Bhisutthibhan J, Pan X Q, Hossler P A, Walker D J, Yowell C A, Carlton J, Dame J B, Meshnick S R
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan 48109-2029, USA.
J Biol Chem. 1998 Jun 26;273(26):16192-8. doi: 10.1074/jbc.273.26.16192.
Artemisinin and its derivatives are important new antimalarial drugs. When Plasmodium falciparum-infected erythrocytes are incubated with [10-3H]dihydroartemisinin, several malaria-specific proteins become labeled. One of these proteins is the P. falciparum translationally controlled tumor protein (TCTP) homolog. In vitro, dihydroartemisinin reacts covalently with recombinant TCTP in the presence of hemin. The association between drug and protein increases with increasing drug concentration, plateauing at approximately 1 drug/TCTP molecule. By Scatchard analysis, there appear to be 2 hemin binding sites on TCTP with dissociation constants of approximately 18 microM. When the single cysteine moiety is blocked by pretreatment with iodoacetamide, hemin binding is not affected, whereas drug binding is reduced by two-thirds. Thus, TCTP reacts with artemisinin in situ and in vitro in the presence of hemin and appears to bind to hemin. The function of the malarial TCTP and the role of this reaction in the mechanism of action of artemisinin await elucidation.
青蒿素及其衍生物是重要的新型抗疟药物。当用[10 - 3H]二氢青蒿素孵育恶性疟原虫感染的红细胞时，几种疟疾特异性蛋白会被标记。其中一种蛋白是恶性疟原虫翻译控制肿瘤蛋白（TCTP）的同源物。在体外，二氢青蒿素在血红素存在下与重组TCTP发生共价反应。药物与蛋白之间的结合随着药物浓度的增加而增加，在大约1个药物/TCTP分子时达到平稳。通过Scatchard分析，TCTP上似乎有2个血红素结合位点，解离常数约为18微摩尔。当用碘乙酰胺预处理使单个半胱氨酸部分被阻断时，血红素结合不受影响，而药物结合减少三分之二。因此，TCTP在血红素存在下在体内和体外与青蒿素发生反应，并且似乎与血红素结合。疟原虫TCTP的功能以及该反应在青蒿素作用机制中的作用有待阐明。
