Disease relevance of FMO4

• Attempts to achieve expression of FMO4 have been made with Escherichia coli, baculovirus, yeast, and COS systems [1].
• Polymorphic expression of functional FMO2 in the individuals of African and Hispanic descent may markedly influence drug metabolism and/or xenobiotic toxicity in the lung [2].
• However, recent development of mapping of flavin-containing monooxygenase 2 (FMO2), the likely enzyme that is defective in fish odor syndrome, to chromosome 1q probably excludes pathogenetic association of fish odor syndrome with the Prader-Willi syndrome [3].

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

• 2. Hepatic microsomes of sexually mature fish contained NADPH-dependent FMO as evidenced by the conversion of N,N-dimethylaniline (DMA) to DMA-N-oxide, and immunorecognition of single bands (approximate apparent molecular weight of 55 kDa) by antibodies to mammalian FMO 1 and FMO 2 [10].

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].

References