Catalytic cycle of mammalian FMOs (WP3281)

Bos taurus

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Flavin-containing monooxygenases are a group of enzymes that catalyze the oxygenation of substrates, mostly soft nucleophiles via the cofactor flavin. In the catalytic cycle, FMO binds to NADPH and to FAD, causing the reduction of FAD to FADH2. Next, molecular oxygen binds to the complex and is reduced to a hydroperoxide form, called 4a-hydroperoxyflavin. This complex is stable in the absence of a substrate. When a substrate is present, the distal O-atom of the complex is transferred to the substrate yielding an oxygenated product and leaving the flavincomplex 4a-hydroxyflavin that breaks down releasing water. At the end of the cycle, NADP+ is released resulting in FAD as the flavin form to start a next cycle. In contrast to cytochrome P450 enzymes, FMOs are generally not induced or inhibited by xenobiotic substances. The five human FMOs are tissue specific: FMO1 is present in the human fetal liver and the adult kidney, FMO2 is present in the lung and FMO3 is present in the adult liver.

Authors

Martina Summer-Kutmon and Egon Willighagen

Activity

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Organisms

Bos taurus

Communities

Annotations

Pathway Ontology

cellular detoxification pathway

Participants

Label Type Compact URI Comment
H2O Metabolite hmdb:HMDB0002111
NADP+ Metabolite hmdb:HMDB0000217
NADP+ Metabolite hmdb:HMDB0000217
O2 Metabolite hmdb:HMDB0001377
NADP+ Metabolite hmdb:HMDB0000217
NADP+ Metabolite hmdb:HMDB0000217
NADP+ Metabolite hmdb:HMDB0000217
NADPH Metabolite hmdb:HMDB0000221
FAD Metabolite hmdb:HMDB0001248
FAD Metabolite hmdb:HMDB0001248
FADH2 Metabolite chebi:17877
H+ Metabolite chebi:15378
FMO2 GeneProduct ensembl:ENSBTAG00000002974 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000094963
FMO3 GeneProduct ensembl:ENSBTAG00000020597 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000007933
FMO1 GeneProduct ensembl:ENSBTAG00000021408 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000010932
FMO5 GeneProduct ensembl:ENSBTAG00000010841 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000131781
FMO4 GeneProduct ensembl:ENSBTAG00000016685 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000076258

References

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  2. Multisubstrate flavin-containing monooxygenases: applications of mechanism to specificity. Poulsen LL, Ziegler DM. Chem Biol Interact. 1995 Apr 28;96(1):57–73. PubMed Europe PMC Scholia
  3. The mammalian flavin-containing monooxygenases: molecular characterization and regulation of expression. Hines RN, Cashman JR, Philpot RM, Williams DE, Ziegler DM. Toxicol Appl Pharmacol. 1994 Mar;125(1):1–6. PubMed Europe PMC Scholia
  4. Potential roles of flavin-containing monooxygenases in sulfoxidation reactions of l-methionine, N-acetyl-l-methionine and peptides containing l-methionine. Elfarra AA, Krause RJ. Biochim Biophys Acta. 2005 Jan 17;1703(2):183–9. PubMed Europe PMC Scholia
  5. Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Krueger SK, Williams DE. Pharmacol Ther. 2005 Jun;106(3):357–87. PubMed Europe PMC Scholia
  6. Some distinctions between flavin-containing and cytochrome P450 monooxygenases. Cashman JR. Biochem Biophys Res Commun. 2005 Dec 9;338(1):599–604. PubMed Europe PMC Scholia
  7. Human flavin-containing monooxygenases. Cashman JR, Zhang J. Annu Rev Pharmacol Toxicol. 2006;46:65–100. PubMed Europe PMC Scholia
  8. Flavin-containing monooxygenases: mutations, disease and drug response. Phillips IR, Shephard EA. Trends Pharmacol Sci. 2008 Jun;29(6):294–301. PubMed Europe PMC Scholia