FMO3

FMO3
Identifikatori
Alijasi	FMO3
Spoljašnji ID	OMIM: 136132 MGI: 1100496 HomoloGene: 128199 GeneCards: FMO3
EC number	1.14.13.148
Genska lokacija (miš)
Hr.	Chromosome 1 (mouse)
Kraj	162,812,097 bp
Obrazac RNK izražavanja
	; ;
	More reference expression data
Genska ontologija
Molecular function	• trimethylamine monooxygenase activity; • oxidoreductase activity; • N,N-dimethylaniline monooxygenase activity; • NADP binding; • flavin adenine dinucleotide binding; • monooxygenase activity; • GO:0001948, GO:0016582 везивање за протеине плазме;
Cellular component	• саставни део мембране; • organelle membrane; • endoplasmic reticulum membrane; • intracellular membrane-bounded organelle; • ендоплазматични ретикулум; • мембрана;
Biological process	• xenobiotic metabolic process;
	Sources:Amigo / QuickGO
Ortolozi
	2328
	14262
	ENSG00000007933
	ENSMUSG00000026691
	P31513
	P97501
	NM_001002294; NM_006894; NM_001319173; NM_001319174
	NM_008030
	NP_001002294; NP_001306102; NP_001306103; NP_008825
	NP_032056
	Wikidata
View/Edit Human	View/Edit Mouse

Monooksigenaza koja sadrži flavin 3 (FMO3), takođe poznata kao dimetilanilinska monooksigenaza [N-oksid-formirajuća] 3 i trimetilaminska monooksigenaza, flavoproteinski je enzim (EC 1.14.13.148) koji je kod ljudi koriran FMO3 genom.^[4]^[5]^[6]^[7] Ovaj enzim katalizuje sledeću hemijsku reakciju:^[7]

N,N,N-trimetilamin + NADPH + H⁺ + O₂

\rightleftharpoons

N,N,N-trimetilamin N-oksid + NADP⁺ + H₂O

FMO3 je glavni izoenzim monooksigenaze koja sadrži flavin koja je izražena u jetri odraslih osoba.^[7]^[8]^[9] Ljudski FMO3 enzim katalizuje nekoliko tipova reakcija, uključujući: N-oksigenaciju primarnih, sekundarnih, i tercijarnih amina;^[8]^[10] S-oksigenaciju nukleofilnih jedinjenja koja sadrže sumpor;^[8]^[10] i 6-metilhidroksilaciju DMXAA.^[8]^[11]

FMO3 je primarni enzim kod ljudi koji katalizuje N-oksidaciju trimetilamina u trimetilamin N-oksid;^[7]^[9] FMO1 takođe N-oksigeniše trimetilamin, mada u znatno manjoj meri od FMO3.^[12]^[13] Genetičke deficijencije FMO3 enzima uzrokuju primarnu trimetilaminuriju, takođe poznatu kao "sindrom ribljeg zadaha".^[7]^[14] FMO3 isto tako učestvuje u metabolizmu mnogih ksenobiotika (i.e., egzogenih jedinjenja koja nisu normalno prisutn u telu),^[8]^[9] kao što je oksidativna deaminacija amfetamina.^[8]^[15]^[16]

