HEMOGLOBIN METABOLISM IN THE MALARIA PARASITEPLASMODIUM FALCIPARUM

Abstract

Hemoglobin degradation in intraerythrocytic malaria parasites is a vast process that occurs in an acidic digestive vacuole. Proteases that participate in this catabolic pathway have been defined. Studies of protease biosynthesis have revealed unusual targeting and activation mechanisms. Oxygen radicals and heme are released during proteolysis and must be detoxified by dismutation and polymerization, respectively. The quinoline antimalarials appear to act by preventing sequestration of this toxic heme. Understanding the disposition of hemoglobin has allowed identification of essential processes and metabolic weakpoints that can be exploited to combat this scourge of mankind.

A Multi-enzyme Cascade of Hemoglobin Proteolysis in the Intestine of Blood-feeding Hookworms

“…Plasmepsin I, like hookworm APR-1, cleaves the Hb tetramer at the hinge region, unraveling the molecule for subsequent enzymatic proteolysis (1). Plasmepsin II is capable of digesting native Hb but is more active against denatured or fragmented globin such as that produced by the action of plasmepsin I (34). In addition to Na-APR-1, we identified a second aspartic protease from the human hookworm, N. americanus, Na-APR-2; APR-2 was most similar to a family of nematodespecific aspartic proteases, termed nemepsins (19).…”

Macrophage populations of different origins have distinct susceptibilities to lipid peroxidation induced by β‐haematin (malaria pigment)

“…of malaria-infected patients contain granules of pigment known as haemozoin (malaria pigment), as a result of the ingestion of intraerythrocytic malaria parasites, residual bodies (the remnant of a parasite after schizont rupture) or possibly free haemozoin [1][2][3]. Haemozoin a polymer of haem units (ferriprotoporphyrin IX, Fe(III)-PPIX) linked through an iron carboxylate bridge [1] appears to contribute to the production of inflammatory cytokines, such as TNFc~ or IL6, during acute malaria attacks [4][5][6]. Accumulation of pigment inside macrophages has also been shown to impair macrophage activation and functions.…”

Macrophage Preconditioning with Synthetic Malaria Pigment Reduces Cytokine Production via Heme Iron-Dependent Oxidative Stress

“…This study may help correlate the different clinical manifestations of malaria, ranging from uncomplicated to severe disease, with dysregulation of phagocyte functions and promote better therapeutic strategies to counteract the effects of hemozoin accumulation. (Lab Invest 2000, 80:1781-1788.I ntraerythrocytic stage plasmodia digest hemoglobin in the food vacuole, where the globin is degraded and heme is detoxified, principally by polymerization/crystallization into hemozoin, an insoluble, microcrystalline derivative of ferri-protoporphyrin IX (␣ hematin, AH) (Bohle et al, 1997;Francis et al, 1997;Pagola et al, 2000;Slater et al, 1991). As parasites mature, hemozoin (malaria pigment) accumulates in the food vacuole and remains in the "residual body" after schizont rupture.…”