Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.
Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.
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DOI：
10.1155/2009/642502
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发表时间：
2009-01-01
影响因子：
--
通讯作者：
Rodrigues, Juliany Cola Fernandes
中科院分区：
文献类型：
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作者：
de Souza, Wanderley;Rodrigues, Juliany Cola Fernandes
甾醇是细胞膜的组成部分，对于它们的正常结构和功能是必不可少的。在哺乳动物细胞中，胆固醇是在各种膜中发现的主要固醇。然而，其他固醇在真核微生物如真菌和原生动物中占主导地位。现在已经确定，真菌和锥虫科成员中的重要代谢途径是产生一类特殊的甾醇，包括麦角甾醇和其他24-甲基甾醇，这些甾醇是寄生虫生长和生存力所需的，但在哺乳动物宿主细胞中不存在。目前，有几种干扰固醇生物合成（SB）的药物用于治疗人类高胆固醇和真菌感染等疾病。在这篇综述中，我们分析了药物如（a）他汀类药物，其通过抑制HMG-CoA还原酶作用于甲羟戊酸途径，（B）二膦酸盐，其干扰法呢基二磷酸合酶催化步骤中的类异戊二烯途径，（c）萨拉戈萨酸和奎宁环，角鲨烯合酶（SQS）抑制剂，其催化甾醇生物合成的第一个关键步骤，（d）烯丙胺，角鲨烯环氧酶抑制剂，（e）唑类，其抑制C14 α-脱甲基酶，和（f）氮杂甾醇类，其抑制δ（24（25））-甾醇甲基转移酶（SMT）。对最后一步的抑制似乎对真菌和锥虫具有高选择性，因为这种酶在哺乳动物细胞中没有发现。我们在这里审查的IC 50值，这些不同的抑制剂，它们对锥虫的生长（无论是在无菌培养和细胞培养）的影响，以及它们对原生动物的结构组织（通过光学和电子显微镜评价）和脂质成分的影响。结果表明，线粒体膜以及原生动物细胞体和鞭毛的内衬膜是主要靶点。可能是由于这些主要的影响，其他重要的变化发生在动质体DNA网络的组织和原生动物的细胞周期。此外，由几种测试的抑制剂诱导的寄生虫样和自噬过程导致寄生虫死亡。
Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB) that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT). Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures), and their effects on protozoan structural organization (as evaluted by light and electron microscopy) and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle. In addition, apoptosis-like and autophagic processes induced by several of the inhibitors tested led to parasite death.