Vaidya A B, Lashgari M S, Pologe L G, Morrisey J
Department of Microbiology and Immunology, Hahnemann University, Philadelphia, PA 19102-1192.
Mol Biochem Parasitol. 1993 Mar;58(1):33-42. doi: 10.1016/0166-6851(93)90088-f.
Appropriate functioning of mitochondria is critical for survival and growth of erythrocytic stages of malarial parasites, making it an attractive target for antimalarial drugs which may take advantage of unique features of parasite mitochondrial metabolism. We have sequenced the presumptive mitochondrial DNA, the 6-kb element, of Plasmodium falciparum, permitting an analysis of the predicted structure of parasite electron transport proteins. Although the overall structures of the 3 polypeptides, cytochrome c oxidase subunit 1, cytochrome c oxidase subunit 3, and cytochrome b (cyt b), were similar to those from other species, some striking differences were observed, especially for the cyt b. Analysis of the cyt b structure showed that the critical quinone binding sites of the protein are quite divergent from those of other species. Comparative analysis suggests that these changes are the likely cause for the resistance of parasite cytochrome bc1 complex to antimycin and related inhibitors. We suggest that the same features are responsible for increased affinity of the parasite cyt b for antimalarial compounds of class 8-aminoquinolines and hydroxynaphthoquinones, explaining the therapeutic value of these drugs.
疟原虫红细胞阶段的线粒体正常功能对于其生存和生长至关重要，这使其成为抗疟药物的一个有吸引力的靶点，这些药物可能会利用寄生虫线粒体代谢的独特特征。我们已经对恶性疟原虫的推测性线粒体DNA（6-kb元件）进行了测序，从而能够分析寄生虫电子传递蛋白的预测结构。虽然细胞色素c氧化酶亚基1、细胞色素c氧化酶亚基3和细胞色素b（cyt b）这三种多肽的总体结构与其他物种的相似，但也观察到了一些显著差异，尤其是细胞色素b。对细胞色素b结构的分析表明，该蛋白的关键醌结合位点与其他物种的有很大不同。比较分析表明，这些变化可能是寄生虫细胞色素bc1复合物对抗霉素和相关抑制剂产生抗性的原因。我们认为，同样的特征导致寄生虫细胞色素b对8-氨基喹啉类和羟基萘醌类抗疟化合物的亲和力增加，这解释了这些药物的治疗价值。
