Chloroquine Binds in the Cofactor Binding Site of Plasmodium falciparum Lactate Dehydrogenase – A Response

Abstract

Studies on the crystal structure of the complex formed between chloroquine (CQ) and Plasmodium falciparum lactate dehydrogenase (PfLDH) have recently been described by J.A. Read et al.1xChloroquine binds in the cofactor binding site of Plasmodium falciparum. Read, J.A. et al. J. Biol. Chem. 1999; 274: 10213–10218Crossref | PubMed | Scopus (33)See all References1, who also assessed the significance of this interaction in considering PfLDH as a target for structure-based design of novel antimalarials.While it is important to analyse the complex of antimalarial CQ with PfLDH, the use of these studies for developing antimalarials warrants caution: PfLDH is not found in the food vacuole of P. falciparum, which is the proposed site of action of CQ. CQ is unique with respect to P. falciparum because, owing to its weak base property, from nanomolar levels in the plasma, it becomes hyperconcentrated (to millimolar levels) in the food vacuole2xIdentification of the acidic compartment of Plasmodium falciparum-infected human erythrocytes as the target of the antimalarial drug chloroquine. Yayon, A. et al. EMBO J. 1984; 3: 2695–2700PubMedSee all References2. It is proposed that CQ exerts its effect in the food vacuole by forming a complex with heme that then either blocks the growing heme polymer3xA common mechanism for blockade of heme polymerization by antimalarial quinolines. Sullivan, D.J. Jr et al. J. Biol. Chem. 1998; 273: 31103–31107Crossref | PubMed | Scopus (110)See all References3 or the enzymatically4xInhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Slater, A.F.G. and Cerami, A. Nature. 1992; 355: 167–169Crossref | PubMed | Scopus (411)See all References4 or nonenzymatically5xQuinoline anti-malarial drugs inhibit spontaneous formation of beta-haematin (malaria pigment). Egan, T.J. et al. FEBS Lett. 1994; 352: 54–57Abstract | Full Text PDF | PubMed | Scopus (277)See all References, 6xMalarial haemozoin/beta-haematin supports haem polymerization in the absence of protein. Dorn, A. et al. Nature. 1995; 374: 269–271Crossref | PubMedSee all References mediated formation of hemozoin. It appears that the CQ mode of action is through heme.We also proposed that CQ inhibits heme-dependent protein synthesis in the parasite, which is an early event mediating the growth-inhibitory effects of the drug7xChloroquine inhibits heme-dependent protein synthesis in Plasmodium falciparum. Surolia, N. and Padmanaban, G. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 4786–4790Crossref | PubMedSee all References7. Thus, if PfLDH is absent from the food vacuole, then it may not be a primary target for CQ action. However, binding of CQ to PfLDH may be one of the several secondary events contributing to the mechanism of CQ action.