Flavin-containing monooxygenase 3
Flavin-containing monooxygenase 3 (FMO3), also known as dimethylaniline monooxygenase [N-oxide-forming] 3 and trimethylamine monooxygenase, is a flavoprotein enzyme (EC 126.96.36.199) that in humans is encoded by the FMO3 gene. This enzyme catalyzes the following chemical reaction:
|, trimethylamine monooxygenase, flavin-containing monooxygenase 3, Dimethylaniline monooxygenase [N-oxide-forming] 3, FMOII, TMAU, dJ127D3.1, flavin containing monooxygenase 3, flavin containing dimethylaniline monoxygenase 3|
- trimethylamine + NADPH + H+ + O2 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 N-oxygenation of primary, secondary, and tertiary amines; the S-oxygenation of nucleophilic sulfur-containing compounds; and the 6-methylhydroxylation of DMXAA.
FMO3 is the primary enzyme in humans which catalyzes the N-oxidation of trimethylamine into trimethylamine N-oxide; FMO1 also N-oxygenates trimethylamine, but to a much lesser extent than FMO3. Genetic deficiencies of the FMO3 enzyme cause primary trimethylaminuria, also known as "fish odor syndrome". 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.
|FMO3 substrates||FMO3 inhibitors||FMO3 inducers||FMO3 activators|
|A † indicates moderate to complete selectivity for FMO3 relative to other FMO isoenzymes.|
FMO3 gene has been observed progressively downregulated in Human papillomavirus-positive neoplastic keratinocytes derived from uterine cervical preneoplastic lesions at different levels of malignancy. For this reason, FMO3 is likely to be associated with tumorigenesis and may be a potential prognostic marker for uterine cervical preneoplastic lesions progression.
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trimethylaminuria (fish-odor syndrome) is associated with defective hepatic N-oxidation of dietary-derived trimethylamine catalyzed by flavin-containing monooxygenase ... FMO3 deficiency results in trimethylaminuria or the fish-like odour syndrome ... isozyme FMO3 regulates the conversion of N,N,N-trimethylamine into its N-oxide and hence controls the release of volatile N,N,N-trimethylamine from the individual
- Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacol. Ther. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC 1828602. PMID 15922018.
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).
Table 5: N-containing drugs and xenobiotics oxygenated by FMO
Table 6: S-containing drugs and xenobiotics oxygenated by FMO
Table 7: FMO activities not involving S- or N-oxygenation
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Other drug substrates have been used for both in vitro and in vivo analyses. ... FMO3 is the most abundantly expressed FMO in the adult human liver . Its structure and function and the implications of its polymorphisms have been widely studied [8,12,13]. This enzyme has a wide substrate specificity, including the dietary-derived tertiary amines trimethylamine, tyramine and nicotine; commonly used drugs including cimetidine, ranitidine, clozapine, methimazole, itopride, ketoconazole, tamoxifen and sulindac sulfide; and agrichemicals, such as organophosphates and carbamates [14–22].
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Human FMO3 N-oxygenates primary, secondary and tertiary amines whereas human FMO1 is only highly efficient at N-oxygenating tertiary amines. Both human FMO1 and FMO3 S-oxygenate a number of nucleophilic sulfur-containing substrates and in some cases, does so with great stereoselectivity. ... For amines with smaller aromatic substituents such as phenethylamines, often these compounds are efficiently N-oxygenated by human FMO3. ... (S)-Nicotine N-1'-oxide formation can also be used as a highly stereoselective probe of human FMO3 function for adult humans that smoke cigarettes. Finally, cimetidine S-oxygenation or ranitidine N-oxidation can also be used as a functional probe of human FMO3. With the recent observation of human FMO3 genetic polymorphism and poor metabolism phenotype in certain human populations, variant human FMO3 may contribute to adverse drug reactions or exaggerated clinical response to certain medications.
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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.
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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).
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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.
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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.
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TMAO is generated from trimethylamine (TMA) via metabolism by hepatic flavin-containing monooxygenase isoform 3 (FMO3). ... FMO3 catalyzes the oxidation of catecholamine or catecholamine-releasing vasopressors, including tyramine, phenylethylamine, adrenaline, and noradrenaline [32, 33].
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