CYP51: A major drug target in the cytochrome P450 superfamily.
CYP51: A major drug target in the cytochrome P450 superfamily.
复制标题
DOI：
10.1007/s11745-008-3225-y
复制
发表时间：
2008-12
期刊：
影响因子：
1.9
通讯作者：
Waterman, Michael R.
中科院分区：
文献类型：
--
作者：
Lepesheva, Galina I.;Hargrove, Tatyana Y.;Kleshchenko, Yuliya;Nes, W. David;Villalta, Fernando;Waterman, Michael R.
关键词：
细胞色素P540 （CYP）超家族目前包括约9000个蛋白质，形成800多个家族。酶催化大量化合物的单氧作用，主要起两个作用。它们提供生物防御（解毒的异种生物，抗生素的生产），并参与重要的内源性分子，特别是类固醇的生物合成。基于这两种作用，甾醇14|* α *|-去甲基化酶（CYP51）属于第二组p450。然而，CYP51家族是非常特殊的，因为它的成员在所有生物王国中都保持着严格的酶活性功能保守。在氨基酸同源性低至25-30%的王国中，它们都催化了本质上相同的三步反应，即氧化去除lanostane框架中的14|* α *|-甲基。该反应是病原微生物合成甾醇的必要步骤。我们已经表明，特异性抑制原生动物CYP51可以潜在地提供治疗人类锥虫病。本研究在体外和锥虫细胞中测试了三组CYP51抑制剂，包括唑类化合物（对克氏锥虫（TC）和布鲁氏锥虫（TB）在<1和1.3µM下分别具有50%的细胞生长抑制效果）、非唑类化合物（在5µM下50%的TC细胞生长抑制）和14|* α *|-去甲基化酶反应的底物类似物。32-亚甲基环丙基lanost-7-烯醇对TC具有选择性，在3µM时细胞生长抑制率为50%。
The cytochrome P540 (CYP) superfamily currently includes about 9,000 proteins forming more than 800 families. The enzymes catalyze monooxygenation of a vast array of compounds and play essentially two roles. They provide biodefense (detoxification of xenobiotics, antibiotic production) and participate in biosynthesis of important endogenous molecules, particularly steroids. Based on these two roles, sterol 14|*alpha*|-demethylases (CYP51) belong to the second group of P450s. The CYP51 family, however, is very special as its members preserve strict functional conservation in enzyme activity in all biological kingdoms. At amino acid identity across the kingdoms as low as 25–30%, they all catalyze essentially the same three-step reaction of oxidative removal of the 14|*alpha*|-methyl group from the lanostane frame. This reaction is the required step in sterol biosynthesis of pathogenic microbes. We have shown that specific inhibition of protozoan CYP51 can potentially provide treatment for human trypanosomiases. Three sets of CYP51 inhibitors tested in vitro and in trypanosomal cells in this study include azoles [best results being 50% cell growth inhibition at <1 and at 1.3 µM for Trypanosoma cruzi (TC) and Trypanosoma brucei (TB), respectively], non-azole compounds (50% TC cell growth inhibition at 5 µM) and substrate analogs of the 14|*alpha*|-demethylase reaction. 32-Methylene cyclopropyl lanost-7-enol exhibited selectivity toward TC with 50% cell growth inhibition at 3 µM.
登录
查看更多内容
影响因子：
3.9
作者：
Lepesheva, G. I.;Hargrove, T. Y.;Waterman, M. R.
通讯作者：
Waterman, M. R.
影响因子：
2.9
作者：
TRZASKOS, JM;KO, SS;GAYLOR, JL
通讯作者：
GAYLOR, JL
影响因子：
--
作者：
Lepesheva, Galina I.;Ott, Robert D.;Waterman, Michael R.
通讯作者：
Waterman, Michael R.
影响因子：
4.9
作者：
Faundez, M;Pino, L;Maya, JD
通讯作者：
Maya, JD
影响因子：
2.9
作者：
Lepesheva, GI;Nes, WD;Waterman, MR
通讯作者：
Waterman, MR