플라빈 함유 모노옥시제 3

Flavin-containing monooxygenase 3
FMO3
식별자
별칭FMO3, 트리메틸아민 모노옥시제나제, 플라빈 함유 모노옥시제나제3, 디메틸란실린 모노옥시제나제[N-산화성형식] 3, FMOII, TMAU, dJ127D3.1, 모노옥시제나제 3, 디메틸라민 모노시제나제나제나제나제나제나제나제나제나제나트륨
외부 IDOMIM: 136132 MGI: 1100496 호몰로Gene: 128199 GeneCard: FMO3
EC 번호1.14.13.148
직교체
종인간마우스
엔트레스

2328

14262

앙상블

ENSG00000007933

ENSMUSG00000026691

유니프로트

P31513

P97501

RefSeq(mRNA)

NM_001002294
NM_006894
NM_001319173
NM_001319174

NM_008030

RefSeq(단백질)

NP_001002294
NP_001306102
NP_001306103
NP_008825

NP_032056

위치(UCSC)Cr 1: 171.09 – 171.12MbChr 1: 162.78 – 162.81Mb
PubMed 검색[3][4]
위키다타
인간 보기/편집마우스 보기/편집

플라빈 함유 모노옥시제 3(FMO3)은 디메틸란닐린 모노옥시제나제[N-산화지질성형식] 3과 트리메틸아민 모노옥시제나제로 알려져 있으며, 인간에서 FMO3 유전자에 의해 인코딩되는 플라보프로테아민 효소(EC 1.14.13.14.148)이다.[5][6][7][8]이 효소는 무엇보다도 다음과 같은 화학 반응을 촉진한다.[8]

트리메틸아민 + NADPH + H+ + O2 rimethylamine N-산화질소+ NADP+ + HO2

FMO3는 성인 인간의 간에서 발현되는 주요 플라빈 함유 모노옥시제네아제 이소엔자임이다.[8][9][10]인간 FMO3 효소는 1차, 2차, 3차 아민의 N-산소 생성,[9][11] 핵소필릭 황 함유 화합물의 S-산소 생성,[9][11] 항암제 디메틸xanthenone 아세트산(DMXAA)의 6-메틸하이드록시화 등 여러 종류의 반응을 촉진한다.[9][12]

FMO3는 트리메틸아민 N-산화물로 트리메틸아민 N-산화질소를 촉진하는 인간의 1차 효소다.[8][10] FMO1도 이와 같은 작용을 하지만 FMO3보다 훨씬 적다.[13][14] FMO3 효소의 유전적 결핍은 1차 트리메틸아민증을 유발하며, '어류 냄새 증후군'[8][15]이라고도 한다.또한 FMO3는 암페타민의 산화적 탈삼화와 같은 많은 항생제(즉, 체내에 일반적으로 존재하지 않는 외생성 화합물)[9][10]의 대사에도 관여한다.[9][16][17]

리간즈

인간 FMO3 기질, 억제제, 유도제 및 활성제 목록
FMO3 기판 FMO3 억제제 FMO3 유도체 FMO3 활성화기
내생생물분자
주목할 만한 외생균제
A는 다른 FMO 등소성 대비 FMO3의 선택도를 중간에서 완전하게 나타낸다.

암

FMO3 유전자는 서로 다른 수준의 악성 종양에서 자궁경부 재생성 병변에서 파생된 인간 유피오마바이러스 양성 신소성 케라틴세포에서 점진적으로 하향 조절된 것으로 관찰되었다.[19]이 때문에 FMO3는 종양기세증과 연관될 가능성이 있으며 자궁경부 재생성 병변 진행을 위한 잠재적 예후 마커일 수 있다.[19]

