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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]].<ref name="pmid8486388">{{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 | pmc =  | doi = 10.1006/geno.1993.1144 }}</ref><ref name="pmid9417913">{{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 | pmc =  | doi = 10.1006/geno.1997.5031 }}</ref><ref name="entrez">{{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| accessdate = }}</ref><ref name="BRENDA FMO3 Homo sapiens" />
'''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]].<ref name="pmid8486388">{{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 | pmc =  | doi = 10.1006/geno.1993.1144 }}</ref><ref name="pmid9417913">{{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 | pmc =  | doi = 10.1006/geno.1997.5031 }}</ref><ref name="entrez">{{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| accessdate = }}</ref><ref name="BRENDA FMO3 Homo sapiens" />
This enzyme [[catalysis|catalyzes]] the following [[chemical reaction]]:<ref name="BRENDA FMO3 Homo sapiens" />
This enzyme [[catalysis|catalyzes]] the following [[chemical reaction]]:<ref name="BRENDA FMO3 Homo sapiens" />
: ''N'',''N'',''N''-trimethylamine + NADPH + H<sup>+</sup> + O<sub>2</sub> <math>\rightleftharpoons</math> ''N'',''N'',''N''-trimethylamine ''N''-oxide + NADP<sup>+</sup> + H<sub>2</sub>O
:trimethylamine + NADPH + H<sup>+</sup> + O<sub>2</sub> <math>\rightleftharpoons</math> trimethylamine ''N''-oxide + NADP<sup>+</sup> + H<sub>2</sub>O


FMO3 is the main [[flavin-containing monooxygenase]] [[isoenzyme]] that is expressed in the liver of adult humans.<ref name="BRENDA FMO3 Homo sapiens" /><ref name="FMO" /><ref name="FMO3 2007 review" />  The human FMO3 enzyme catalyzes several types of reactions, including: the {{nowrap|''N''-oxygenation}} of primary, secondary, and tertiary [[amine]]s;<ref name="FMO" /><ref name="FMO3 2000 review" /> the {{nowrap|''S''-oxygenation}} of [[nucleophilic]] [[sulfur]]-containing compounds;<ref name="FMO" /><ref name="FMO3 2000 review" /> and the {{nowrap|6-methylhydroxylation}} of [[DMXAA]].<ref name="FMO" /><ref name="DMXAA primary">{{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| 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.}}</ref>
FMO3 is the main [[flavin-containing monooxygenase]] [[isoenzyme]] that is expressed in the liver of adult humans.<ref name="BRENDA FMO3 Homo sapiens" /><ref name="FMO" /><ref name="FMO3 2007 review" />  The human FMO3 enzyme catalyzes several types of reactions, including: the {{nowrap|''N''-oxygenation}} of primary, secondary, and tertiary [[amine]]s;<ref name="FMO" /><ref name="FMO3 2000 review" /> the {{nowrap|''S''-oxygenation}} of [[nucleophilic]] [[sulfur]]-containing compounds;<ref name="FMO" /><ref name="FMO3 2000 review" /> and the {{nowrap|6-methylhydroxylation}} of [[DMXAA]].<ref name="FMO" /><ref name="DMXAA primary">{{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| 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.}}</ref>


