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Gene Review

FMO3  -  flavin containing monooxygenase 3

Homo sapiens

Synonyms: Dimethylaniline oxidase 3, FMO 3, FMO II, FMO form 2, FMOII, ...
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Disease relevance of FMO3

  • The cDNA for the adult human liver flavin-containing monooxygenase (form 3) (FMO3) was cloned, sequenced, and expressed in Escherichia coli [1].
  • Oxidative activation of thiacetazone by the Mycobacterium tuberculosis flavin monooxygenase EtaA and human FMO1 and FMO3 [2].
  • These genes are involved in the metabolism of xenobiotics (eg GPX2 and FMO3) and may represent cigarette smoke-induced, cancer-related molecular targets that may be utilized to identify smokers with increased risk for lung cancer [3].
  • Here, we determined whether these FMO3 polymorphisms correlated with the ability of sulindac to regress polyposis in patients with FAP who had polyps prior to treatment [4].
  • The baculovirus expression vector system was used to overexpress human FMO3 in insect cells for catalytic, structural, and immunochemical studies [5].

High impact information on FMO3


Chemical compound and disease context of FMO3


Biological context of FMO3

  • As part of the human genome effort, an FMO-like gene, FMO6, was identified between FMO3 and FMO2 (GenBank accession no. AL021026) [14].
  • Both cDNA-expressed FMO3 and adult human liver microsomes N-oxygenated trifluoperazine or 10-(N,N-dimethylaminoalkyl)-phenothiazines with similar substrate specificities [1].
  • Knowledge of the exon/intron organization of the human FMO3 gene enabled each of the coding exons of the gene, together with their associated flanking intron sequences, to be amplified from genomic DNA and will thus facilitate the identification of mutations in FMO3 in families affected with fish-odor syndrome [15].
  • Three of these genes (FMO1, FMO3, and FMO4) have previously been localized to human chromosome 1q, raising the possibility that the entire gene family is clustered in this chromosomal region [16].
  • The localization of FMO1, FMO2, and FMO3 has been refined to the long arm of chromosome 1 [17].

Anatomical context of FMO3

  • In general, the stereoselectivity observed for S-oxygenation in the presence of FMO3 was similar to that observed in the presence of adult human liver microsomes [1].
  • Tolperisone inhibited methyl p-tolyl sulfide oxidation (K(i) = 1200 microM) in recombinant flavin-containing monooxygenase 3 (FMO3) and resulted in a 3-fold (p < 0.01) higher turnover number using rFMO3 than that of control microsomes [18].
  • We conclude that CYP1As and FMO3 are the major phase I enzymes involved in the metabolism of S 16020 and that this molecule is a potent hydrocarbon-like inducer able to stimulate its own metabolism in primary human hepatocytes and liver [19].
  • METHODS: Inhibition of individual CYP and FMO3 activities in the reconstituted system and in artificial membranes (bactosomes) was studied [20].
  • The human FMO3 cDNA was amplified from lymphocytes of affected patients [11].

Associations of FMO3 with chemical compounds

  • Purified mini-pig liver FMO1, rabbit lung FMO2, and human cDNA-expressed FMO3 efficiently oxidized sulindac sulfide with a high degree of stereoselectivity towards the R-isomer, but FMO5 lacked catalytic activity [21].
  • The cDNA-expressed FMO3 was used to investigate the regio- and stereoselective N- and S-oxygenation of a number of tertiary amines and sulfides, respectively [1].
  • Nucleophilic sulfur-containing compounds [i.e., thiobenzamide, (4-bromophenyl)-1,3-oxathiolane, and 2-methyl-1,3-benzodithiole] were efficiently S-oxygenated by cDNA-expressed FMO3 and adult human liver microsomes [1].
  • Therefore, benzydamine, but not caffeine, is a potential in vivo probe for human FMO3 [22].
  • FMO3 metabolized fenthion to its sulfoxide at a lower catalytic efficiency than FMO1 (27%) and with less stereoselectivity (74% (+)-sulfoxide) [23].

Enzymatic interactions of FMO3

  • The current study demonstrates that human FMO1 and FMO3 catalyze TAM N-oxidation to TNO and that cytochromes P450 (P450s), but not FMOs, reduce TNO to TAM [24].

Regulatory relationships of FMO3

  • Only FMO3 formed 6-OH-MXAA at a similar rate to that in cDNA-expressed cytochromes P-450 (CYP)1A2 [25].
  • The conclusion that FMO was predominantly responsible for trans oxime formation in human liver microsomes was based on the effect of incubation conditions on tyramine N-oxygenation and the observation that cDNA-expressed human FMO3 also N-oxygenated tyramine to give exclusively the trans oxime [26].

