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Gene Review

FMO4  -  flavin containing monooxygenase 4

Homo sapiens

Synonyms: Dimethylaniline oxidase 4, FMO 4, FMO2, Hepatic flavin-containing monooxygenase 4
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Disease relevance of FMO4


High impact information on FMO4

  • The derived amino acid sequences of FMO1, -2, -3, and -5 from all species examined contain about the same number of residues (531-535 residues), whereas the derived sequences of human and rabbit FMO4 contain 558 and 555 residues, respectively [1].
  • For FMO5 and particularly for FMO4, more complex alternative splice patterns were observed, with five and seven splice variants detected, respectively [4].
  • As part of the human genome effort, an FMO-like gene, FMO6, was identified between FMO3 and FMO2 (GenBank accession no. AL021026) [5].
  • Cloning, primary sequence and chromosomal localization of human FMO2, a new member of the flavin-containing mono-oxygenase family [6].
  • The localization of FMO1, FMO2, and FMO3 has been refined to the long arm of chromosome 1 [7].

Biological context of FMO4

  • FMO2 mRNA expression was observed in most individuals, but failed to correlate with genotype or protein expression [8].
  • Two human FMO2 point mutations have been reported: a cytosine to thymidine transition at position 1414 resulting in a premature stop codon and a thymidine insertion at position 1589 resulting in a frameshift [8].
  • CONCLUSIONS: SNPs would not alter FMO2 activity in individuals possessing at least one FMO2*1 allele [9].
  • Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics [9].

Anatomical context of FMO4


Associations of FMO4 with chemical compounds

  • Activity studies were done with two selective functional FMO substrates, methimazole, and 10-(N,N-dimethylaminopentyl)-2-(trifluoromethyl)phenothiazine and exon 3- (exon 4 for FMO4) deleted FMOs were not able to catalyze the S- and N-oxygenation of these substrates, respectively [4].
  • Recombinant FMO4 catalyzed S-oxidation of both methionine and S-allyl-l-cysteine, with similar diastereoselectivity to the high-affinity microsomal S-oxidase; however, the Km values for both reactions appeared to be greater than 10 mM [11].
  • Gill microsomal activity in each species was unaffected by the mammalian FMO 2 substrate (competitive inhibitor) n-octylamine [12].
  • FMO2 and FMO5, although expressed slightly in human liver, kidney and lung, were not efficient producers of ranitidine N- and S-oxides [13].

Analytical, diagnostic and therapeutic context of FMO4

  • By Northern blotting and/or RT-PCR, the long-form FMO4 mRNA was detected in the rat kidney, intestine, and liver and the short form particularly in the brain [14].
  • By Western blotting using the two different forms of FMO4 antibodies, a long FMO4 protein was detected in the rat kidney, whereas in the rat brain, only the short form of FMO4 was observed [14].
  • Southern blot hybridization with single-exon probes demonstrated that human FMO2 and FMO1 are the products of single genes [6].
  • Sequence analysis, however, was consistent with the 1414C allele encoding an active FMO2 enzyme [8].


  1. Expression and characterization of a modified flavin-containing monooxygenase 4 from humans. Itagaki, K., Carver, G.T., Philpot, R.M. J. Biol. Chem. (1996) [Pubmed]
  2. Genetic polymorphisms of flavin-containing monooxygenase (FMO). Krueger, S.K., Williams, D.E., Yueh, M.F., Martin, S.R., Hines, R.N., Raucy, J.L., Dolphin, C.T., Shephard, E.A., Phillips, I.R. Drug Metab. Rev. (2002) [Pubmed]
  3. Trimethylaminuria in a girl with Prader-Willi syndrome and del(15)(q11q13). Chen, H., Aiello, F. Am. J. Med. Genet. (1993) [Pubmed]
  4. Alternative processing events in human FMO genes. Lattard, V., Zhang, J., Cashman, J.R. Mol. Pharmacol. (2004) [Pubmed]
  5. 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]
  6. Cloning, primary sequence and chromosomal localization of human FMO2, a new member of the flavin-containing mono-oxygenase family. Dolphin, C.T., Shephard, E.A., Povey, S., Smith, R.L., Phillips, I.R. Biochem. J. (1992) [Pubmed]
  7. 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]
  8. Ethnic differences in human flavin-containing monooxygenase 2 (FMO2) polymorphisms: detection of expressed protein in African-Americans. Whetstine, J.R., Yueh, M.F., McCarver, D.G., Williams, D.E., Park, C.S., Kang, J.H., Cha, Y.N., Dolphin, C.T., Shephard, E.A., Phillips, I.R., Hines, R.N. Toxicol. Appl. Pharmacol. (2000) [Pubmed]
  9. Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics. Krueger, S.K., Siddens, L.K., Henderson, M.C., Andreasen, E.A., Tanguay, R.L., Pereira, C.B., Cabacungan, E.T., Hines, R.N., Ardlie, K.G., Williams, D.E. Pharmacogenet. Genomics (2005) [Pubmed]
  10. Characterization of hepatic flavin monooxygenase from the marine teleost turbot (Scophthalmus maximus L.). Peters, L.D., Livingstone, D.R., Shenin-Johnson, S., Hines, R.N., Schlenk, D. Xenobiotica (1995) [Pubmed]
  11. Methionine S-oxidation in human and rabbit liver microsomes: evidence for a high-affinity methionine S-oxidase activity that is distinct from flavin-containing monooxygenase 3. Ripp, S.L., Itagaki, K., Philpot, R.M., Elfarra, A.A. Arch. Biochem. Biophys. (1999) [Pubmed]
  12. Differential expression and activity of flavin-containing monooxygenases in euryhaline and stenohaline flatfishes indicates potential osmoregulatory role. Schlenk, D., Peters, L., Shehin-Johnson, S., Hines, R.N., Livingstone, D.R. Comp. Biochem. Physiol. C, Pharmacol. Toxicol. Endocrinol. (1995) [Pubmed]
  13. Oxidation of ranitidine by isozymes of flavin-containing monooxygenase and cytochrome P450. Chung, W.G., Park, C.S., Roh, H.K., Lee, W.K., Cha, Y.N. Jpn. J. Pharmacol. (2000) [Pubmed]
  14. Cloning, sequencing and tissue distribution of rat flavin-containing monooxygenase 4: two different forms are produced by tissue-specific alternative splicing. Lattard, V., Longin-Sauvageon, C., Benoit, E. Mol. Pharmacol. (2003) [Pubmed]
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