Hematin-Hematin Self-Association States Involved in the Formation and Reactivity of the Malaria Parasite Pigment, Hemozoin

被引:47
作者
Klonis, Nectarios [1 ,2 ]
Dilanian, Ruben [2 ,3 ]
Hanssen, Eric [1 ,2 ]
Darmanin, Connie [2 ,4 ]
Streltsov, Victor [2 ,4 ]
Deed, Samantha [1 ,2 ]
Quiney, Harry [2 ,3 ]
Tilley, Leann [1 ,2 ]
机构
[1] La Trobe Univ, La Trobe Inst Mol Sci, Melbourne, Vic 3086, Australia
[2] Univ Melbourne, ARC Ctr Excellence Coherent Xray Sci, Melbourne, Vic 3010, Australia
[3] Univ Melbourne, Sch Phys, Melbourne, Vic 3010, Australia
[4] CSIRO, Melbourne, Vic, Australia
基金
英国医学研究理事会; 澳大利亚研究理事会;
关键词
PLASMODIUM-FALCIPARUM; FOOD VACUOLE; BETA-HEMATIN; FERRIPROTOPORPHYRIN-IX; ANTIMALARIAL ACTIVITY; HEME POLYMERIZATION; OXIDATIVE STRESS; HAEMOZOIN; IRON; CHLOROQUINE;
D O I
10.1021/bi100567j
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The malaria parasite pigment, hemozoin, is a crystal of ferriprotoporphyrin IX (FP-Fe(III)), a product of hemoglobin digestion. Hemozoin formation is essential for FP-Fe(III) detoxification in the parasite; it is the main target of quinoline antimalarials and can modulate immune and inflammation responses. To gain further insight into the likely mechanisms of crystal formation and hemozoin reactivity, we have reanalyzed the crystal structure data for beta-hematin and solved the crystal structure of Plasmodium falciparum hemozoin. The analysis reveals that the structures are very similar and highlights two previously unexplored modes of FP-Fe(III) self-association involving pi-pi interactions that may initiate crystal formation and help to stabilize the extended structure. Hemozoin can be considered to be a crystal composed of pi-pi: dimers stabilized by iron-carboxylate linkages. As a result, it is predicted that two surfaces of the crystal would consist of pi-pi dimers with Fe(III) partly exposed to solvent and capable of undergoing redox reactions. Accordingly, we demonstrate that the crystal possesses both general peroxidase activity and the ability to cause lipid oxidation.
引用
收藏
页码:6804 / 6811
页数:8
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