Other interactions of FMO3

  • For FMO1, FMO2, and FMO3, two to three different splice variants were identified, and their corresponding expression was always low in the tissues examined [27].
  • 3. Recombinant human FMO1 and FMO5 produced M3 in greater quantities than recombinant human FMO3 [28].
  • 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 [25].
  • CONCLUSIONS: Alterations in the activity of CYP3A4, CYP2C9 and FMO3 through genetic polymorphisms, enzyme induction or inhibition bear the potential to cause clinically significant changes in perazine clearance [29].
  • Kinetic studies showed the Km values obtained with both CYP3A4 and FMO3 were similar [30].

Analytical, diagnostic and therapeutic context of FMO3


  1. Regio- and stereoselective oxygenations by adult human liver flavin-containing monooxygenase 3. Comparison with forms 1 and 2. Lomri, N., Yang, Z., Cashman, J.R. Chem. Res. Toxicol. (1993) [Pubmed]
  2. Oxidative activation of thiacetazone by the Mycobacterium tuberculosis flavin monooxygenase EtaA and human FMO1 and FMO3. Qian, L., Ortiz de Montellano, P.R. Chem. Res. Toxicol. (2006) [Pubmed]
  3. Smoking and cancer-related gene expression in bronchial epithelium and non-small-cell lung cancers. Woenckhaus, M., Klein-Hitpass, L., Grepmeier, U., Merk, J., Pfeifer, M., Wild, P., Bettstetter, M., Wuensch, P., Blaszyk, H., Hartmann, A., Hofstaedter, F., Dietmaier, W. J. Pathol. (2006) [Pubmed]
  4. Genetic polymorphisms of flavin monooxygenase 3 in sulindac-induced regression of colorectal adenomas in familial adenomatous polyposis. Hisamuddin, I.M., Wehbi, M.A., Schmotzer, B., Easley, K.A., Hylind, L.M., Giardiello, F.M., Yang, V.W. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  5. Baculovirus-mediated expression and purification of human FMO3: catalytic, immunochemical, and structural characterization. Haining, R.L., Hunter, A.P., Sadeque, A.J., Philpot, R.M., Rettie, A.E. Drug Metab. Dispos. (1997) [Pubmed]
  6. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Dolphin, C.T., Janmohamed, A., Smith, R.L., Shephard, E.A., Phillips, I.R. Nat. Genet. (1997) [Pubmed]
  7. Molecular cloning of the flavin-containing monooxygenase (form II) cDNA from adult human liver. Lomri, N., Gu, Q., Cashman, J.R. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  8. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Treacy, E.P., Akerman, B.R., Chow, L.M., Youil, R., Bibeau, C., Lin, J., Bruce, A.G., Knight, M., Danks, D.M., Cashman, J.R., Forrest, S.M. Hum. Mol. Genet. (1998) [Pubmed]
  9. Discovery of novel flavin-containing monooxygenase 3 (FMO3) single nucleotide polymorphisms and functional analysis of upstream haplotype variants. Koukouritaki, S.B., Poch, M.T., Cabacungan, E.T., McCarver, D.G., Hines, R.N. Mol. Pharmacol. (2005) [Pubmed]
  10. Deleterious mutations in the flavin-containing monooxygenase 3 (FMO3) gene causing trimethylaminuria. Zhang, J., Tran, Q., Lattard, V., Cashman, J.R. Pharmacogenetics (2003) [Pubmed]
  11. Human flavin-containing monooxygenase form 3: cDNA expression of the enzymes containing amino acid substitutions observed in individuals with trimethylaminuria. Cashman, J.R., Bi, Y.A., Lin, J., Youil, R., Knight, M., Forrest, S., Treacy, E. Chem. Res. Toxicol. (1997) [Pubmed]
  12. Role of hepatic flavin-containing monooxygenase 3 in drug and chemical metabolism in adult humans. Cashman, J.R., Park, S.B., Berkman, C.E., Cashman, L.E. Chem. Biol. Interact. (1995) [Pubmed]
  13. Thiourea toxicity in mouse C3H/10T1/2 cells expressing human flavin-dependent monooxygenase 3. Smith, P.B., Crespi, C. Biochem. Pharmacol. (2002) [Pubmed]
  14. Alternative processing of the human FMO6 gene renders transcripts incapable of encoding a functional flavin-containing monooxygenase. Hines, R.N., Hopp, K.A., Franco, J., Saeian, K., Begun, F.P. Mol. Pharmacol. (2002) [Pubmed]
  15. Structural organization of the human flavin-containing monooxygenase 3 gene (FMO3), the favored candidate for fish-odor syndrome, determined directly from genomic DNA. Dolphin, C.T., Riley, J.H., Smith, R.L., Shephard, E.A., Phillips, I.R. Genomics (1997) [Pubmed]