FMO3 is the primary enzyme in humans which catalyzes the [[N-oxidation|''N''-oxidation]] of [[trimethylamine]] into [[trimethylamine N-oxide|trimethylamine ''N''-oxide]];<ref name="BRENDA FMO3 Homo sapiens" /><ref name="FMO3 2007 review" /> [[FMO1]] also ''N''-oxygenates trimethylamine, but to a much lesser extent than FMO3.<ref name="Review – TMA1+TMA2 N-oxygenate TMA">{{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). }}</ref><ref name="FMO1 also metabolizes TMA – primary source">{{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.}}</ref> Genetic deficiencies of the FMO3 enzyme cause [[primary trimethylaminuria]], also known as "fish odor syndrome".<ref name="BRENDA FMO3 Homo sapiens" /><ref name="FMO3, trimethylamine, and 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 | url = }}</ref> FMO3 is also involved in the metabolism of many [[xenobiotics]] (i.e., exogenous compounds which are not normally present in the body),<ref name="FMO" /><ref name="FMO3 2007 review" /> such as the [[oxidative deamination]] of [[amphetamine]].<ref name="FMO">{{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|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).&nbsp;... 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).&nbsp;... 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).&nbsp;... 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).}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T5/ Table 5: N-containing drugs and xenobiotics oxygenated by FMO]<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T6/ Table 6: S-containing drugs and xenobiotics oxygenated by FMO]<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T7/ Table 7: FMO activities not involving S- or N-oxygenation]</ref><ref name="Substituted amphetamines, FMO, and DBH">{{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=9781609133450 | pages=646–648 | edition=7th | section-url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA646&q=substituted%20derivatives%20substituents%20hydroxyamphetamine%20flavin%20monooxygenase#v=onepage | accessdate=11 September 2015 | 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).&nbsp;... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase.}}</ref><ref name="FMO3-Primary">{{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 |pmid = 10027866 }}</ref>
FMO3 is the primary enzyme in humans which catalyzes the [[N-oxidation|''N''-oxidation]] of [[trimethylamine]] into [[trimethylamine N-oxide|trimethylamine ''N''-oxide]];<ref name="BRENDA FMO3 Homo sapiens" /><ref name="FMO3 2007 review" /> [[FMO1]] also ''N''-oxygenates trimethylamine, but to a much lesser extent than FMO3.<ref name="Review – TMA1+TMA2 N-oxygenate TMA">{{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). }}</ref><ref name="FMO1 also metabolizes TMA – primary source">{{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.}}</ref> Genetic deficiencies of the FMO3 enzyme cause [[primary trimethylaminuria]], also known as "fish odor syndrome".<ref name="BRENDA FMO3 Homo sapiens" /><ref name="FMO3, trimethylamine, and 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 | url = }}</ref> FMO3 is also involved in the metabolism of many [[xenobiotics]] (i.e., exogenous compounds which are not normally present in the body),<ref name="FMO" /><ref name="FMO3 2007 review" /> such as the [[oxidative deamination]] of [[amphetamine]].<ref name="FMO">{{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|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).&nbsp;... 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).&nbsp;... 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).&nbsp;... 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).}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T5/ Table 5: N-containing drugs and xenobiotics oxygenated by FMO]<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T6/ Table 6: S-containing drugs and xenobiotics oxygenated by FMO]<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T7/ Table 7: FMO activities not involving S- or N-oxygenation]</ref><ref name="Substituted amphetamines, FMO, and DBH">{{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=9781609133450 | pages=646–648 | edition=7th | section-url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA646&q=substituted%20derivatives%20substituents%20hydroxyamphetamine%20flavin%20monooxygenase#v=onepage | accessdate=| 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).&nbsp;... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase.}}</ref><ref name="FMO3-Primary">{{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 |pmid = 10027866 }}</ref>


