Growth of Cryptococcus neoformans was inhibited by nine nitrogen and sulfur-containing sterols with a heteroatom positioned at C3, C7, C24, C25 or C32 in the lanostane frame. Analysis of the sterol composition of control and treated cells by GC-MS and (1)H NMR has proven that the C-methylation reaction catalyzed by the sterol 24-C-methyltransferase (24-SMT) is the crucial first step in a kinetically favored pathway that fails to include obtusifoliol or zymosterol as intermediates. Cultures fed [methyl-(2)H(3)]methionine led to two deuterium atoms into each of the newly biosynthesized sterols forming a route lanosterol, eburicol (24(28)-methylene-24,25-dihydrolanosterol), 32-noreburicol and ergost-7-enol to ergosterol. Examination of the substrate specificity of a soluble 24-SMT from C. neoformans showed lanosterol to be the optimal acceptor molecule. Incubation with the test compounds generated induced amounts of lanosterol, eburicol or 32-noreburicol concurrent with a decrease of ergosterol. Among them 24(R,S),25-epiminolanosterol (inhibitor of 24-SMT) showed the most potent in vitro antifungal activity comparable to those of itraconazole (inhibitor of the 14-demethylase). Taken together, these data indicate that treatment with substrate-based inhibitors of 24-SMT, a catalyst not found in humans, can disrupt ergosterol homeostasis involved with fungal growth and therefore these compounds can provide leads for rational drug design of opportunistic pathogens.

译文

新隐球菌的生长被九种含氮和硫的固醇抑制,其杂原子位于羊毛烷框架中的C3,C7,C24,C25或C32。通过gc-ms和 (1)H NMR分析对照和处理过的细胞的固醇组成已证明,由固醇24-C-甲基转移酶 (24-SMT) 催化的C-甲基化反应是至关重要的第一步。动力学上偏爱的途径未能包括obtusifoolol或zymosterol作为中间体。饲喂 [甲基-(2)H(3)] 甲硫氨酸的培养物导致两个氘原子进入每个新生物合成的甾醇中,形成途径羊毛甾醇,伊布里考 (24(28)-亚甲基-24,25-二氢羊毛甾醇),32-去甲纤维醇和ergost-7-enol麦角固醇。对来自新孢子虫的可溶性24-smt的底物特异性的检查表明,羊毛甾醇是最佳受体分子。与测试化合物一起孵育会产生诱导量的羊毛甾醇,埃布里考或32-去甲布里考,同时麦角固醇降低。其中24(R,S),25-表氨基醇 (24-smt抑制剂) 显示出与伊曲康唑 (14-脱甲基酶抑制剂) 相当的最有效的体外抗真菌活性。综上所述,这些数据表明,用基于底物的24-SMT抑制剂 (一种在人类中未发现的催化剂) 治疗可以破坏与真菌生长有关的麦角固醇稳态,因此这些化合物可以为机会性病原体的合理药物设计提供线索。

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