  16. Localization of human flavin-containing monooxygenase genes FMO2 and FMO5 to chromosome 1q. McCombie, R.R., Dolphin, C.T., Povey, S., Phillips, I.R., Shephard, E.A. Genomics (1996) [Pubmed]
  17. Localization of genes encoding three distinct flavin-containing monooxygenases to human chromosome 1q. Shephard, E.A., Dolphin, C.T., Fox, M.F., Povey, S., Smith, R., Phillips, I.R. Genomics (1993) [Pubmed]
  18. Identification of metabolic pathways involved in the biotransformation of tolperisone by human microsomal enzymes. Dalmadi, B., Leibinger, J., Szeberényi, S., Borbás, T., Farkas, S., Szombathelyi, Z., Tihanyi, K. Drug Metab. Dispos. (2003) [Pubmed]
  19. The olivacine derivative s 16020 (9-hydroxy-5,6-dimethyl-N-[2-(dimethylamino)ethyl)-6H-pyrido(4,3-B)-carbazole-1-carboxamide) induces CYP1A and its own metabolism in human hepatocytes in primary culture. Pichard-Garcia, L., Weaver, R.J., Eckett, N., Scarfe, G., Fabre, J.M., Lucas, C., Maurel, P. Drug Metab. Dispos. (2004) [Pubmed]
  20. Experimental approaches to studies on drug metabolism and drug interactions in man: interaction of acyclic nucleoside phosphonates with human liver cytochromes P450 and flavin-containing monooxygenase 3. Matal, J., Orsag, J., Nekvindova, J., Anzenbacherova, E., Veinlichova, A., Anzenbacher, P., Zidek, Z., Holy, A. Neuro Endocrinol. Lett. (2006) [Pubmed]
  21. Stereoselective sulfoxidation of sulindac sulfide by flavin-containing monooxygenases. Comparison of human liver and kidney microsomes and mammalian enzymes. Hamman, M.A., Haehner-Daniels, B.D., Wrighton, S.A., Rettie, A.E., Hall, S.D. Biochem. Pharmacol. (2000) [Pubmed]
  22. In vitro evaluation of potential in vivo probes for human flavin-containing monooxygenase (FMO): metabolism of benzydamine and caffeine by FMO and P450 isoforms. Lang, D.H., Rettie, A.E. British journal of clinical pharmacology. (2000) [Pubmed]
  23. Evaluation of xenobiotic N- and S-oxidation by variant flavin-containing monooxygenase 1 (FMO1) enzymes. Furnes, B., Schlenk, D. Toxicol. Sci. (2004) [Pubmed]
  24. Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. Parte, P., Kupfer, D. Drug Metab. Dispos. (2005) [Pubmed]
  25. 6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3. Zhou, S., Kestell, P., Paxton, J.W. European journal of drug metabolism and pharmacokinetics. (2002) [Pubmed]
  26. Detoxication of tyramine by the flavin-containing monooxygenase: stereoselective formation of the trans oxime. Lin, J., Cashman, J.R. Chem. Res. Toxicol. (1997) [Pubmed]
  27. Alternative processing events in human FMO genes. Lattard, V., Zhang, J., Cashman, J.R. Mol. Pharmacol. (2004) [Pubmed]
  28. S-oxidation of S-methyl-esonarimod by flavin-containing monooxygenases in human liver microsomes. Ohmi, N., Yoshida, H., Endo, H., Hasegawa, M., Akimoto, M., Higuchi, S. Xenobiotica (2003) [Pubmed]
  29. Cytochrome P-450 enzymes and FMO3 contribute to the disposition of the antipsychotic drug perazine in vitro. Störmer, E., Brockmöller, J., Roots, I., Schmider, J. Psychopharmacology (Berl.) (2000) [Pubmed]
  30. Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes. Rawden, H.C., Kokwaro, G.O., Ward, S.A., Edwards, G. British journal of clinical pharmacology. (2000) [Pubmed]
  31. Investigation of structure and function of a catalytically efficient variant of the human flavin-containing monooxygenase form 3. Borb??s, T., Zhang, J., Cerny, M.A., Lik??, I., Cashman, J.R. Drug Metab. Dispos. (2006) [Pubmed]
  32. Species and sex differences in expression of flavin-containing monooxygenase form 3 in liver and kidney microsomes. Ripp, S.L., Itagaki, K., Philpot, R.M., Elfarra, A.A. Drug Metab. Dispos. (1999) [Pubmed]
  33. A novel mutation in the flavin-containing monooxygenase 3 gene, FM03, that causes fish-odour syndrome: activity of the mutant enzyme assessed by proton NMR spectroscopy. Murphy, H.C., Dolphin, C.T., Janmohamed, A., Holmes, H.C., Michelakakis, H., Shephard, E.A., Chalmers, R.A., Phillips, I.R., Iles, R.A. Pharmacogenetics (2000) [Pubmed]
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