A physiochemical mechanism of hemozoin (beta-hematin) synthesis by malaria parasite.
Malaria parasite homogenate, the lipid extracts, and an unsaturated fatty acid, linoleic acid, which have been shown to promote beta-hematin formation in vitro, were used to investigate the mechanism of hemozoin biosynthesis, a distinct metabolic function of the malaria parasite. In vitro beta-hematin formation promoted by Plasmodium yoelii homogenate, the lipid extracts, and linoleic acid were blocked by ascorbic acid, reduced glutathione, sodium dithionite, beta-mercaptoethanol, dithiothreitol, and superoxide dismutase. Oxidized glutathione did not show any effect. Preoxidized preparations of the lipids extracts or the P. yoelii homogenate failed to catalyze beta-hematin formation. Depletion of oxygen in the reaction mixtures also inhibited the lipid-catalyzed beta-hematin formation. Under the reaction conditions similar to those used for the in vitro beta-hematin formation assay, the antioxidants and reducing agents mentioned above, except the DTT and beta-mercaptoethanol, did not cause degradation of heme. beta-Hematin formation was also inhibited by p-aminophenol, a free radical chain reaction breaker. Hemozoin biosynthesis within the digestive vacuoles of the malaria parasite may be a lipid-catalyzed physiochemical reaction. An oxidative mechanism may be proposed for lipid-mediated beta-hematin formation, which may be mediated by generation of some free radical intermediates of heme.
Tripathi
Abhai K
AK
Division of Biochemistry, Central Drug Research Institute, Lucknow-226001 (UP), India.
Garg
Satyendra K
SK
Tekwani
Babu L
BL
D000627:Aminophenols / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D004227:Dithionite / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D005609:Free Radicals; D005978:Glutathione / Q000494:pharmacology; D006418:Heme / Q000378:metabolism; D006420:Hemeproteins / Q000096:biosynthesis* / Q000737:chemistry*; D006427:Hemin / Q000378:metabolism; D019787:Linoleic Acid / Q000378:metabolism; D050356:Lipid Metabolism; D008288:Malaria / Q000378:metabolism; D008623:Mercaptoethanol / Q000494:pharmacology; D051379:Mice; D008956:Models, Chemical; D010100:Oxygen / Q000378:metabolism; D010967:Plasmodium yoelii / Q000378:metabolism*; D019163:Reducing Agents / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology; D013696:Temperature; D017962:alpha-Linolenic Acid / Q000378:metabolism
D000627:Aminophenols; D000975:Antioxidants; D005609:Free Radicals; D006420:Hemeproteins; D019163:Reducing Agents; D017962:alpha-Linolenic Acid; D004227:Dithionite; C020753:hemozoin; D006418:Heme; D008623:Mercaptoethanol; D006427:Hemin; D019787:Linoleic Acid; D013482:Superoxide Dismutase; D005978:Glutathione; D010100:Oxygen; D004229:Dithiothreitol