^ ^а ^б ^в GRCm38: Ensembl release 89: ENSMUSG00000026691 - Ensembl, May 2017
^ „Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ „Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Shephard EA, Dolphin CT, Fox MF, Povey S, Smith R, Phillips IR (1993). „Localization of genes encoding three distinct flavin-containing monooxygenases to human chromosome 1q”. Genomics. 16 (1): 85—9. PMID 8486388. doi:10.1006/geno.1993.1144.
^ Dolphin CT, Riley JH, Smith RL, Shephard EA, Phillips IR (1998). „Structural organization of the human flavin-containing monooxygenase 3 gene (FMO3), the favored candidate for fish-odor syndrome, determined directly from genomic DNA”. Genomics. 46 (2): 260—7. PMID 9417913. doi:10.1006/geno.1997.5031.
^ „Entrez Gene: FMO3 flavin containing monooxygenase 3”.
^ ^а ^б ^в ^г ^д Грешка код цитирања: Неважећа ознака <ref>; нема текста за референце под именом BRENDA FMO3 Homo sapiens.
^ ^а ^б ^в ^г ^д ^ђ Krueger SK, Williams DE (2005). „Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism”. Pharmacol. Ther. 106 (3): 357—387. PMC 1828602 . PMID 15922018. doi:10.1016/j.pharmthera.2005.01.001. „A second precaution with respect to predicting FMO enzyme substrate specificity is that factors other than size and charge must play a role, but these parameters are not well understood. 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). ... The most efficient human FMO in phenethylamine N-oxygenation is FMO3, the major FMO present in adult human liver; the Km is between 90 and 200 μM (Lin & Cashman, 1997b). ... Of particular significance for this review is that individuals homozygous for certain FMO3 allelic variants (e.g., null variants) also demonstrate impaired metabolism toward other FMO substrates including ranitidine, nicotine, thio-benzamide, and phenothiazine derivatives (Table 4; Cashman et al., 1995, 2000; Kang et al., 2000; Cashman, 2002; Park et al., 2002; Lattard et al., 2003a, 2003b). ... The metabolic activation of ethionamide by the bacterial FMO is the same as the mammalian FMO activation of thiobenzamide to produce hepatotoxic sulfinic and sulfinic acid metabolites. Not surprisingly, Dr. Ortiz de Montellano’s laboratory and our own have found ethionamide to be a substrate for human FMO1, FMO2, and FMO3 (unpublished observations).”
Table 5: N-containing drugs and xenobiotics oxygenated by FMO
Table 6: S-containing drugs and xenobiotics oxygenated by FMO
Table 7: FMO activities not involving S- or N-oxygenation
^ ^а ^б ^в Грешка код цитирања: Неважећа ознака <ref>; нема текста за референце под именом FMO3 2007 review.
^ ^а ^б Грешка код цитирања: Неважећа ознака <ref>; нема текста за референце под именом FMO3 2000 review.
^ Zhou S, Kestell P, Paxton JW (2002). „6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3”. Eur J Drug Metab Pharmacokinet. 27 (3): 179—183. PMID 12365199. „Only FMO3 formed 6-OH-MXAA at a similar rate to that in cDNA-expressed cytochromes P-450 (CYP)1A2. The results of this study indicate that human FMO3 has the capacity to form 6-OH-MXAA, but plays a lesser important role for this reaction than CYP1A2 that has been demonstrated to catalyse 6-OH-MXAA formation.”
^ Tang WH, Hazen SL (2014). „The contributory role of gut microbiota in cardiovascular disease”. J. Clin. Invest. 124 (10): 4204—4211. PMC 4215189 . PMID 25271725. doi:10.1172/JCI72331. „In recent studies each of the FMO family members were cloned and expressed, to determine which possessed synthetic capacity to use TMA as a substrate to generate TMAO. FMO1, FMO2, and FMO3 were all capable of forming TMAO, though the specific activity of FMO3 was at least 10-fold higher than that the other FMOs (54). Further, FMO3 overexpression in mice significantly increased plasma TMAO levels, while silencing FMO3 decreased TMAO levels (54). In both humans and mice, hepatic FMO3 expression was observed to be reduced in males compared with females (25, 54) and could be induced by dietary bile acids through a mechanism that involves FXR (54).”
^ Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ (2013). „Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation”. Cell Metab. 17 (1): 49—60. PMC 3771112 . PMID 23312283. doi:10.1016/j.cmet.2012.12.011. „Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1.”
^ Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR (1997). „Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome”. Nat. Genet. 17 (4): 491—4. PMID 9398858. doi:10.1038/ng1297-491.
^ Glennon RA (2013). „Phenylisopropylamine stimulants: amphetamine-related agents”. Ур.: Lemke TL, Williams DA, Roche VF, Zito W. Foye's principles of medicinal chemistry (7th изд.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. стр. 646—648. ISBN 9781609133450. Приступљено 11. 09. 2015. „The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase.”
^ Cashman JR, Xiong YN, Xu L, Janowsky A (1999). „N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication”. J. Pharmacol. Exp. Ther. 288 (3): 1251—1260. PMID 10027866.

[refGRCm38Ensembl-1] а ^б ^в GRCm38: Ensembl release 89: ENSMUSG00000026691 - Ensembl, May 2017

[2] „Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.

[3] „Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid8486388-4] Shephard EA, Dolphin CT, Fox MF, Povey S, Smith R, Phillips IR (1993). „Localization of genes encoding three distinct flavin-containing monooxygenases to human chromosome 1q”. Genomics. 16 (1): 85—9. PMID 8486388. doi:10.1006/geno.1993.1144.

[pmid9417913-5] Dolphin CT, Riley JH, Smith RL, Shephard EA, Phillips IR (1998). „Structural organization of the human flavin-containing monooxygenase 3 gene (FMO3), the favored candidate for fish-odor syndrome, determined directly from genomic DNA”. Genomics. 46 (2): 260—7. PMID 9417913. doi:10.1006/geno.1997.5031.

[entrez-6] „Entrez Gene: FMO3 flavin containing monooxygenase 3”.

