Flavin-containing monooxygenase 3

{{Short description|Protein-coding gene in the species Homo sapiens}}

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Flavin-containing monooxygenase 3 (FMO3), also known as dimethylaniline monooxygenase [N-oxide-forming] 3 and trimethylamine monooxygenase, is a flavoprotein enzyme ({{EC number|1.14.13.148}}) that in humans is encoded by the FMO3 gene.{{cite journal |vauthors=Shephard EA, Dolphin CT, Fox MF, Povey S, Smith R, Phillips IR | title = Localization of genes encoding three distinct flavin-containing monooxygenases to human chromosome 1q | journal = Genomics | volume = 16 | issue = 1 | pages = 85–9 |date=June 1993 | pmid = 8486388 | doi = 10.1006/geno.1993.1144 }}{{cite journal |vauthors=Dolphin CT, Riley JH, Smith RL, Shephard EA, Phillips IR | title = Structural organization of the human flavin-containing monooxygenase 3 gene (FMO3), the favored candidate for fish-odor syndrome, determined directly from genomic DNA | journal = Genomics | volume = 46 | issue = 2 | pages = 260–7 |date=February 1998 | pmid = 9417913 | doi = 10.1006/geno.1997.5031 }}{{cite web | title = Entrez Gene: FMO3 flavin containing monooxygenase 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2328}}

This enzyme catalyzes the following chemical reaction, among others:

:trimethylamine + NADPH + H⁺ + O₂ $\backslash rightleftharpoons$ trimethylamine N-oxide + NADP⁺ + H₂O

FMO3 is the main flavin-containing monooxygenase isoenzyme that is expressed in the liver of adult humans. The human FMO3 enzyme catalyzes several types of reactions, including: the {{nowrap|N-oxygenation}} of primary, secondary, and tertiary amines; the {{nowrap|S-oxygenation}} of nucleophilic sulfur-containing compounds; and the {{nowrap|6-methylhydroxylation}} of the anti-cancer agent dimethylxanthenone acetic acid (DMXAA).{{cite journal | vauthors = Zhou S, Kestell P, Paxton JW | title = 6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3 | journal = Eur J Drug Metab Pharmacokinet | volume = 27 | issue = 3 | pages = 179–183 | date = July 2002 | pmid = 12365199 | doi = 10.1007/bf03190455| s2cid = 21583717 | quote = Only FMO3 formed 6-OH-MXAA at a similar rate to that in cDNA-expressed cytochromes P-450 (CYP)1A2. The results of this study indicate that human FMO3 has the capacity to form 6-OH-MXAA, but plays a lesser important role for this reaction than CYP1A2 that has been demonstrated to catalyse 6-OH-MXAA formation.}}

FMO3 is the primary enzyme in humans which catalyzes the N-oxidation of trimethylamine into trimethylamine N-oxide; FMO1 also does this, but to a much lesser extent than FMO3.{{cite journal | vauthors = Tang WH, Hazen SL | title = The contributory role of gut microbiota in cardiovascular disease | journal = J. Clin. Invest. | volume = 124 | issue = 10 | pages = 4204–4211 | date = October 2014 | pmid = 25271725 | pmc = 4215189 | doi = 10.1172/JCI72331 | quote = In recent studies each of the FMO family members were cloned and expressed, to determine which possessed synthetic capacity to use TMA as a substrate to generate TMAO. FMO1, FMO2, and FMO3 were all capable of forming TMAO, though the specific activity of FMO3 was at least 10-fold higher than that the other FMOs (54). Further, FMO3 overexpression in mice significantly increased plasma TMAO levels, while silencing FMO3 decreased TMAO levels (54). In both humans and mice, hepatic FMO3 expression was observed to be reduced in males compared with females (25, 54) and could be induced by dietary bile acids through a mechanism that involves FXR (54). }}{{cite journal | vauthors = Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ | title = Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation | journal = Cell Metab. | volume = 17 | issue = 1 | pages = 49–60 | year = 2013 | pmid = 23312283 | pmc = 3771112 | doi = 10.1016/j.cmet.2012.12.011 | quote = Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1.}} Genetic deficiencies of the FMO3 enzyme cause primary trimethylaminuria, also known as "fish odor syndrome".{{cite journal | vauthors = Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR | title = Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome | journal = Nat. Genet. | volume = 17 | issue = 4 | pages = 491–4 | year = 1997 | pmid = 9398858 | doi = 10.1038/ng1297-491 | s2cid = 24732203 }} FMO3 is also involved in the metabolism of many xenobiotics (i.e., exogenous compounds which are not normally present in the body), such as the oxidative deamination of amphetamine.{{cite journal |vauthors=Krueger SK, Williams DE | title = Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism | journal = Pharmacol. Ther. | volume = 106 | issue = 3 | pages = 357–387 |date=June 2005 | pmid = 15922018 | pmc = 1828602 | doi = 10.1016/j.pharmthera.2005.01.001 | doi-access = free |quote = A second precaution with respect to predicting FMO enzyme substrate specificity is that factors other than size and charge must play a role, but these parameters are not well understood. An example is the high selectivity observed with human FMO3, compared to the other FMO enzymes, in the N-oxygenation of the important constitutive substrate trimethylamine (Lang et al., 1998). ... The most efficient human FMO in phenethylamine N-oxygenation is FMO3, the major FMO present in adult human liver; the Km is between 90 and 200 μM (Lin & Cashman, 1997b). ... Of particular significance for this review is that individuals homozygous for certain FMO3 allelic variants (e.g., null variants) also demonstrate impaired metabolism toward other FMO substrates including ranitidine, nicotine, thio-benzamide, and phenothiazine derivatives (Table 4; Cashman et al., 1995, 2000; Kang et al., 2000; Cashman, 2002; Park et al., 2002; Lattard et al., 2003a, 2003b). ... The metabolic activation of ethionamide by the bacterial FMO is the same as the mammalian FMO activation of thiobenzamide to produce hepatotoxic sulfinic and sulfinic acid metabolites. Not surprisingly, Dr. Ortiz de Montellano's laboratory and our own have found ethionamide to be a substrate for human FMO1, FMO2, and FMO3 (unpublished observations).}}
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T5/ Table 5: N-containing drugs and xenobiotics oxygenated by FMO]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T6/ Table 6: S-containing drugs and xenobiotics oxygenated by FMO]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T7/ Table 7: FMO activities not involving S- or N-oxygenation]{{cite book | author = Glennon RA |veditors=Lemke TL, Williams DA, Roche VF, Zito W | title=Foye's principles of medicinal chemistry | date=2013 | publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins | location=Philadelphia, USA | isbn=978-1-60913-345-0 | pages=646–648 | edition=7th | section-url=https://books.google.com/books?id=Sd6ot9ul-bUC&q=substituted%20derivatives%20substituents%20hydroxyamphetamine%20flavin%20monooxygenase&pg=PA646 | section=Phenylisopropylamine stimulants: amphetamine-related agents | quote=The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase.}}{{cite journal |vauthors=Cashman JR, Xiong YN, Xu L, Janowsky A | title = N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication | journal = J. Pharmacol. Exp. Ther. | volume = 288 | issue = 3 | pages = 1251–1260 | date = March 1999 | doi = 10.1016/S0022-3565(24)38081-4 |pmid = 10027866 }}