Characterization of Flavin-Containing Monooxygenase-5 (FMO5) Cloned from Human and Guinea-Pig: Evidence That the Unique Catalytic Properties of FMO5 Are Not Confined to the Rabbit Ortholog

Overby, Lila H.; Buckpitt, Alan R.; Lawton, Michael; Atta-Asafo-Adjei, Emmanuel; Schulze, Johannes; Philpot, Richard M.

doi:10.1006/abbi.1995.1163

Cited by 74 publications

(48 citation statements)

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“…An example is the high selectivity observed with human FMO3, compared to the other FMO enzymes, in the N-oxygenation of the important constitutive substrate trimethylamine (Lang et al, 1998). We also do not know what structure/function factors result in the observed restricted substrate specificity for FMO5 (Rettie et al, 1994;Overby et al, 1995;Cherrington et al, 1998). FMO5 exhibits little activity toward methimazole or other typical FMO substrates, but does carry out the N-oxygenation of short-chain aliphatic primary amines such as N-octylamine.…”

Section: Substrate Specificity Of Enzyme-restricted Substrate Access mentioning

confidence: 96%

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

Krueger

Williams

2005

Pharmacology & Therapeutics

515

444

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Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "softnucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics.In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences.The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.

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Section: Substrate Specificity Of Enzyme-restricted Substrate Access mentioning

confidence: 96%

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

Krueger

Williams

2005

Pharmacology & Therapeutics

515

444

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“…Methimazole is only metabolized to a moderate extent (1/5000 the activity of FMO3) (Overby et al, 1995), and its involvement in drug-metabolism is probably not significant. The low affinity of FMO5 for xenobiotics is also species-independent.…”

Section: Furnes Et Almentioning

confidence: 99%

Identification of Novel Variants of the Flavin-Containing Monooxygenase Gene Family in African Americans

Furnes¹,

Feng²,

Sommer³

et al. 2003

Drug Metabolism and Disposition

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ABSTRACT:Sequence polymorphisms in enzymes involved in drug metabolism have been widely implicated in the differences observed in the sensitivity to various xenobiotics. The flavin-containing monooxygenase (FMO) gene family in humans catalyzes the monooxygenation of numerous N-, P-and S-containing drugs, pesticides, and environmental toxicants. Six genes (FMO1-6) have been identified so far, but the major alleles of FMO2 and FMO6 encode nonfunctional proteins due to a nonsense mutation and splice-site abnormalities, respectively. Data on structural variants exist for human FMO2 and 3, whereas very little is known about the other FMO genes. FMO1-6 were scanned in 50 individuals of African-American descent using the method, detection of virtually all mutationssingle-strand conformational polymorphism. A total of 49 sequence variants were identified in a total 1.35 megabases of scanned sequence, of which 29 were variants affecting protein structure or expression. Some of these are expected to affect the activity of the protein, including a nonsense mutation in FMO1 (R502X) and missense mutations in FMO1 (I303T), FMO4 (E339Q), and FMO5 (P457L) that occur in highly conserved amino acids. Additional deleterious substitutions in FMO2 (del337G) and FMO6 (Q105X) were also identified. Multiple structural variants in the FMO gene family were observed in this African-American sample. Some of the substitutions identified in this study might be useful markers in future association studies assessing sensitivity to environmental toxicants and common disease.

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“…In human liver, FMO3 is quite abundant, approaching levels as much as 0.5% of total microsomal protein (Overby et al, 1997). Because FMO5 is an atypical FMO that does not show any of the typical activity against FMO substrates (Overby et al, 1995) and FMO4 activity is barely detectable (Dolphin et al, 1996b), FMO3 is the gene associated with the majority of FMO-mediated hepatic metabolism (Cashman, 2002a,b).…”

Section: Hepatic Human Fmomentioning

confidence: 99%

Interindividual Differences of Human Flavin-Containing Monooxygenase 3: Genetic Polymorphisms and Functional Variation

Cashman¹,

Zhang²

2002

Drug Metabolism and Disposition

102

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ABSTRACT:The human flavin-containing monooxygenase (form 3) (FMO3) participates in the oxygenation of nucleophilic heteroatom-containing drugs, xenobiotics, and endogenous materials. Currently, six forms of the FMO gene are known, but it is FMO3 that is the major form in adult human liver that is likely responsible for the majority of FMO-mediated metabolism. The substrate structural feature requirements for human FMO3 is beginning to become known to a greater extent and a few chemicals extensively metabolized by FMO3 have been reported. Expression of FMO3 is species-and tissue-specific, but unlike human cytochrome P450, mammalian FMO3 does not appear to be inducible. Interindividual variation in FMO3-dependent metabolism of drugs, chemicals, and endogenous material is therefore more likely due to genetic effects and not environmental ones. Examples of such interindividual variation come from the study of very rare mutations of the human The flavin-containing monooxygenases (FMOs 1 ) (E.C.1.14.13.8) constitute a family of FAD-, NADPH-, and O 2 -dependent microsomal enzymes that catalyze the oxygenation of many nitrogen-, sulfur-, phosphorous-, selenium-, and other nucleophilic heteroatom-containing chemicals (Ziegler, 1980), drugs (Cashman, 1995), and agrichemicals (Hajjar and Hodgson, 1982). There are as many as six forms of mammalian FMO, and some can be present in multiple tissues of the same organism. Some of this information has been previously summarized (Cashman, 2002a). In humans, there is considerable interindividual and interethnic variability in the levels of FMO. In the past few years, a considerable increase in our understanding of the genetic variability of human FMO has occurred and a summary of the current picture focusing on FMO3 will be presented.Evidence for five functional forms of human FMO exist, each encoded by its own gene, that exhibit between 50 to 58% amino acid identity across species lines (Lawton et al., 1994). With the deposit of FMO6 into GenBank, an analysis of the protein encoded by this gene revealed that this protein shares 70% amino acid sequence identity with human FMO3, however, no function for this gene has been described. The description of multiple forms of FMO was advanced by elucidation of the primary sequences by amino acid (Ozols, 1990;Korsmeyer et al., 1998) and nucleotide analysis Lawton et al., 1994;Phillips et al., 1995). As human FMOs were discovered, the common names assigned to enzymes were formalized and a nomenclature was adopted Lawton et al., 1994). The nomenclature was developed on the basis of nucleotide sequence identity. If a human FMO gene has a sequence with Ն82% identity, it is grouped within a family, and the family is indicated by the first numeral of the designation (i.e., 1, 2, 3. . .). The order of naming followed the chronology of publication of the sequence for each member of the family (Dolphin et al., 1997b). The italicized prefix "FMO" is used to designate the gene or an allelic variant. Allelic variants have been observed for FMO that usu...

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Characterization of Flavin-Containing Monooxygenase-5 (FMO5) Cloned from Human and Guinea-Pig: Evidence That the Unique Catalytic Properties of FMO5 Are Not Confined to the Rabbit Ortholog

Cited by 74 publications

References 0 publications

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

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

Identification of Novel Variants of the Flavin-Containing Monooxygenase Gene Family in African Americans

Interindividual Differences of Human Flavin-Containing Monooxygenase 3: Genetic Polymorphisms and Functional Variation

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