Mutations in the cytochrome b gene of Plasmodium berghei conferring resistance to atovaquone
Mutations in the cytochrome b gene of Plasmodium berghei conferring resistance to atovaquone
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DOI：
10.1016/s0166-6851(99)00148-6
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发表时间：
1999-11-30
影响因子：
1.5
通讯作者：
Marzuki, S
中科院分区：
文献类型：
--
作者：
Syafruddin, D;Siregar, JE;Marzuki, S
研究了疟原虫对辅酶Q类似物阿托伐醌耐药性的分子损伤。在药物剂量增加的情况下，在小鼠中长期繁殖后，分离出伯氏疟原虫ANKA株的耐药克隆，并对其细胞色素B基因进行测序。检测到三个突变，在nt 431处的T-C取代，在nt 399处的G-A和在nt 850处的G-T，导致推定的细胞色素B产物中残基133、144和284处的氨基酸变化。V284 F氨基酸变化在蛋白质的第六跨膜螺旋中，并且在所有抗性克隆中观察到。在膜外两亲性螺旋的Q（o）位点内的额外的M133 I或L144 S氨基酸变化显著增加对阿托伐醌的抗性。我们的研究结果（a）提供了阿托伐醌的抗疟活性确实涉及与细胞色素B的相互作用的证据;（B）将阿托伐醌定义为细胞色素bc（1）复合物的泛醇氧化酶活性的抑制剂;（c）定义哺乳动物细胞色素B中的氨基酸残基，这可能是决定其对阿托伐醌的相对抗性的关键。(C)1999 Elsevier Science B. V.保留所有权利。
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 Q(o) 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 bc(1) complex; and (c) define amino acid residues in the mammalian cytochrome b which might be critical in determining its relative resistance to atovaquone. (C) 1999 Elsevier Science B.V. All rights reserved.