
  17. ↑ Shea JE, Feinstein SC, Lapointe NE, Larini L, Levine ZA (2015-03-03). "Regulation and aggregation of intrinsically disordered peptides". Proceedings of the National Academy of Sciences of the United States of America. 112 (9): 2758–2763. Bibcode:2015PNAS..112.2758L. doi: 10.1073/pnas.1418155112 . PMC   4352815 . PMID   25691742.
  18. ↑ Su Z, Mahmoudinobar F, Dias CL (2017). "Effects of Trimethylamine-N-oxide on the Conformation of Peptides and its Implications for Proteins". Physical Review Letters. 119 (10): 108102. Bibcode:2017PhRvL.119j8102S. doi:10.1103/physrevlett.119.108102. PMID   28949191.
  19. ↑ Treacy, E.P., Akerman BR, Chow LM, Youil R, Bibeau C, Lin J, et al. (1998). "Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication". Human Molecular Genetics. 7 (5): 839–45. doi: 10.1093/hmg/7.5.839 . PMID   9536088.
  20. ↑ Zschocke J, Kohlmueller D, Quak E, Meissner T, Hoffmann GF, Mayatepek E (1999). "Mild trimethylaminuria caused by common variants in FMO3 gene". Lancet. 354 (9181): 834–5. doi:10.1016/S0140-6736(99)80019-1. PMID   10485731. S2CID   9555588.
  21. ↑ Guasti L, Galliazzo S, Molaro M, Visconti E, Pennella B, Gaudio GV, Lupi A, Grandi AM, Squizzato A. (2021). "TMAO as a biomarker of cardiovascular events: a systematic review and meta-analysis". Intern Emerg Med. 16 (1): 201–207. doi:10.1007/s11739-020-02470-5. PMID   32779113. S2CID   221099557.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ↑ Ge X, Zheng L, Zhuang R, Yu P, Xu Z, Liu G, Xi X, Zhou X, Fan H. (2020). "The Gut Microbial Metabolite Trimethylamine N-Oxide and Hypertension Risk: A Systematic Review and Dose-Response Meta-analysis". Adv Nutr. 11 (1): 66–76. doi:10.1093/advances/nmz064. PMC   7442397 . PMID   31269204.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ↑ Han JM, Guo L, Chen XH, Xie Q, Song XY, Ma YL. (2024). "Relationship between trimethylamine N-oxide and the risk of hypertension in patients with cardiovascular disease: A meta-analysis and dose-response relationship analysis". Medicine (Baltimore). 103 (1): e36784. doi:10.1097/MD.0000000000036784. PMC   10766215 . PMID   38181288.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ↑ Zhang H, Yao G. (2023). "Significant correlation between the gut microbiota-derived metabolite trimethylamine-N-oxide and the risk of stroke: evidence based on 23 observational studies". European Journal of Clinical Nutrition. 77 (7): 731–740. doi:10.1038/s41430-022-01104-7. PMID   35468932. S2CID   248368447.
  25. ↑ Directorate-General for Employment SA, Scientific Committee on Occupational Exposure Limits, Nielsen GD, Pospischil E, Johanson G, Klein CL, et al. (2017). SCOEL/REC/179 trimethylamine: recommendation from the Scientific Committee on Occupational Exposure Limits. Publications Office of the European Union. doi:10.2767/440659. ISBN   978-92-79-66627-8 . Retrieved 2023-12-17.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.