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伯氏疟原虫细胞色素b基因中赋予对阿托伐醌抗性的突变。

Mutations in the cytochrome b gene of Plasmodium berghei conferring resistance to atovaquone.

作者信息

Syafruddin D, Siregar J E, Marzuki S

机构信息

Eijkman Institute for Molecular Biology, Jakarta, Indonesia.

出版信息

Mol Biochem Parasitol. 1999 Nov 30;104(2):185-94. doi: 10.1016/s0166-6851(99)00148-6.

Abstract

The molecular lesions which underlie the resistance of the malaria parasites to atovaquone, a coenzyme Q analogue, were investigated. Resistant clones of Plasmodium berghei ANKA strain were isolated following prolonged propagation in mice in the presence of increasing doses of the drug, and their cytochrome b gene sequenced. Three mutations were detected, T-C substitution at nt 431, G-A at nt 399 and G-T at nt 850, resulting in amino acid changes in the putative cytochrome b product at residues 133, 144 and 284. The V284F amino acid change is in the sixth transmembrane helix of the protein and was observed in all resistant clones. An additional M133I or L144S amino acid change within the Qo site at an extramembranous amphipathic helix significantly increases the resistance to atovaquone. Our results (a) provide evidence that the antimalarial activity of atovaquone indeed involves an interaction with the cytochrome b; (b) define atovaquone as an inhibitor of the ubiquinol oxidase activity of the cytochrome bc1 complex; and (c) define amino acid residues in the mammalian cytochrome b which might be critical in determining its relative resistance to atovaquone.

摘要

对疟原虫对辅酶Q类似物阿托伐醌产生抗性的分子损伤进行了研究。在递增剂量药物存在的情况下,在小鼠体内长期传代后分离出伯氏疟原虫ANKA株的抗性克隆,并对其细胞色素b基因进行测序。检测到三个突变,分别为第431位核苷酸的T-C替换、第399位核苷酸的G-A替换和第850位核苷酸的G-T替换,导致假定的细胞色素b产物在第133、144和284位氨基酸发生变化。V284F氨基酸变化位于该蛋白的第六个跨膜螺旋中,在所有抗性克隆中均有观察到。在膜外两亲性螺旋的Qo位点内额外的M133I或L144S氨基酸变化显著增加了对阿托伐醌的抗性。我们的结果(a)提供了证据表明阿托伐醌的抗疟活性确实涉及与细胞色素b的相互作用;(b)将阿托伐醌定义为细胞色素bc1复合物泛醇氧化酶活性的抑制剂;(c)确定了哺乳动物细胞色素b中可能对确定其对阿托伐醌的相对抗性至关重要的氨基酸残基。

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