Investigation of Structure and Function of a Catalytically Efficient Variant of the Human Flavin-Containing Monooxygenase Form 3

Borbás, Tímea; Zhang, Jun; Cerny, Matt A.; Láng, István; Cashman, John R.

doi:10.1124/dmd.106.010827

Cited by 13 publications

(7 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alterations in in vitro FMO3 function associated with these variants appear to be substrate specific [7, 8]. There is also evidence for rare FMO3 variants associated with increased catalytic activity in both African and European populations [4, 9–12]. …”

Section: Introductionmentioning

confidence: 99%

Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption

Bloom

Murphy

Martínez

et al. 2013

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

Background Flavin-containing monooxygenases (FMO) catalyze the metabolism of nucleophilic heteroatom containing drugs and xenobiotics including nicotine. Rare mutations in FMO3 are responsible for defective N-oxygenation of dietary trimethylamine leading to trimethylaminuria, and common genetic variation in FMO3 has been linked to interindividual variability in metabolic function that may be substrate specific. Methods A genetic model of CYP2A6 function is used as a covariate to reveal functional polymorphism in FMO3 that indirectly influences the ratio of deuterated nicotine metabolized to cotinine following oral administration. The association is tested between FMO3 haplotype and cigarette consumption in a set of nicotine dependent smokers. Results FMO3 haplotype, based on all common coding variants in Europeans, significantly predicts nicotine metabolism and accounts for approximately 2% of variance in the apparent percent of nicotine metabolized to cotinine. The metabolic ratio is not associated with FMO2 haplotype or an FMO1 expression quantitative trait locus (eQTL). Cross validation demonstrates calculated FMO3 haplotype parameters to be robust and significantly improve the predictive nicotine metabolism model over CYP2A6 genotype alone. Functional classes of FMO3 haplotypes, as determined by their influence on nicotine metabolism to cotinine, are also significantly associated with cigarettes per day (CPD) in nicotine dependent European Americans (n=1,025, p=0.04), and significantly interact (p=0.016) with CYP2A6 genotype to predict CPD. Conclusion These findings suggest that common polymorphisms in FMO3 influence nicotine clearance, and that these genetic variants in turn influence cigarette consumption.

show abstract

Section: Introductionmentioning

confidence: 99%

Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption

Bloom

Murphy

Martínez

et al. 2013

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

show abstract

“…The D132H polymorphism has also been shown to decrease methimazole and phenothiazine metabolism [30]. By contrast, the L360 P polymorphism has been shown to increase the catalytic efficiency of FMO3 [30,31]. In addition, Sachse and colleagues, using a population-based analysis model, did not establish a clear link between certain FMO3 polymorphisms and the metabolism of clozapine or caffeine, suggesting that the mutations examined have only minor functional effects, or that substrate affinity may be too low to be clinically relevant [17].…”

Section: Effects Of Fmo3 Polymorphisms On Substrate Metabolism In Vitromentioning

confidence: 99%

“…This is of particular interest to clinicians, pharmacologists, policy makers and patients because of the potential for practical application. Recent studies of the genotype-phenotype relationship between FMO3 mutations and their effects on enzyme activity range from in vitro models [31,34] to translational studies examining the direct impact of these mutations in humans [40,47,48]. Trimethylaminuria is a good example; this disorder has been a cornerstone for the developing field of FMO3 polymorphisms.…”

Section: Expert Commentarymentioning

confidence: 99%

Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

Hisamuddin

Yang

2007

Pharmacogenomics

View full text Add to dashboard Cite

Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases. Keywords chemoprevention; familial adenomatous polyposis; flavin-containing monooxygenase 3; gastrointestinal diseases; SNP; sulindac sulfide; trimethylaminuria Humans metabolize a vast array of endogenous and exogenous compounds, including drugs and xenobiotics. It has been observed that different individuals, genders and ethnicities respond differently to the same compounds. This has been attributed to multiple factors, one of which is SNPs. With the completion of the human genome sequence and the discovery of existing SNPs in the genome, interest has focused on the role of genetic polymorphisms of enzymeencoding genes involved in the metabolism of both endogenous and exogenous substances.The flavin-containing monooxygenases (FMOs) belong to a family of flavoprotein enzymes that catalyze the oxidation of a broad array of nucleophilic heteroatom-containing drugs, pesticides and chemicals [1][2][3][4]. There are six human isoforms of flavin-containing monooxygenases, of which five are functional. An additional gene cluster containing five pseudogenes has also been identified in both the human and mouse genome [5][6][7][8][9][10].

show abstract

“…From the primary sequence, the mutation is immediately upstream of the essential FMO3 NADPH binding domain (GXGXXG) (Figure 4). According to the human FMO3 homology structure model we developed based on four related proteins [29], the residue V187 resides at the beginning part of a β-sheet leading to the NADPH binding domain. The residue is also conserved in FMO from Schizosaccaromyces pombe and Methylophaga sp.…”

Section: Discussionmentioning

confidence: 99%

Novel variants of the human flavin-containing monooxygenase 3 (FMO3) gene associated with trimethylaminuria

Motika

Zhang

Zheng

et al. 2009

Molecular Genetics and Metabolism

Self Cite

View full text Add to dashboard Cite

The disorder trimethylaminuria (TMAu) often manifests itself in a body odor for individuals affected. TMAu is due to decreased metabolism of dietary-derived trimethylamine (TMA). In a healthy individual, 95% or more of TMA is converted by the flavin-containing monooxygenase 3 (FMO3, EC 1.14.13.8) to non-odorous trimethylamine N-oxide (TMA N-oxide). Several single nucleotide polymorphisms (SNPs) of the FMO3 gene have been described and result in an enzyme with decreased or abolished functional activity for TMA N-oxygenation thus leading to TMAu. Herein, we report two novel mutations observed from phenotyping and genotyping two self-reporting individuals. Sequence analysis of the exon regions of the FMO3 gene of a young woman with severe TMAu revealed heterozygous mutations at positions 187 (V187A), 158 (E158K), 308 (E308G), and 305 (E305X). Familial genetic analysis showed that the E158K/V187A/E308G derived from the same allele from the mother, and the E305X was derived from the father. FMO3 variants V187A and V187A/E158K were characterized for oxygenation of several common FMO3 substrates (i.e., 5- and 8-DPT, mercaptoimidazole (MMI), TMA, and sulindac sulfide) and for its thermal stability. Our findings show that with the combination of V187A/E158K mutations in FMO3, the enzyme activity is severely affected and possibly contributes to the TMAu observed. In another study, genotyping analysis of a 17 year old female revealed a mutation that caused a frame shift after K415 and resulted in a protein variant with only 486 amino acid residues that was associated with severe TMAu.

show abstract

Investigation of Structure and Function of a Catalytically Efficient Variant of the Human Flavin-Containing Monooxygenase Form 3

Abstract: ABSTRACT:To characterize the contribution of amino acid 360 to the functional activity of the human flavin-containing monooxygenase form 3 (FMO3) and form 1 (FMO1) in the oxygenation of drugs and chemicals, we expressed four FMO3 variants (i.

Cited by 13 publications

References 44 publications

Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption

Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption

Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

Novel variants of the human flavin-containing monooxygenase 3 (FMO3) gene associated with trimethylaminuria

Contact Info

Product

Resources

About