儿茶酚-O-甲基转移酶:修订间差异
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catechol-O-methyltransferase | |||||||
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识别码 | |||||||
EC編號 | 2.1.1.6 | ||||||
CAS号 | 9012-25-3 | ||||||
数据库 | |||||||
IntEnz | IntEnz浏览 | ||||||
BRENDA | BRENDA入口 | ||||||
ExPASy | NiceZyme浏览 | ||||||
KEGG | KEGG入口 | ||||||
MetaCyc | 代谢路径 | ||||||
PRIAM | 概述 | ||||||
PDB | RCSB PDB PDBj PDBe PDBsum | ||||||
基因本体 | AmiGO / EGO | ||||||
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兒茶酚-O-甲基轉移酶 (COMT; EC 2.1.1.6)是分解兒茶酚胺(如多巴胺、腎上腺素和去甲腎上腺素)的幾種酶之一。在人體,兒茶酚-O-甲基轉移酶由COMT基因編碼[2]。鑒於在一些疾病中兒茶酚胺的調節受損,數種藥物以COMT為標靶,調整其活性來控制兒茶酚胺的濃度[3]。
COMT在1957年由生物化學家 朱利叶斯·阿克塞尔罗德發現[4]。
功能
兒茶酚-O-甲基轉移酶參與了儿茶酚胺神经递质(多巴胺、肾上腺素以及去甲肾上腺素)的去活性化,它在兒茶酚胺上加入由 S-腺苷甲硫氨酸 (SAM)給予的甲基。具有鄰苯二酚結構的物質都是COMT的基質,如兒茶酚雌激素以及含有鄰苯二酚的黃酮類化合物。 L-多巴,兒茶酚胺的前驅物,是COMT重要的基質。COMT抑制劑如恩他卡朋,使L-多巴不被COMT分解為3-O-甲基多巴(3-OMD),剩下芳香族L-氨基酸脫羧酶(DACC)途徑,同時增加其半衰期。[5][6]
由COMT催化的反應包含:
- 多巴胺 → 3-Methoxytyramine
- DOPAC → HVA (homovanillic acid)
- 去甲肾上腺素 → Normetanephrine
- 肾上腺素 → Metanephrine
- Dihydroxyphenylethylene glycol (DOPEG) → Methoxyhydroxyphenylglycol (MOPEG)
- 3,4-Dihydroxymandelic acid (DOMA) → Vanillylmandelic acid (VMA)
In the brain, COMT-dependent dopamine degradation is of particular importance in brain regions with low expression of the presynaptic 多巴胺轉運體 (DAT), such as the 前額葉皮質.
This process is supposed to take place in postsynaptic neurons, as, in general, COMT is located intracellularly in the central nervous system (CNS).
COMT can also be found extracellularly, although extracellular COMT plays a less significant role in the CNS than it does peripherally.[11] Despite its importance in neurons, COMT is actually primarily expressed in the liver.[12]
命名
COMT是編碼這個酶的基因的名字。名字中的O意指氧,不是ortho。
COMT抑制劑
COMT抑制劑包括托卡朋以及恩他卡朋,常被用於治療帕金森氏症[13]。
參見
額外圖片
參考資料
- ^ Figure 11-4 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. 2007. ISBN 0-443-06911-5.
- ^ Grossman MH, Emanuel BS, Budarf ML. Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1-q11.2. Genomics. April 1992, 12 (4): 822–5. PMID 1572656. doi:10.1016/0888-7543(92)90316-K.
- ^ Tai CH, Wu RM. Catechol-O-methyltransferase and Parkinson's disease. Acta Med. Okayama. February 2002, 56 (1): 1–6. PMID 11873938.
- ^ Axelrod J. O-Methylation of Epinephrine and Other Catechols in vitro and in vivo. Science. August 1957, 126 (3270): 400–1. PMID 13467217. doi:10.1126/science.126.3270.400.
- ^ H. M. Ruottinen & U. K. Rinne. COMT inhibition in the treatment of Parkinson's disease. Journal of neurology. 1998 November, 245 (11 Suppl 3): P25–P34. PMID 9808337.
- ^ Goetz CG. Influence of COMT inhibition on levodopa pharmacology and therapy.. Neurology. 1998, 50 (5 Suppl 5): S26–30. PMID 9591519.
- ^ Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Herman MM, Kleinman JE, Weinberger DR. Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience. 2003, 116 (1): 127–37. PMID 12535946. doi:10.1016/S0306-4522(02)00556-0.
