Trimethylamine ''N''-oxide

Trimethylamine N-oxide
Structural formula
Ball-and-stick model
Names
IUPAC name
trimethylamine oxide
Preferred IUPAC name
N,N-dimethylmethanamine oxide
Other names
trimethylamine oxide, TMAO, TMANO
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.013.341
KEGG
UNII
Properties
C3H9NO
Molar mass 75.11
Appearance colorless 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).
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Infobox references

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.

Occurrence in nature

Trimethylamine N-oxide is an osmolyte found in saltwater fish, sharks, rays, molluscs, and crustaceans. 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.[1] TMAO decomposes to trimethylamine (TMA), which is the main odorant that is characteristic of degrading seafood.

TMAO is biosynthesized from trimethylamine, which is derived from choline.[2]

Trimethylaminuria

Trimethylaminuria is a rare defect in the production of the enzyme flavin containing monooxygenase 3 (FMO3).[3][4] 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.

Microbiotic associations

The order Clostridiales, the genus Ruminococcus, and the taxon Lachnospiraceae are positively associated with TMA and TMAO levels.[5] In contrast, proportions of S24-7, an abundant family from Bacteroidetes, are inversely associated with TMA and TMAO levels.[5]

Health issues

Studies published in 2013 indicate that high levels of TMAO in the blood are associated with an increased risk of major adverse cardiovascular events.[6] The concentration of TMAO in the blood increases after consuming foods containing carnitine[7] or lecithin[6] if the bacteria that convert those substances to TMAO are present in the gut.[8] High concentrations of carnitine are found in red meat, some energy drinks, and some dietary supplements; lecithin is found in soy, eggs,[8] as an ingredient in processed food and is sold as a dietary supplement. 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.[9]

The link between cardiovascular diseases and TMAO is disputed by other researchers[10] who are employees of Lonza, a company that sells carnitine.[11] 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.[12]

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[13] and thrombosis (blood clots) in atherosclerotic disease.[14] A 2017 meta-analysis found higher circulating TMAO was associated with 23% higher risk of cardiovascular events and a 55% higher risk of mortality.[15]

Inhibition

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.[7]

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.[5] It is found in some balsamic vinegars, red wines, and some cold-pressed extra virgin olive oils and grape seed oils.[5]

Resveratrol has been shown to reduce TMAO in mice by remodeling gut microbiota.[16]

Effects of TMAO 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]

Organic chemistry of TMAO

TMAO can be synthesized from trimethylamine by treatment with hydrogen peroxide:[19]

H2O2 + (CH3)3N → H2O + (CH3)3NO

The dihydrate is dehydrated by azeotropic distillation from dimethylformamide.[20]

Laboratory applications

Trimethylamine oxide is used in protein folding experiments to counteract the unfolding effects of urea.[21]

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.[19]

It is used in certain oxidation reactions, e.g. the conversion of alkyl iodides to the corresponding aldehyde.[22]

