Catalytic cycle of mammalian Flavin-containing MonoOxygenases (FMOs) (Homo sapiens)

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1-8SubstrateSubstrate-OEndoplasmic reticulumNADPHFMO1FMO4FMO2FAD-OOHFADFMO3H2OFADFADH2FMO5NADP+NADP+NADP+O2NADP+FAD-OHNADP+H+


Description

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.

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Bibliography

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  1. Elfarra AA, Krause RJ; ''Potential roles of flavin-containing monooxygenases in sulfoxidation reactions of l-methionine, N-acetyl-l-methionine and peptides containing l-methionine.''; Biochim Biophys Acta, 2005 PubMed Europe PMC
  2. Krueger SK, Williams DE; ''Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism.''; Pharmacol Ther, 2005 PubMed Europe PMC
  3. Ziegler DM; ''Flavin-containing monooxygenases: enzymes adapted for multisubstrate specificity.''; Trends Pharmacol Sci, 1990 PubMed Europe PMC
  4. Hines RN, Cashman JR, Philpot RM, Williams DE, Ziegler DM; ''The mammalian flavin-containing monooxygenases: molecular characterization and regulation of expression.''; Toxicol Appl Pharmacol, 1994 PubMed Europe PMC
  5. Poulsen LL, Ziegler DM; ''Multisubstrate flavin-containing monooxygenases: applications of mechanism to specificity.''; Chem Biol Interact, 1995 PubMed Europe PMC
  6. Phillips IR, Shephard EA; ''Flavin-containing monooxygenases: mutations, disease and drug response.''; Trends Pharmacol Sci, 2008 PubMed Europe PMC
  7. Cashman JR; ''Some distinctions between flavin-containing and cytochrome P450 monooxygenases.''; Biochem Biophys Res Commun, 2005 PubMed Europe PMC
  8. Cashman JR, Zhang J; ''Human flavin-containing monooxygenases.''; Annu Rev Pharmacol Toxicol, 2006 PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
107912view09:33, 10 November 2019EgonwReplaced a sub-optimal PubChem CID with a ChEBI identifier.
106823view13:30, 17 September 2019MaintBotHMDB identifier normalization
94198view14:44, 25 August 2017DeSlAdded ID for FAD-OH
94195view14:38, 25 August 2017DeSlChanged metabolite nodes into textlabels, since they were not metabolites.
84769view16:25, 17 March 2016EveloModified title
79222view13:47, 15 March 2015EgonwReplaced the HMDB H2 identifier with H+ from ChEBI.
63157view20:18, 8 May 2013MaintBotUpdating gpml version
59115view22:27, 21 February 2013MaintBotUpdated Ensembl and UniProt data source
48246view06:16, 17 May 2012MaintBotUpdating PubChem xrefs
44984view14:33, 6 October 2011MartijnVanIerselOntology Term : 'cellular detoxification pathway' added !
41065view23:18, 1 March 2011MaintBotRemoved redundant pathway information and comments
34638view19:41, 7 January 2010KhanspersModified categories
33407view14:49, 30 November 2009MaintBotRemoved group label
30258view04:47, 25 July 2009AlexanderPicoModified categories
29954view06:26, 15 June 2009Pieter GiesbertzSpecify description
29591view11:49, 19 May 2009Pieter GiesbertzAdded datanodes
29590view10:26, 19 May 2009Pieter GiesbertzModified description
29507view07:54, 11 May 2009Pieter GiesbertzAdded literature reference
29506view07:26, 11 May 2009Pieter GiesbertzAdded literature references
29290view08:53, 22 April 2009Pieter GiesbertzSpecify description
29280view07:38, 22 April 2009Pieter GiesbertzSpecify description
29255view11:29, 20 April 2009Pieter GiesbertzSpecify description
29234view07:57, 17 April 2009Pieter GiesbertzSpecify description
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29151view09:57, 7 April 2009Pieter GiesbertzSpecify description
29150view09:56, 7 April 2009Pieter GiesbertzSpecify description
29107view14:14, 2 April 2009Pieter GiesbertzSpecify description
29106view14:12, 2 April 2009Pieter GiesbertzPeriodical save, work in progress
29105view14:01, 2 April 2009Pieter GiesbertzSpecify description
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29103view11:57, 2 April 2009Pieter GiesbertzSpecify description
29102view11:56, 2 April 2009Pieter GiesbertzSpecify description
29101view11:50, 2 April 2009Pieter GiesbertzPeriodical save, work in progress
29100view11:42, 2 April 2009Pieter GiesbertzSpecify description
29099view11:33, 2 April 2009Pieter GiesbertzSpecify description
29098view11:19, 2 April 2009Pieter GiesbertzSpecify description
29097view10:51, 2 April 2009Pieter GiesbertzSpecify description
29096view09:32, 2 April 2009Pieter GiesbertzPeriodical save, work in progress
29095view09:22, 2 April 2009Pieter GiesbertzPeriodical save, work in progress
29094view09:10, 2 April 2009Pieter GiesbertzPeriodical save, work in progress
29093view08:57, 2 April 2009Pieter GiesbertzPeriodical save, work in progress
29092view08:46, 2 April 2009Pieter GiesbertzPeriodical save, work in progress
29091view08:06, 2 April 2009Pieter GiesbertzPeriodical save, work in progress
29090view07:31, 2 April 2009Pieter GiesbertzPeriodical save, work in progress
29081view14:56, 31 March 2009Pieter GiesbertzCatalytic cycle of mammalian FMOs
29080view14:48, 31 March 2009Pieter GiesbertzPeriodical save, work in progress
29079view14:38, 31 March 2009Pieter GiesbertzNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
FAD-OHMetabolite4369241 (PubChem-compound)
FAD-OOHMetaboliteHydroperoxyflavone
FADH2MetaboliteCHEBI:17877 (ChEBI)
FADMetaboliteHMDB0001248 (HMDB)
FMO1GeneProductENSG00000010932 (Ensembl)
FMO2GeneProductENSG00000094963 (Ensembl)
FMO3GeneProductENSG00000007933 (Ensembl)
FMO4GeneProductENSG00000076258 (Ensembl)
FMO5GeneProductENSG00000131781 (Ensembl)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteHMDB0002111 (HMDB)
NADP+MetaboliteHMDB0000217 (HMDB)
NADPHMetaboliteHMDB0000221 (HMDB)
O2MetaboliteHMDB0001377 (HMDB)

Annotated Interactions

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