- ^ Karoum F, Chrapusta SJ, Egan MF. 3-Methoxytyramine is the Major Metabolite of Released Dopamine in the Rat Frontal Cortex: Reassessment of the Effects of Antipsychotics on the Dynamics of Dopamine Release and Metabolism in the Frontal Cortex, Nucleus Accumbens, and Striatum by a Simple T. Journal of Neurochemistry. 2002, 63 (3): 972–9. PMID 7914228. doi:10.1046/j.1471-4159.1994.63030972.x.
- ^ Ulmanen I, Peränen J, Tenhunen J, Tilgmann C, Karhunen T, Panula P, Bernasconi L, Aubry JP, Lundström K. Expression and Intracellular Localization of Catechol O-methyltransferase in Transfected Mammalian Cells. European Journal of Biochemistry. 1997, 243 (1–2): 452–9. PMID 9030772. doi:10.1111/j.1432-1033.1997.0452a.x.
- ^ Schott et al., 2010 http://www.frontiersin.org/molecular_psychiatry/10.3389/fpsyt.2010.00142/abstract
- ^ Golan, David E.; Armen H. Tashjian Jr. Principles of pharmacology 3rd. Philadelphia: Wolters Kluwer Health. : 210. ISBN 1-60831-270-4.
- ^ Golan, David E.; Armen H. Tashjian Jr. Principles of pharmacology 3rd. Philadelphia: Wolters Kluwer Health. : 135. ISBN 1-60831-270-4.
- ^ Bonifácio MJ, Palma PN, Almeida L, Soares-da-Silva P. Catechol-O-methyltransferase and its inhibitors in Parkinson's disease. CNS Drug Rev. 2007, 13 (3): 352–79. PMID 17894650. doi:10.1111/j.1527-3458.2007.00020.x.
進一步閱讀
- Wichers M, Aguilera M, Kenis G, Krabbendam L, Myin-Germeys I, Jacobs N, Peeters F, Derom C, Vlietinck R, Mengelers R, Delespaul P, van Os J. The Catechol-O-Methyl Transferase Val158Met Polymorphism and Experience of Reward in the Flow of Daily Life. Neuropsychopharmacology. 2008, 33 ((2008) 33, 3030–3036): 3030–6. PMID 17687265. doi:10.1038/sj.npp.1301520.http://www.nature.com/npp/journal/v33/n13/full/1301520a.html
- Trendelenburg U. The interaction of transport mechanisms and intracellular enzymes in metabolizing systems. J. Neural Transm. Suppl. 1991, 32: 3–18. PMID 2089098. doi:10.1007/978-3-7091-9113-2_1.
- Tai CH, Wu RM. Catechol-O-methyltransferase and Parkinson's disease. Acta Med. Okayama. 2002, 56 (1): 1–6. PMID 11873938.
- Zhu BT. On the mechanism of homocysteine pathophysiology and pathogenesis: a unifying hypothesis. Histol. Histopathol. 2003, 17 (4): 1283–91. PMID 12371153.
- Oroszi G, Goldman D. Alcoholism: genes and mechanisms. Pharmacogenomics. 2005, 5 (8): 1037–48. PMID 15584875. doi:10.1517/14622416.5.8.1037.
- Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, Feng GY, St Clair D, He L. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol. Psychiatry. 2005, 57 (2): 139–44. PMID 15652872. doi:10.1016/j.biopsych.2004.10.018.
- Tunbridge EM, Harrison PJ, Weinberger DR. Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol. Psychiatry. 2006, 60 (2): 141–51. PMID 16476412. doi:10.1016/j.biopsych.2005.10.024.
- Diaz-Asper CM, Weinberger DR, Goldberg TE. Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics. NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics. 2006, 3 (1): 97–105. PMC 3593358 . PMID 16490416. doi:10.1016/j.nurx.2005.12.010.
- Craddock N, Owen MJ, O'Donovan MC. The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Mol. Psychiatry. 2006, 11 (5): 446–58. PMID 16505837. doi:10.1038/sj.mp.4001808.
- Frank MJ, Moustafa AA, Haughey HM, Curran T, Hutchison KE. Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning. Proc Natl Acad Sci USA. 2007, 104 (41): 16311–6. PMC 2042203 . PMID 17913879. doi:10.1073/pnas.0706111104.
對外連結
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