Lux H, Heise N, Klenner T, Hart D, Opperdoes F R
Infection and Immunity Research Group, Division of Life Sciences, King's College London, London SEI 8WA, UK.
Mol Biochem Parasitol. 2000 Nov;111(1):1-14. doi: 10.1016/s0166-6851(00)00278-4.
Ether-lipid (alkyl-phospholipid) analogues such as Miltefosine possess potent in vitro and in vivo anti-leishmanial activity and these compounds are currently undergoing clinical trials in humans. These analogues are also effective against Trypanosoma cruzi and Trypanosoma brucei subspecies but their mode of action is not known. Leishmania have high levels of ether-lipids and these are mainly found in the glycosylphosphatidylinositol-anchored glycolipids and glycoproteins present on the surface of the parasites. In Leishmania mexicana promastigotes we have studied both the initiating steps for the biosynthesis of ether-lipids, and key remodelling steps. The effect of Miltefosine and Edelfosine, on key enzymes involved in the metabolism of ether-lipids has been studied. The enzymes include dihydroxyacetonephosphate acyltransferase, sn-l-acyl-2-lyso-glycero-3-phosphocholine and sn-l-alkyl-2-lyso-glycero-3-phosphocholine acyltransferases. We confirm that the initiating steps in ether-lipid metabolism in Leishmania are present in glycosomes, and that Miltefosine or Edelfosine did not perturb these enzymes. The metabolism of the latter phosphatidylcholine base intermediates, which may be involved in the remodelling of acyl- and alkyl-glycerophospholipids, was also seemingly associated with glycosomes. Both Miltefosine and Edelfosine inhibited this microbody (glycosomal) located alkyl-specific-acyl-CoA acyltransferase in a dose-dependent manner with an inhibitory concentration of 50 microM. It is suggested therefore that a perturbation of ether-lipid remodelling could be responsible for the anti-leishmanial action of these drugs.
醚脂（烷基磷脂）类似物，如米替福新，具有强大的体外和体内抗利什曼原虫活性，目前这些化合物正在进行人体临床试验。这些类似物对克氏锥虫和布氏锥虫亚种也有效，但它们的作用方式尚不清楚。利什曼原虫含有高水平的醚脂，主要存在于寄生虫表面的糖基磷脂酰肌醇锚定糖脂和糖蛋白中。在墨西哥利什曼原虫前鞭毛体中，我们研究了醚脂生物合成的起始步骤和关键重塑步骤。研究了米替福新和依地福新对醚脂代谢中关键酶的影响。这些酶包括磷酸二羟丙酮酰基转移酶、sn-1-酰基-2-溶血甘油-3-磷酸胆碱和sn-1-烷基-2-溶血甘油-3-磷酸胆碱酰基转移酶。我们证实利什曼原虫醚脂代谢的起始步骤存在于糖体中，米替福新或依地福新不会干扰这些酶。后一种磷脂胆碱碱基中间体的代谢可能参与酰基和烷基甘油磷脂的重塑，似乎也与糖体有关。米替福新和依地福新都以剂量依赖的方式抑制这种位于微体（糖体）中的烷基特异性酰基辅酶A酰基转移酶，抑制浓度为50微摩尔。因此，有人认为醚脂重塑的扰动可能是这些药物抗利什曼原虫作用的原因。
