Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.
Curr Pharm Des. 2012;18(24):3480-9. doi: 10.2174/138161212801327266.
α-Lipoic acid (6,8-thioctic acid; LA) is a vital co-factor of α-ketoacid dehydrogenase complexes and the glycine cleavage system. In recent years it was shown that biosynthesis and salvage of LA in Plasmodium are necessary for the parasites to complete their complex life cycle. LA salvage requires two lipoic acid protein ligases (LplA1 and LplA2). LplA1 is confined to the mitochondrion while LplA2 is located in both the mitochondrion and the apicoplast. LplA1 exclusively uses salvaged LA and lipoylates α-ketoglutarate dehydrogenase, branched chain α-ketoacid dehydrogenase and the H-protein of the glycine cleavage system. LplA2 cannot compensate for the loss of LplA1 function during blood stage development suggesting a specific function for LplA2 that has yet to be elucidated. LA salvage is essential for the intra-erythrocytic and liver stage development of Plasmodium and thus offers great potential for future drug or vaccine development. LA biosynthesis, comprising octanoyl-acyl carrier protein (ACP) : protein N-octanoyltransferase (LipB) and lipoate synthase (LipA), is exclusively found in the apicoplast of Plasmodium where it generates LA de novo from octanoyl-ACP, provided by the type II fatty acid biosynthesis (FAS II) pathway also present in the organelle. LA is the co-factor of the acetyltransferase subunit of the apicoplast located pyruvate dehydrogenase (PDH), which generates acetyl-CoA, feeding into FAS II. LA biosynthesis is not vital for intra-erythrocytic development of Plasmodium, but the deletion of several genes encoding components of FAS II or PDH was detrimental for liver stage development of the parasites indirectly suggesting that the same applies to LA biosynthesis. These data provide strong evidence that LA salvage and biosynthesis are vital for different stages of Plasmodium development and offer potential for drug and vaccine design against malaria.
α-硫辛酸（6,8-硫代辛酸；LA）是α-酮酸脱氢酶复合物和甘氨酸裂解系统的重要辅酶。近年来的研究表明，疟原虫体内 LA 的生物合成和回收对于寄生虫完成其复杂的生命周期是必需的。LA 的回收需要两种硫辛酸蛋白连接酶（LplA1 和 LplA2）。LplA1 局限于线粒体，而 LplA2 则存在于线粒体和类质体中。LplA1 专门使用回收的 LA 和脂酰化α-酮戊二酸脱氢酶、支链α-酮酸脱氢酶和甘氨酸裂解系统的 H 蛋白。LplA2 不能补偿血期发育过程中 LplA1 功能的丧失，这表明 LplA2 具有尚未阐明的特定功能。LA 的回收对于疟原虫的红细胞内和肝期发育是必不可少的，因此为未来的药物或疫苗开发提供了巨大的潜力。LA 的生物合成，包括辛酰-酰基载体蛋白（ACP）：蛋白 N-辛酰转移酶（LipB）和脂酰合成酶（LipA），仅存在于疟原虫的类质体中，它从辛酰-ACP 中从头生成 LA，由同样存在于细胞器中的 II 型脂肪酸生物合成（FAS II）途径提供。LA 是位于类质体中的丙酮酸脱氢酶（PDH）乙酰基转移酶亚基的辅酶，它生成乙酰-CoA，进入 FAS II。LA 生物合成对于疟原虫的红细胞内发育不是必需的，但缺失编码 FAS II 或 PDH 组件的几个基因对寄生虫的肝期发育有害，这间接表明同样适用于 LA 生物合成。这些数据为 LA 回收和生物合成对于疟原虫不同发育阶段的重要性提供了强有力的证据，并为疟疾的药物和疫苗设计提供了潜力。
