trimethyl amine and trimethylamide oxide

From choline to TMA to TMAO

This is what Protein Atlas has to say about FMO3: “Plays an important role in the metabolism of trimethylamine (TMA), via the production of trimethylamine N-oxide (TMAO) metabolite 3. TMA is generated by the action of gut microbiota using dietary precursors such as choline, choline containing compounds, betaine or L-carnitine. Flavin-containing monooxygenases (FMO) are an important class of drug-metabolizing enzymes that catalyze the NADPH-dependent oxygenation of various nitrogen-,sulfur-, and phosphorous-containing xenobiotics such as therapeutic drugs, dietary compounds, pesticides, and other foreign compounds. The human FMO gene family is composed of 5 genes and multiple pseudogenes. FMO members have distinct developmental- and tissue-specific expression patterns. The expression of this FMO3 gene, the major FMO expressed in adult liver, can vary up to 20-fold between individuals. This inter-individual variation in FMO3 expression levels is likely to have significant effects on the rate at which xenobiotics are metabolised and, therefore, is of considerable interest to the pharmaceutical industry. This transmembrane protein localizes to the endoplasmic reticulum of many tissues. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. Mutations in this gene cause the disorder trimethylaminuria (TMAu) which is characterized by the accumulation and excretion of unmetabolized trimethylamine and a distinctive body odor. In healthy individuals, trimethylamine is primarily converted to the non odorous trimethylamine N-oxide”

Increased plasma TMAO is seen in autistic Han Chinese vs theirtypical development couterparts. [1] This study did not establich a causal relationship. A recent study suggests that the TMAO precursor choline may be protective. [2]

Finally a plausible target

A recent study has established that TMAO can activate an actual enzyme .[3]

And why OMT may help

Mixed bacterial flora cultured from dental plaque and saliva converted choline to trimethylamine. The only organism with trimethylamine-forming capability isolated from these mixed cultures was identified as Streptococcus sanguis I (a facultative anaerobe). The other products formed when choline was cleaved were ethanol and acetate. The formation of trimethylamine by S. sanguis I was enzyme-mediated. Activity was destroyed by heating at 100 degrees C, and obeyed Michaelis-Menten kinetics (K(apparent) for choline = 184 +/- 58 microM; V(max apparent) = 1.7 +/- 0.1 micromol/mg protein/h). Activity was maximal at pH 7.5 to 8.5, was membrane-bound, and required a divalent metal cation (cobalt or iron). More trimethylamine was produced by bacteria incubated under a nitrogen than under an aerobic atmosphere. Activity was inhibited by deanol, betaine aldehyde, hemicholinium-3, iodoacetate, semicarbazide, and 2,4-dinitrophenol, and was enhanced by sulfhydryl-reducing agents (glutathione, 2-mercaptoethanol, DL-dithiothreitol) and sodium bisulfite. The enzyme activity that we describe in S. sanguis I is similar to that previously described in the anaerobic bacteria isolated from intestinal flora.[3]

References

1. Quan L, Yi J, Zhao Y, Zhang F, Shi XT, Feng Z, Miller HL. Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with autism spectrum disorders. Neurotoxicology. 2020 Jan;76:93-98. PMC free article PMC free article
2. Liu D, Bu D, Li H, Wang Q, Ding X, Fang X. Intestinal metabolites and the risk of autistic spectrum disorder: A two-sample Mendelian randomization study. Front Psychiatry. 2023 Jan 12;13:1034214. PMC free article
3. Chao CK, Zeisel SH.Formation of trimethylamine from dietary choline by Streptococcus sanguis I, which colonizes the mouth. J Nutr Biochem. 1990 Feb;1(2):89-97.
4. Li Y, Zhu M, Liu Y
5. Chen S, Henderson A, Petriello MC, Romano KA, Gearing M, Miao J, Schell M, Sandoval-Espinola WJ, Tao J, Sha B, Graham M, Crooke R, Kleinridders A, Balskus EP, Rey FE, Morris AJ, Biddinger SB. Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. Cell Metab. 2019 PMC.free article

Other References to be explored if interested at a later date

1. Ma SR, Tong Q, Lin Y, Pan LB, Fu J, Peng R, Zhang XF, Zhao ZX, Li Y, Yu JB, Cong L, Han P, Zhang ZW, Yu H, Wang Y, Jiang JD. Berberine treats atherosclerosis via a vitamine-like effect down-regulating Choline-TMA-TMAO production pathway in gut microbiota. Signal Transduct Target Ther. 2022 Jul 7;7(1):207. PMC free article
2. Govindarajulu, M.; Pinky, P.D.; Steinke, I.; Bloemer, J.; Ramesh, S.; Kariharan, T.; Rella, R.T.; Bhattacharya, S.; Dhanasekaran,
   M.; Suppiramaniam, V.; et al. Gut metabolite TMAO induces synaptic plasticity deficits by promoting endoplasmic reticulum
   stress. Front. Mol. Neurosci. 2020, 13, 138, doi:10.3389/fnmol.2020.00138.
   94. Li, T.; Chen, Y.; Gua, C.; Li, X. Elevated circulating Trimethylamine N-Oxide levels contribute to endothelial dysfunction in
   aged rats through vascular inflammation and oxidative stress. Front. Physiol. 2017, 8, 350, doi:10.3389/fphys.2017.00350.
   95. Romano, K.A.; Vivas, E.I.; Amador-Noguez, D.; Rey, F.E. Intestinal microbiota composition modulates choline bioavailability
   from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio 2015, 6, e02481,
   doi:10.1128/mBio.02481-14.
   96. Wu, W.K.; Panyod, S.; Liu, P.Y.; Chen, C.C.; Kao, H.L.; Chuang, H.L.; Chen, Y.H.; Zou, H.B.; Kuo, H.C.; Kuo, C.H.; et al.
   Characterization of TMAO productivity from carnitine challenge facilitates personalized nutrition and microbiome signatures
   discovery. Microbiome 2020, 8, 162, doi:10.1186/s40168-020-00912-y.
   97. Falony, G.; Vieira-Silva, S.; Raes, J. Microbiology meets big data: The case of gut microbiota-derived trimethylamine. Annu. Rev.
   Microbiol. 2015, 69, 305–321, doi:10.1146/annurev-micro-091014-104422.
   98. Martinez-del Campo, A.; Bodea, S.; Hamer, H.A.; Marks, J.A.; Haiser, H.J.; Turnbaugh, P.J.; Balskus, E.P. Characterization and
   detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. mBio 2015, 6,
   e00042, doi:10.1128/mBio.00042-15.
   99. Kalnins, G.; Kuka, J.; Grinberga, S.; Makrecka-Kuka, M.; Liepinsh, E.; Dambrova, M.; Tars, K. Structure and function of CutC
   choline lyase from human microbiota bacterium klebsiella pneumoniae. J. Biol. Chem. 2015, 290, 21732–21740,
   doi:10.1074/jbc.M115.670471