Mammalian flavin-containing monooxygenases : structure/function, genetic polymorphisms and role in drug metabolism

Trimethylaminuria is a disorder in which the volatile, fish-smelling compound, trimethylamine (TMA) accumulates and is excreted in the urine, but is also found in the sweat and breath of these patients. Because many patients have associated body odours or halitosis, trimethylaminuria sufferers can meet serious difficulties in a social context, leading to other problems such as isolation and depression. TMA is formed by bacteria in the mammalian gut from reduction of compounds such as trimethylamine-N-oxide (TMAO) and choline. Primary trimethylaminuria sufferers have an inherited enzyme deficiency where TMA is not efficiently converted to the non-odorous TMAO in the liver. Secondary causes of trimethylaminuria have been described, sometimes accompanied by genetic variations. Diagnosis of trimethylaminuria requires the measurement of TMA and TMAO in urine, which should be collected after a high substrate meal in milder or intermittent cases, most simply, a marine-fish meal. The symptoms of trimethylaminuria can be improved by changes in the diet to avoid precursors, in particular TMAO which is found in high concentrations in marine fish. Treatment with antibiotics to control bacteria in the gut, or activated charcoal to sequester TMA, may also be beneficial.

Trimethylaminuria: causes and diagnosis of a socially distressing condition.

Ethnic Differences in Human Flavin-Containing Monooxygenase 2 (FMO2) Polymorphisms: Detection of Expressed Protein in African-Americans

The flavin-containing monooxygenases (FMOs) are important for xenobiotic metabolism. FMO3, the predominant FMO enzyme in human adult liver, exhibits significant interindividual variation that is poorly understood. This study was designed to identify common FMO3 genetic variants and determine their potential for contributing to interindividual differences in FMO3 expression. FMO3 single nucleotide polymorphism (SNP) discovery was accomplished by resequencing DNA samples from the Coriell Polymorphism Discovery Resource. Population-specific SNP frequencies were determined by multiplexed, single-base extension using DNA from 201 Hispanic American (Mexican descent), 201 African American, and 200 White (northern European descent) subjects. Haplotypes were inferred and population frequencies estimated using PHASE version 2.1. Multiple site-directed mutagenesis was used to introduce inferred upstream haplotypes into an FMO3/luciferase construct for functional analysis in HepG2 cells. Sequence analysis revealed seven FMO3 upstream SNPs, 11 exon SNPs, and 22 intron SNPs. Five of the latter fell within consensus splice sites. A g.72G>T variant (E24D) is predicted to impact the structure of the Rossmann fold involved in FAD binding, whereas a g.11177C>A variant (N61K) is predicted to disrupt the secondary structure of a conserved membrane interaction domain. Seven common (>1%) promoter region haplotypes were inferred in one or more of the study populations that differed in estimated frequency among the groups. Haplotype 2 resulted in an 8-fold increase in promoter activity, whereas haplotypes 8 and 15 exhibited a near complete loss of activity. In conclusion, FMO3 promoter haplotype variants modulate gene function and probably contribute to interindividual differences in FMO3 expression.

Discovery of Novel Flavin-Containing Monooxygenase 3 (FMO3) Single Nucleotide Polymorphisms and Functional Analysis of Upstream Haplotype Variants

The flavin-containing monooxygenases (FMOs) metabolize a broad range of therapeutics. Consisting of five gene products in humans (FMO1-5), the different FMO family members exhibit pronounced tissue- and temporal-specific expression patterns. Substantial interindividual differences are also observed, and the inability to modulate with exogenous agents is consistent with an important role for genetic variation. Several rare FMO3 alleles causative for trimethylaminuria have been well characterized. However, the identification and characterization of functional FMO1-5 polymorphisms has been more recent. Although none of these polymorphisms has been associated with an adverse drug reaction, the continued broadening of our therapeutic armamentarium makes such an event likely in the future. Furthermore, at least one example has been reported for a direct association between FMO3 polymorphism and therapeutic efficacy. Thus, it is anticipated that knowledge regarding functionally-relevant FMO genetic variability will become increasingly important for making drug development and patient therapeutic choices.

Flavin-containing monooxygenase genetic polymorphism: impact on chemical metabolism and drug development.

Trimethylaminuria is inherited recessively as a defect in hepatic N-oxidation of dietary derived trimethylamine (TMA) which causes excess excretion of TMA so that affected individuals have a body odour resembling rotten fish. Flavin-containing mono-oxygenase 3 (FMO3) catalyses TMA oxidation and mutations in the FMO3 gene have recently been shown to underlie trimethylaminuria/fish odour syndrome. We searched for FMO3 mutations in a previously unreported individual with this disorder using polymerase chain reaction of genomic DNA, heteroduplex analysis and direct sequencing of heteroduplex band shifts. We identified a heterozygous missense Pro153-->Leu153 mutation in exon 4. Leu153 has been reported previously as a homozygous mutation in two unrelated siblings with trimethylaminuria and has been shown to result in total loss of FMO3 enzyme activity. In our patient, two further missense mutations were identified on the other FMO3 allele, Val143-->Glu143 and Glu158-->Lys158. Lys158 is known to be a common polymorphism, but has functional significance in reducing enzyme activity by 10%. Glu143 has not been documented previously, but was shown to be a rare polymorphism and may be of further relevance in reducing FMO3 activity. Mutagenesis studies and enzyme assays will be necessary to confirm or refute the potential pathogenic significance of Glu143 in this patient, but the mutation Pro153-->Leu153 appears to be a recurrent cause of this distressing metabolic disorder.

Sequence variations in the flavin-containing mono-oxygenase 3 gene (FMO3) in fish odour syndrome

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Sequence variations in the flavin-containing mono-oxygenase 3 gene (FMO3) in fish odour syndrome