Physiological role of HMG-CoA reductase in regulating egg production by Schistosoma mansoni.
Physiological role of HMG-CoA reductase in regulating egg production by Schistosoma mansoni.
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HMG-CoA还原酶在调节曼氏血吸虫产卵中的生理作用。
DOI：
10.1152/ajpregu.1989.257.3.r618
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Bennett,JL
中科院分区：
文献类型：
--
作者：
Vandewaa,EA;Mills,G;Chen,GZ;Foster,LA;Bennett,JL
在感染曼氏血吸虫的人身上观察到的病理损害是由雌性寄生虫产生的卵造成的。Mevinolin是羟甲基戊二酰辅酶A(HMG-CoA)还原酶的有效抑制剂，可以阻止这种寄生虫的产卵。在这份报告中，我们证明了胆固醇前体甲氧戊酸和法尼醇可以刺激雌性寄生虫的产卵，并且这些前体可以逆转梅维诺林诱导的产卵抑制。因为寄生虫不能合成胆固醇，所以我们在含有放射性标记醋酸酯的培养液中孵化寄生虫，其中有和没有甲氧诺林。我们从寄生虫中分离出非甾醇类脂，观察到梅维诺林极大地减少了将醋酸酯转化为寄生虫的聚异戊二烯(多烯)脂类。多糖醇和其他非甾醇类脂类不会刺激产蛋量。在寄生虫的匀浆中观察到HMG-CoA还原酶的活性，并被甲氧西林(Ki=52 nM)抑制，但当长期接触低剂量的药物时，其活性增加两倍。还原酶活性增强的寄生虫产生的卵子要多五到六倍。最后，对感染的小鼠长期服用大剂量的梅维诺林可显著减少与感染相关的病理改变。这些结果表明，曼氏血吸虫的产卵量与寄生虫的HMG-CoA还原酶活性有关，在该酶调节的生化途径中产生的非甾醇类脂刺激产卵量。
Pathological lesions observed in humans infected with Schistosoma mansoni are due to the eggs produced by the female parasite. Mevinolin, a potent inhibitor of the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) reductase, blocks egg production by this parasite. In this report, we demonstrate that cholesterol precursors, mevalonate and farnesol, stimulate egg production by the female parasite and that these precursors can reverse the mevinolin-induced inhibition of egg production. Because the parasite cannot synthesize cholesterol, we incubated parasites in a culture media containing radiolabeled acetate with and without mevinolin. We isolated nonsterol lipids from the parasite and observed that mevinolin dramatically reduced the conversion of acetate into the polyisoprenoid (dolichols) lipids of the parasite. Dolichols and other nonsterol lipids did not stimulate egg production. HMG-CoA reductase activity was observed in homogenates of the parasite and was inhibited by mevinolin (Ki = 52 nM), but its activity was tripled when the parasite was chronically exposed to low doses of the drug. Parasites with increased reductase activity produced five to six times more eggs. Lastly, chronic administration of large doses of mevinolin to infected mice resulted in a marked reduction of the pathology associated with the infection. These results suggest that egg production in S. mansoni is associated with the parasite's HMG-CoA reductase activity and that a nonsterol lipid produced in the biochemical pathway regulated by this enzyme stimulates egg production.