Altered lipid composition and enzyme activities of plasma membranes from Trypanosoma (Schizotrypanum) cruzi epimastigotes grown in the presence of sterol biosynthesis inhibitors
Altered lipid composition and enzyme activities of plasma membranes from Trypanosoma (Schizotrypanum) cruzi epimastigotes grown in the presence of sterol biosynthesis inhibitors
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DOI：
10.1016/s0006-2952(96)00903-3
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发表时间：
1997-03-07
影响因子：
5.8
通讯作者：
Urbina, JA
中科院分区：
文献类型：
--
作者：
Contreras, LM;Vivas, J;Urbina, JA
甾醇生物合成抑制剂（SBI）对原生动物寄生虫锥虫（裂殖吸虫）克氏锥虫（锥虫是南美锥虫病的病原体）的抗增殖作用的公认机制是消耗特定的寄生虫甾醇，所述寄生虫甾醇是必需的生长因子并且不能被胆固醇（存在于脊椎动物宿主中的主要甾醇）替代。然而，这些特定的寄生虫固醇的确切代谢作用是未知的。我们通过使T.研究了甾醇C-14脱甲基酶抑制剂和δ（24（25））甲基转移酶抑制剂对粗上鞭毛体细胞膜脂质组成和酶活性的影响。我们发现，在纯化的质膜从SBI处理的细胞，连同预期的变化中的甾醇组合物，也有一个反转的磷脂酰胆碱（PC）的磷脂酰乙醇胺（PE）的比例和大量增加的饱和脂肪酸酯化磷脂的含量。磷脂头基组合物的修改与膜结合的PC-PE-N-甲基转移酶SBI处理的细胞的比活性降低70%相关;结果表明，这种抑制不是由于药物对酶的直接影响。最后，Mg 2+依赖性，钒酸敏感的ATP酶的比活性存在于膜也被抑制钙。在SBI处理的细胞中为50%。结果表明，SBI引起的内源性甾醇耗竭的主要效应之一是对T。cruzi是由于PE-PC-N-甲基转移酶和可能的酰基Delta（9）和Delta（6）去饱和酶的活性降低而引起的细胞磷脂组成的改变;反过来，这可能影响其他酶和转运蛋白的活性。(C)1997年爱思唯尔科学公司
The accepted mechanism for the antiproliferative effects of sterol biosynthesis inhibitors (SBI) against the protozoan parasite Trypanosoma (Schizotryparuan) cruzi, the causative agent of Chagas' disease, is the depletion of specific parasite sterols that are essential growth factors and cannot be replaced by cholesterol, the main sterol present in che vertebrate host. However, the precise metabolic roles of these specific parasite steroles are unknown. We approached this problem by subjecting T. crud epimastigotes to two types of SBI, inhibitors of sterol C-14 demethylase and Delta(24(25))) methyl transferase, and investigating the modification of lipid composition and enzyme activities in the plasma membranes of the parasite. We found in purified plasma membrane from SBI-treated cells that, together with the expected changes in the sterol composition, there was also an inversion of the phosphatidylcholine (PC) to phosphatidylethanolamine (PE) ratio and a large increase in the content of saturated fatty acids esterified to phospholipids. The modification of the phospholipid headgroup composition correlated with a 70% reduction in the specific activity of the membrane-bound PC-PE-N-methyl transferase SBI-treated cells; it was shown that this inhibition was not due to a direct effect of the drug on the enzyme. Finally, the specific activity of the Mg2+-dependent, vanadate-sensitive ATPase present in the membranes was also inhibited by ca. 50% in SBI-treated cells. The results suggest that one of the primary effects of the depletion of endogenous sterols induced by SBI in T. cruzi is a modification of the cellular phospholipid composition as a consequence of a reduced activity of PE-PC-N-methyl transferase and probably of the acyl Delta(9) and Delta(6) desaturases; this, in rum, could affect the activity of other enzymatic and transport proteins. (C) 1997 Elsevier Science Inc.