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{{PBB_Further_reading  
{{PBB_Further_reading  
| citations =  
| citations =  
*{{cite journal  |vauthors=Cashman JR, Park SB, Berkman CE, Cashman LE |title=Role of hepatic flavin-containing monooxygenase 3 in drug and chemical metabolism in adult humans. |journal=Chem. Biol. Interact. |volume=96 |issue= 1 |pages= 33–46 |year= 1995 |pmid= 7720103 |doi=10.1016/0009-2797(94)03581-R  }}
*{{cite journal  |vauthors=Cashman JR, Park SB, Berkman CE, Cashman LE |title=Role of hepatic flavin-containing monooxygenase 3 in drug and chemical metabolism in adult humans |journal=Chem. Biol. Interact. |volume=96 |issue= 1 |pages= 33–46 |year= 1995 |pmid= 7720103 |doi=10.1016/0009-2797(94)03581-R  }}
*{{cite journal  | author=Cashman JR |title=The implications of polymorphisms in mammalian flavin-containing monooxygenases in drug discovery and development. |journal=Drug Discov. Today |volume=9 |issue= 13 |pages= 574–81 |year= 2004 |pmid= 15203093 |doi= 10.1016/S1359-6446(04)03136-8 }}
*{{cite journal  | author=Cashman JR |title=The implications of polymorphisms in mammalian flavin-containing monooxygenases in drug discovery and development |journal=Drug Discov. Today |volume=9 |issue= 13 |pages= 574–81 |year= 2004 |pmid= 15203093 |doi= 10.1016/S1359-6446(04)03136-8 }}
*{{cite journal  |vauthors=Zhou J, Shephard EA |title=Mutation, polymorphism and perspectives for the future of human flavin-containing monooxygenase 3. |journal=Mutat. Res. |volume=612 |issue= 3 |pages= 165–71 |year= 2006 |pmid= 16481213 |doi= 10.1016/j.mrrev.2005.09.001 }}
*{{cite journal  |vauthors=Zhou J, Shephard EA |title=Mutation, polymorphism and perspectives for the future of human flavin-containing monooxygenase 3 |journal=Mutat. Res. |volume=612 |issue= 3 |pages= 165–71 |year= 2006 |pmid= 16481213 |doi= 10.1016/j.mrrev.2005.09.001 }}
*{{cite journal  |vauthors=Lomri N, Gu Q, Cashman JR |title=Molecular cloning of the flavin-containing monooxygenase (form II) cDNA from adult human liver. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 5 |pages= 1685–9 |year= 1992 |pmid= 1542660 |doi=10.1073/pnas.89.5.1685  | pmc=48517  }}
*{{cite journal  |vauthors=Lomri N, Gu Q, Cashman JR |title=Molecular cloning of the flavin-containing monooxygenase (form II) cDNA from adult human liver |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 5 |pages= 1685–9 |year= 1992 |pmid= 1542660 |doi=10.1073/pnas.89.5.1685  | pmc=48517  }}
*{{cite journal  |vauthors=Humbert JA, Hammond KB, Hathaway WE |title=Trimethylaminuria: the fish-odour syndrome. |journal=Lancet |volume=2 |issue= 7676 |pages= 770–1 |year= 1970 |pmid= 4195988 |doi=10.1016/S0140-6736(70)90241-2  }}
*{{cite journal  |vauthors=Humbert JA, Hammond KB, Hathaway WE |title=Trimethylaminuria: the fish-odour syndrome |journal=Lancet |volume=2 |issue= 7676 |pages= 770–1 |year= 1970 |pmid= 4195988 |doi=10.1016/S0140-6736(70)90241-2  }}
*{{cite journal  |vauthors=Higgins T, Chaykin S, Hammond KB, Humbert JR |title=Trimethylamine N-oxide synthesis: a human variant. |journal=Biochemical medicine |volume=6 |issue= 4 |pages= 392–6 |year= 1972 |pmid= 5048998 |doi=10.1016/0006-2944(72)90025-7  }}
*{{cite journal  |vauthors=Higgins T, Chaykin S, Hammond KB, Humbert JR |title=Trimethylamine N-oxide synthesis: a human variant |journal=Biochemical Medicine |volume=6 |issue= 4 |pages= 392–6 |year= 1972 |pmid= 5048998 |doi=10.1016/0006-2944(72)90025-7  }}
*{{cite journal  |vauthors=Lomri N, Gu Q, Cashman JR |title=Molecular cloning of the flavin-containing monooxygenase (form II) cDNA from adult human liver. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 21 |pages= 9910 |year= 1995 |pmid= 7568243 |doi=10.1073/pnas.92.21.9910  | pmc=40912  }}
*{{cite journal  |vauthors=Lomri N, Gu Q, Cashman JR |title=Molecular cloning of the flavin-containing monooxygenase (form II) cDNA from adult human liver |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 21 |pages= 9910 |year= 1995 |pmid= 7568243 |doi=10.1073/pnas.92.21.9910  | pmc=40912  }}
*{{cite journal  |vauthors=Bhamre S, Bhagwat SV, Shankar SK |title=Flavin-containing monooxygenase mediated metabolism of psychoactive drugs by human brain microsomes. |journal=Brain Res. |volume=672 |issue= 1–2 |pages= 276–80 |year= 1995 |pmid= 7749747 |doi=10.1016/0006-8993(94)01135-5  |display-authors=etal}}
*{{cite journal  |vauthors=Bhamre S, Bhagwat SV, Shankar SK |title=Flavin-containing monooxygenase mediated metabolism of psychoactive drugs by human brain microsomes |journal=Brain Res. |volume=672 |issue= 1–2 |pages= 276–80 |year= 1995 |pmid= 7749747 |doi=10.1016/0006-8993(94)01135-5  |display-authors=etal}}
*{{cite journal  |vauthors=Cashman JR, Park SB, Yang ZC |title=Chemical, enzymatic, and human enantioselective S-oxygenation of cimetidine |journal=Drug Metab. Dispos. |volume=21 |issue= 4 |pages= 587–97 |year= 1993 |pmid= 8104117 |doi=  |display-authors=etal}}
*{{cite journal  |vauthors=Cashman JR, Park SB, Yang ZC |title=Chemical, enzymatic, and human enantioselective S-oxygenation of cimetidine |journal=Drug Metab. Dispos. |volume=21 |issue= 4 |pages= 587–97 |year= 1993 |pmid= 8104117 |doi=  |display-authors=etal}}
*{{cite journal  |vauthors=Park SB, Jacob P, Benowitz NL, Cashman JR |title=Stereoselective metabolism of (S)-(−)-nicotine in humans: formation of trans-(S)-(−)-nicotine N-1'-oxide |journal=Chem. Res. Toxicol. |volume=6 |issue= 6 |pages= 880–8 |year= 1994 |pmid= 8117928 |doi=10.1021/tx00036a019  }}
*{{cite journal  |vauthors=Park SB, Jacob P, Benowitz NL, Cashman JR |title=Stereoselective metabolism of (S)-(−)-nicotine in humans: formation of trans-(S)-(−)-nicotine N-1'-oxide |journal=Chem. Res. Toxicol. |volume=6 |issue= 6 |pages= 880–8 |year= 1994 |pmid= 8117928 |doi=10.1021/tx00036a019  }}

