Hematin-hematin self-association states involved in the formation and reactivity of the malaria parasite pigment, hemozoin.
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.
Klonis
Nectarios
N
La Trobe Institute of Molecular Science, La Trobe University, Melbourne 3086, Australia.
Dilanian
Ruben
R
Hanssen
Eric
E
Darmanin
Connie
C
Streltsov
Victor
V
Deed
Samantha
S
Quiney
Harry
H
Tilley
Leann
L
D000818:Animals; D003460:Crystallization; D018360:Crystallography, X-Ray; D006420:Hemeproteins / Q000737:chemistry* / Q000502:physiology; D015227:Lipid Peroxidation; D010544:Peroxidases; D010860:Pigments, Biological; D010963:Plasmodium falciparum / Q000737:chemistry*; D055503:Protein Multimerization
D006420:Hemeproteins; D010860:Pigments, Biological; C020753:hemozoin; D010544:Peroxidases