[BRENDA_FMO3_Homo_sapiens-7] а ^б ^в ^г ^д Грешка код цитирања: Неважећа ознака <ref>; нема текста за референце под именом BRENDA FMO3 Homo sapiens.

[FMO-8] а ^б ^в ^г ^д ^ђ Krueger SK, Williams DE (2005). „Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism”. Pharmacol. Ther. 106 (3): 357—387. PMC 1828602 . PMID 15922018. doi:10.1016/j.pharmthera.2005.01.001. „A second precaution with respect to predicting FMO enzyme substrate specificity is that factors other than size and charge must play a role, but these parameters are not well understood. 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). ... The most efficient human FMO in phenethylamine N-oxygenation is FMO3, the major FMO present in adult human liver; the Km is between 90 and 200 μM (Lin & Cashman, 1997b). ... Of particular significance for this review is that individuals homozygous for certain FMO3 allelic variants (e.g., null variants) also demonstrate impaired metabolism toward other FMO substrates including ranitidine, nicotine, thio-benzamide, and phenothiazine derivatives (Table 4; Cashman et al., 1995, 2000; Kang et al., 2000; Cashman, 2002; Park et al., 2002; Lattard et al., 2003a, 2003b). ... The metabolic activation of ethionamide by the bacterial FMO is the same as the mammalian FMO activation of thiobenzamide to produce hepatotoxic sulfinic and sulfinic acid metabolites. Not surprisingly, Dr. Ortiz de Montellano’s laboratory and our own have found ethionamide to be a substrate for human FMO1, FMO2, and FMO3 (unpublished observations).”
Table 5: N-containing drugs and xenobiotics oxygenated by FMO
Table 6: S-containing drugs and xenobiotics oxygenated by FMO
Table 7: FMO activities not involving S- or N-oxygenation

[FMO3_2007_review-9] а ^б ^в Грешка код цитирања: Неважећа ознака <ref>; нема текста за референце под именом FMO3 2007 review.

[FMO3_2000_review-10] а ^б Грешка код цитирања: Неважећа ознака <ref>; нема текста за референце под именом FMO3 2000 review.

[DMXAA_primary-11] Zhou S, Kestell P, Paxton JW (2002). „6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3”. Eur J Drug Metab Pharmacokinet. 27 (3): 179—183. PMID 12365199. „Only FMO3 formed 6-OH-MXAA at a similar rate to that in cDNA-expressed cytochromes P-450 (CYP)1A2. The results of this study indicate that human FMO3 has the capacity to form 6-OH-MXAA, but plays a lesser important role for this reaction than CYP1A2 that has been demonstrated to catalyse 6-OH-MXAA formation.”

[Review_-_TMA1+TMA2_N-oxygenate_TMA-12] Tang WH, Hazen SL (2014). „The contributory role of gut microbiota in cardiovascular disease”. J. Clin. Invest. 124 (10): 4204—4211. PMC 4215189 . PMID 25271725. doi:10.1172/JCI72331. „In recent studies each of the FMO family members were cloned and expressed, to determine which possessed synthetic capacity to use TMA as a substrate to generate TMAO. FMO1, FMO2, and FMO3 were all capable of forming TMAO, though the specific activity of FMO3 was at least 10-fold higher than that the other FMOs (54). Further, FMO3 overexpression in mice significantly increased plasma TMAO levels, while silencing FMO3 decreased TMAO levels (54). In both humans and mice, hepatic FMO3 expression was observed to be reduced in males compared with females (25, 54) and could be induced by dietary bile acids through a mechanism that involves FXR (54).”

[FMO1_also_metabolizes_TMA_-_primary_source-13] Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ (2013). „Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation”. Cell Metab. 17 (1): 49—60. PMC 3771112 . PMID 23312283. doi:10.1016/j.cmet.2012.12.011. „Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1.”

[FMO3,_trimethylamine,_and_fish-odor_syndrome-14] Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR (1997). „Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome”. Nat. Genet. 17 (4): 491—4. PMID 9398858. doi:10.1038/ng1297-491.

[Substituted_amphetamines,_FMO,_and_DBH-15] Glennon RA (2013). „Phenylisopropylamine stimulants: amphetamine-related agents”. Ур.: Lemke TL, Williams DA, Roche VF, Zito W. Foye's principles of medicinal chemistry (7th изд.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. стр. 646—648. ISBN 9781609133450. Приступљено 11. 09. 2015. „The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase.”

[FMO3-Primary-16] Cashman JR, Xiong YN, Xu L, Janowsky A (1999). „N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication”. J. Pharmacol. Exp. Ther. 288 (3): 1251—1260. PMID 10027866.

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