References

  1. ↑ 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.
  2. ↑ Baker, J.R.; Chaykin, S. (1 April 1962). "The biosynthesis of trimethylamine-N-oxide". J. Biol. Chem. 237 (4): 1309–13. PMID 13864146.
  3. ↑ Treacy, E.P.; Akerman, BR; 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.
  4. ↑ 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.
  5. 1 2 3 4 Wang, Zeneng; Roberts, Adam B.; Buffa, Jennifer A.; Levison, Bruce S.; Zhu, Weifei; Org, Elin; Gu, Xiaodong; Huang, Ying; Zamanian-Daryoush, Maryam; Culley, Miranda K.; DiDonato, Anthony J.; Fu, Xiaoming; Hazen, Jennie E.; Krajcik, Daniel; DiDonato, Joseph A.; Lusis, Aldons J.; Hazen, Stanley L. (December 2015). "Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis". Cell. 163 (7): 1585–1595. doi:10.1016/j.cell.2015.11.055. PMC 4871610. PMID 26687352.
    • 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.
    • DMB was detected in some balsamic vinegars, in red wines, and in some cold-pressed extra virgin olive oils and grape seed oils
  6. 1 2 Tang, W.H. Wilson; Zeneng Wang; Bruce S. Levison; Robert A. Koeth; Earl B. Britt; Xiaoming Fu; Yuping Wu; Stanley L. Hazen (April 25, 2013). "Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk". The New England Journal of Medicine. 368 (17): 1575–1584. doi:10.1056/NEJMoa1109400. PMC 3701945. PMID 23614584. Retrieved April 26, 2013. 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
  7. 1 2 Koeth, Robert A; Wang, Zeneng; Levison, Bruce S; Buffa, Jennifer A; Org, Elin; Sheehy, Brendan T; Britt, Earl B; Fu, Xiaoming; Wu, Yuping; Li, Lin; Smith, Jonathan D; DiDonato, Joseph A; Chen, Jun; Li, Hongzhe; Wu, Gary D; Lewis, James D; Warrier, Manya; Brown, J Mark; Krauss, Ronald M; Tang, W H Wilson; Bushman, Frederic D; Lusis, Aldons J; Hazen, Stanley L (April 7, 2013). "Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis". Nature Medicine. 19 (5): 576–85. doi:10.1038/nm.3145. PMC 3650111. PMID 23563705. Retrieved April 26, 2013.
  8. 1 2 Gina Kolata (April 24, 2013). "Eggs, Too, May Provoke Bacteria to Raise Heart Risk". The New York Times. Retrieved April 25, 2013.
  9. ↑ Hazen, Stanley. "New Research On Red Meat And Heart Disease". The Diane Rehm Show (Transcript). WAMU 88.5 American University Radio. Retrieved 10 April 2013.
  10. ↑ Collins, Heidi L.; Drazul-Schrader, Denise; Sulpizio, Anthony C.; Koster, Paul D.; Williamson, Yuping; Adelman, Steven J.; Owen, Kevin; Sanli, Toran; Bellamine, Aouatef (2016). "L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE−/− transgenic mice expressing CETP". Atherosclerosis. 244: 29–37. doi:10.1016/j.atherosclerosis.2015.10.108. ISSN 0021-9150. PMID 26584136.
  11. ↑ "Carnipure®". Lonza.com. Retrieved 2018-09-19.
  12. ↑ Johri, A.M.; Heyland, D.K.; Hétu, M.-F.; Crawford, B.; Spence, J.D. (2014). "Carnitine therapy for the treatment of metabolic syndrome and cardiovascular disease: Evidence and controversies". Nutrition, Metabolism and Cardiovascular Diseases. 24 (8): 808–814. doi:10.1016/j.numecd.2014.03.007. ISSN 0939-4753.
  13. ↑ http://www.onlinecjc.ca/article/S0828-282X%2814%2901363-4/abstract
  14. ↑ Tilg, Herbert (2016-06-22). "A Gut Feeling about Thrombosis". New England Journal of Medicine. 374 (25): 2494–2496. doi:10.1056/nejmcibr1604458. PMID 27332910.
  15. ↑ Qi, Jiaqian; You, Tao; Li, Jing; Pan, Tingting; Xiang, Li; Han, Yue; Zhu, Li. "Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies". Journal of Cellular and Molecular Medicine: n/a–n/a. doi:10.1111/jcmm.13307. ISSN 1582-4934.
  16. ↑ Dimitrov D, Thiele I, Ferguson LR (2016). "Editorial: The Human Gutome: Nutrigenomics of Host-Microbiome Interactions". Frontiers in Genetics. 7: 158. doi:10.3389/fgene.2016.00158. PMC 5012120. PMID 27656194. Retrieved 2017-08-13. 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.
  17. ↑ "Regulation and aggregation of intrinsically disordered peptides". Proceedings of the National Academy of Sciences of the United States of America. 112 (9): 2758–2763. doi:10.1073/pnas.1418155112. PMC 4352815.
  18. ↑ "Effects of Trimethylamine-N-oxide on the Conformation of Peptides and its Implications for Proteins". Physical Review Letters. 119 (10). doi:10.1103/physrevlett.119.108102.
  19. 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
  20. ↑ Soderquist, J. A.; Anderson, C. L. (1986). "Crystalline anhydrous trimethylamine N-oxide". Tetrahedron Lett. 27: 3961–3962. doi:10.1016/S0040-4039(00)84884-4.
  21. ↑ Zou, Q.; et al. (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.
  22. ↑ Volker Franzen (1973). "Octanal". Organic Syntheses. ; Collective Volume, 5, p. 872

See also

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