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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 1.14.13.148) that in humans is encoded by the FMO3 gene.[1][2][3][4] This enzyme catalyzes the following chemical reaction:[4]

trimethylamine + NADPH + H+ + O2 <math>\rightleftharpoons</math> trimethylamine N-oxide + NADP+ + H2O

FMO3 is the main flavin-containing monooxygenase isoenzyme that is expressed in the liver of adult humans.[4][5][6] The human FMO3 enzyme catalyzes several types of reactions, including: the N-oxygenation of primary, secondary, and tertiary amines;[5][7] the S-oxygenation of nucleophilic sulfur-containing compounds;[5][7] and the 6-methylhydroxylation of DMXAA.[5][8]

FMO3 is the primary enzyme in humans which catalyzes the N-oxidation of trimethylamine into trimethylamine N-oxide;[4][6] FMO1 also N-oxygenates trimethylamine, but to a much lesser extent than FMO3.[9][10] Genetic deficiencies of the FMO3 enzyme cause primary trimethylaminuria, also known as "fish odor syndrome".[4][11] FMO3 is also involved in the metabolism of many xenobiotics (i.e., exogenous compounds which are not normally present in the body),[5][6] such as the oxidative deamination of amphetamine.[5][12][13]

Ligands

List of human FMO3 substrates, inhibitors, inducers, and activators
FMO3 substrates FMO3 inhibitors FMO3 inducers FMO3 activators
Endogenous biomolecules
Notable exogenous xenobiotics
A † indicates moderate to complete selectivity for FMO3 relative to other FMO isoenzymes.

See also

References

  1. ↑ Shephard EA, Dolphin CT, Fox MF, Povey S, Smith R, Phillips IR (June 1993). "Localization of genes encoding three distinct flavin-containing monooxygenases to human chromosome 1q". Genomics. 16 (1): 85–9. doi:10.1006/geno.1993.1144. PMID 8486388.
  2. ↑ Dolphin CT, Riley JH, Smith RL, Shephard EA, Phillips IR (February 1998). "Structural organization of the human flavin-containing monooxygenase 3 gene (FMO3), the favored candidate for fish-odor syndrome, determined directly from genomic DNA". Genomics. 46 (2): 260–7. doi:10.1006/geno.1997.5031. PMID 9417913.
  3. ↑ "Entrez Gene: FMO3 flavin containing monooxygenase 3".
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 "Trimethylamine monooxygenase (Homo sapiens)". BRENDA. Technische Universität Braunschweig. July 2016. Retrieved 18 September 2016. 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
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 5.18 5.19 5.20 5.21 5.22 5.23 5.24 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
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 Hisamuddin IM, Yang VW (June 2007). "Genetic polymorphisms of human flavin-containing monooxygenase 3: implications for drug metabolism and clinical perspectives". Pharmacogenomics. 8 (6): 635–643. doi:10.2217/14622416.8.6.635. PMC 2213907. PMID 17559352. 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 [12]. 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].
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Cashman JR (September 2000). "Human flavin-containing monooxygenase: substrate specificity and role in drug metabolism". Curr. Drug Metab. 1 (2): 181–191. doi:10.2174/1389200003339135. PMID 11465082. 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.
  8. ↑ 8.0 8.1 Zhou S, Kestell P, Paxton JW (July 2002). "6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3". Eur J Drug Metab Pharmacokinet. 27 (3): 179–183. doi:10.1007/bf03190455. PMID 12365199. 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.
  9. ↑ Tang WH, Hazen SL (October 2014). "The contributory role of gut microbiota in cardiovascular disease". J. Clin. Invest. 124 (10): 4204–4211. doi:10.1172/JCI72331. PMC 4215189. PMID 25271725. 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).
  10. ↑ 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 (2013). "Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation". Cell Metab. 17 (1): 49–60. doi:10.1016/j.cmet.2012.12.011. PMC 3771112. PMID 23312283. 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.
  11. ↑ Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR (1997). "Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome". Nat. Genet. 17 (4): 491–4. doi:10.1038/ng1297-491. PMID 9398858.
  12. ↑ Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W. Foye's principles of medicinal chemistry (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN 9781609133450. 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.
  13. ↑ 13.0 13.1 13.2 Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication". J. Pharmacol. Exp. Ther. 288 (3): 1251–1260. PMID 10027866.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 Robinson-Cohen C, Newitt R, Shen DD, Rettie AE, Kestenbaum BR, Himmelfarb J, Yeung CK (August 2016). "Association of FMO3 Variants and Trimethylamine N-Oxide Concentration, Disease Progression, and Mortality in CKD Patients". PLoS ONE. 11 (8): e0161074. doi:10.1371/journal.pone.0161074. PMC 4981377. PMID 27513517. 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].

Further reading

External links


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