Heme detoxification

Wright AD, Wang H, Gurrath M, Kdnig GM, Kocak G, Neumann G, Loria P, Foley M, Tilley L (2001) Inhibition of Heme Detoxification Processes Underlies the Antimalarial Activity of Terpene Isonitrile Compounds from Marine Sponges. J Med Chem 44 873... 

Carney CK, Pasierb L, Wright DW. Heme detoxification in malaria a target rich environment. In Medicinal Inorganic Chemistry. Sessler JL, Doctrow SR, McMurry TJ, Lippard SJ, eds. 2005. American Chemical Society, Washington, DC. pp. 263-280. 

Interaction of marine isonitriles derivatives with heme was shown to inhibit the transformation of heme into / -hematin and then hemozoin, a polymer produced by Plasmodium in order to neutralize the toxic (detergent-like) free heme produced in the food vacuole. In addition, isonitriles were shown to prevent both the peroxidative and glutathione-mediated destruction of heme under conditions that mimic the environment within the malaria parasite. In summary, isonitriles, similarly to quinoline antimalarials [38], exert their antiplasmodial activity by preventing heme detoxification. 

Wright, A.D., Wang, H., Gurrath, M., Kdnig, G.M., Kocak, G., Neumann, G., Loria, P., Foley, M., and Tilley, L. (2001) Inhibition of heme detoxification processes underlies the antimalarial activity of terpene isonitrile compounds from marine sponges. I. Med. Chem., 44, 873-885. 

Heme Detoxification in Malaria A Target Rich Environment... 

Any perturbation of this heme-detoxification process that is unique to Plasmodium is expected to have drastic consequences for the parasite survival. The inhibition of heme aggregation is the targeted action of conventional quinoline based antimalarial drugs such as quinine, chlmnquine and mefloquine. 

The heme coordination polymer which results from the heme polymerase activity of the plasmodium parasite is an insoluble crystalline solid with prc ionate interheme links. How the quinine antimalarials inhibit heme polymerase and how this enzyme is associated with jS-hematin remain important, albeit poorly understood, aspects of this biochemistry. Furthermore, heme detoxification by malaria is the only currently recognized example of iron excretion. The homeostasis of iron is usually srictly controlled, and excess is usually stored in ferritin for subsequent... 

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