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Fish Odor Syndrome/Trimethylaminuria
Published in Charles Theisler, Adjuvant Medical Care, 2023
Riboflavin (vitamin B2) supplements (30–40 mg taken 3–5 times per day with food) enhances existing amounts of FMO3 enzyme so that larger amounts of trimethylamine are converted to its odorless form of oxide.3
Gut Microbiome
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Brian J. Bennett, Katie A. Meyer, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
Thus, this meta-organismal pathway may be an important new paradigm to consider for an improved understanding of atherosclerotic heart disease and perhaps other cardiometabolic disease processes (Tang and Hazen 2014). We give a brief overview of this pathway with a focus on the metabolism of dietary nutrients. One route for the initial catabolism of dietary choline and l-carnitine (a nutrient important for fat metabolism) is mediated by intestinal microbes and leads to the formation of trimethylamine (TMA). Foods rich in choline and l-carnitine, such as eggs, milk, and red meat, can thus lead to increased TMA production (Zeisel et al. 2003). TMA is efficiently absorbed from the gastrointestinal tract and oxidized in the liver by the flavin-containing monooxygenase (FMO) enzymes to form trimethylamine N-oxide (TMAO) (Bennett et al. 2013). Studies have shown that Fmo3 is indeed the primary FMO responsible for hepatic metabolism of TMA to TMAO through a series of experiments that modulated Fmo3 mRNA levels using adenoviral overexpression, transgenic overexpression, and in vivo antisense oligonucleotides and examined the effect on circulating levels of TMAO (Bennett et al. 2013).
Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease
Published in Xenobiotica, 2020
Ian R. Phillips, Elizabeth A. Shephard
Most drug substrates of FMO3 are also substrates of other enzymes, particularly CYPs, and the FMO3-catalyzed reaction does not represent the major route of metabolism. However, in individuals who possess genetic variants that decrease the catalytic activity of CYPs, the contribution of FMO3 to drug metabolism is likely to be greater. An example is that of nicotine, which is metabolized predominantly by CYP2A6 (Cashman et al., 1992; Nakajima et al., 1996), but also by FMO3 (Park et al., 1993) (see below). The metabolism of a drug by CYPs and FMOs usually results in the production of distinct products; in the case of aliphatic tertiary amines, CYP-mediated oxidation usually results in N-dealkylation, whereas FMOs produce exclusively the N-oxide (Cashman, 2008).
Novel variants and haplotypes of human flavin-containing monooxygenase 3 gene associated with Japanese subjects suffering from trimethylaminuria
Published in Xenobiotica, 2019
Makiko Shimizu, Hiromi Yoda, Narumi Igarashi, Miki Makino, Emi Tokuyama, Hiroshi Yamazaki
In conclusion, subjects carrying homozygous/heterozygous combinations of any of the missense or nonsense variant FMO3 alleles found in the current study together with those previously identified mutated FMO3 alleles likely have polymorphic FMO3 that may result in reduced trimethylamine N-oxygenation capacity or efficiency. Consequently, such subjects may suffer from mild or severe trimethylaminuria. The current study provides important insights into the variable activities of FMO3 and the effects of such variation on its functionality in humans. Follow-up studies on further FMO3 polymorphisms and their effects on the oxygenation of a variety of drugs would also be worthwhile.
Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health
Published in Gut Microbes, 2020
Aimée Parker, Sonia Fonseca, Simon R. Carding
Trimethylamines: are metabolites produced from gut microbial metabolism of dietary choline, lecithin, carnitine and trimethylamine-N-oxide (TMAO) that are present in foods such as eggs, nuts, dairy products, meat, and fish. Choline is degraded into trimethylamine (TMA), which is converted in the liver by flavin-containing monooxygenases (FMOs) into TMAO, and demethylated into dimethylamine and methylamine.51 Gut-derived TMA is generated by bacteria of the genera Anaerococcus, Clostridium, Escherichia, Proteus, Providencia, and Edwardsiella.52 The presence of TMAO in human brains indicates its ability to cross the BBB.53 TMAs have been associated with both beneficial and detrimental health effects. High plasma levels of TMAO have been associated with increased risk of colorectal cancer54 and with risk of developing atherosclerosis and cardiovascular disease via effects on cholesterol metabolism.55 This is of interest regarding neurodegenerative diseases including AD and vascular dementia, in which cardiovascular disease and altered cholesterol metabolism are strongly associated with increased risk. In individuals with a hereditary defect in FMO3, bacterial TMA production contributes to the symptoms of trimethylaminuria (TMAU) or fish-odor syndrome.56 Therapy with archaebiotics and attempting to modulate the gut microbiota by administering specific strains of TMA metabolizing Archaea has been proposed as a treatment for cardiovascular diseases and TMAU. The methanogen, Methanomassiliicoccales can reduce TMA concentration in the gut by converting it to methane, thus decreasing the production of TMAO from TMA in the liver.57,58 TMAO’s beneficial effects include reducing endoplasmic reticulum stress and lipogenesis in adipocytes, increasing insulin secretion in pancreatic islets, and attenuating diet-induced impaired glucose tolerance.59,60 Again, by extension, such therapies may also be beneficial in protecting against neurodegenerative disease as diabetes which is another dementia-associated risk-factor. More specific to AD, TMAO has also been shown to restore the ability of mutant tau protein to promote microtubule assembly61,62 with microtubule disassembly and neuron death being hallmark pathological features of AD.63 In addition to its potential use as an AD biomarker,64 TMAO may also have a therapeutic effect in AD and other protein-misfolding conditions, by preferentially hydrating partially denatured proteins to correct folding defects and entropically stabilizing native conformations.65,66