참고 항목

참조

  1. ^ a b c GRCh38: 앙상블 릴리스 89: ENSG00000007933 - 앙상블, 2017년 5월
  2. ^ a b c GRCm38: 앙상블 릴리스 89: ENSMUSG000026691 - 앙상블, 2017년 5월
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Shephard EA, Dolphin CT, Fox MF, Povey S, Smith R, Phillips IR (June 1993). "Localization of genes encoding three distinct flavin-containing monooxygenases to human chromosome 1q". Genomics. 16 (1): 85–9. doi:10.1006/geno.1993.1144. PMID 8486388.
  6. ^ Dolphin CT, Riley JH, Smith RL, Shephard EA, Phillips IR (February 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. doi:10.1006/geno.1997.5031. PMID 9417913.
  7. ^ "Entrez Gene: FMO3 flavin containing monooxygenase 3".
  8. ^ a b c d e f g h i j k l m "Trimethylamine monooxygenase (Homo sapiens)". BRENDA. Technische Universität Braunschweig. July 2016. Retrieved 18 September 2016. trimethylaminuria (fish-odor syndrome) is associated with defective hepatic N-oxidation of dietary-derived trimethylamine catalyzed by flavin-containing monooxygenase ... FMO3 deficiency results in trimethylaminuria or the fish-like odour syndrome ... isozyme FMO3 regulates the conversion of N,N,N-trimethylamine into its N-oxide and hence controls the release of volatile N,N,N-trimethylamine from the individual
  9. ^ a b c d e f g h i j k l m n o p q r s t u v w x y Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacol. Ther. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC 1828602. PMID 15922018. 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).
    표 5: FMO에 의해 산소가 함유된 N 함유 의약품 및 항생제
    표 6: FMO에 의해 산소가 공급되는 S 함유 의약품 및 항생제
    표 7: S- 또는 N-산소를 포함하지 않는 FMO 활동
  10. ^ a b c d e f g h i Hisamuddin IM, Yang VW (June 2007). "Genetic polymorphisms of human flavin-containing monooxygenase 3: implications for drug metabolism and clinical perspectives". Pharmacogenomics. 8 (6): 635–643. doi:10.2217/14622416.8.6.635. PMC 2213907. PMID 17559352. Other drug substrates have been used for both in vitro and in vivo analyses. ... FMO3 is the most abundantly expressed FMO in the adult human liver [12]. Its structure and function and the implications of its polymorphisms have been widely studied [8,12,13]. This enzyme has a wide substrate specificity, including the dietary-derived tertiary amines trimethylamine, tyramine and nicotine; commonly used drugs including cimetidine, ranitidine, clozapine, methimazole, itopride, ketoconazole, tamoxifen and sulindac sulfide; and agrichemicals, such as organophosphates and carbamates [14–22].
  11. ^ a b c d e Cashman JR (September 2000). "Human flavin-containing monooxygenase: substrate specificity and role in drug metabolism". Curr. Drug Metab. 1 (2): 181–191. doi:10.2174/1389200003339135. PMID 11465082. Human FMO3 N-oxygenates primary, secondary and tertiary amines whereas human FMO1 is only highly efficient at N-oxygenating tertiary amines. Both human FMO1 and FMO3 S-oxygenate a number of nucleophilic sulfur-containing substrates and in some cases, does so with great stereoselectivity. ... For amines with smaller aromatic substituents such as phenethylamines, often these compounds are efficiently N-oxygenated by human FMO3. ... (S)-Nicotine N-1'-oxide formation can also be used as a highly stereoselective probe of human FMO3 function for adult humans that smoke cigarettes. Finally, cimetidine S-oxygenation or ranitidine N-oxidation can also be used as a functional probe of human FMO3. With the recent observation of human FMO3 genetic polymorphism and poor metabolism phenotype in certain human populations, variant human FMO3 may contribute to adverse drug reactions or exaggerated clinical response to certain medications.
  12. ^ a b Zhou S, Kestell P, Paxton JW (July 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. doi:10.1007/bf03190455. PMID 12365199. S2CID 21583717. 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.
  13. ^ Tang WH, Hazen SL (October 2014). "The contributory role of gut microbiota in cardiovascular disease". J. Clin. Invest. 124 (10): 4204–4211. doi:10.1172/JCI72331. PMC 4215189. PMID 25271725. 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).
  14. ^ 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. doi:10.1016/j.cmet.2012.12.011. PMC 3771112. PMID 23312283. 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.
  15. ^ 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. doi:10.1038/ng1297-491. PMID 9398858. S2CID 24732203.
  16. ^ Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.). Foye's principles of medicinal chemistry (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN 9781609133450. 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.
  17. ^ a b c Cashman JR, Xiong YN, Xu L, Janowsky A (March 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.
  18. ^ a b c d e Robinson-Cohen C, Newitt R, Shen DD, Rettie AE, Kestenbaum BR, Himmelfarb J, Yeung CK (August 2016). "Association of FMO3 Variants and Trimethylamine N-Oxide Concentration, Disease Progression, and Mortality in CKD Patients". PLOS ONE. 11 (8): e0161074. doi:10.1371/journal.pone.0161074. PMC 4981377. PMID 27513517. TMAO is generated from trimethylamine (TMA) via metabolism by hepatic flavin-containing monooxygenase isoform 3 (FMO3). ... FMO3 catalyzes the oxidation of catecholamine or catecholamine-releasing vasopressors, including tyramine, phenylethylamine, adrenaline, and noradrenaline [32, 33].
  19. ^ a b Rotondo JC, Bosi S, Bassi C, Ferracin M, Lanza G, Gafà R, Magri E, Selvatici R, Torresani S, Marci R, Garutti P, Negrini M, Tognon M, Martini F (April 2015). "Gene expression changes in progression of cervical neoplasia revealed by microarray analysis of cervical neoplastic keratinocytes". J Cell Physiol. 230 (4): 802–812. doi:10.1002/jcp.24808. PMID 25205602. S2CID 24986454.

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