Hemozoin

Haemozoin is a disposal product formed from the digestion of

Later, in 1891, T. Carbone and W.H. Brown (1911) published papers linking the hemoglobin degradation with pigment production, describing the malaria pigment as a form of hematin and disproving the widely held idea that it is related to melanin. Brown observed that all melanins were bleaching rapidly with potassium permanganate, while with this reagent malarial pigment manifests not the slightest sign of a true bleach reaction.^[5][6] The name "hemozoin" was proposed by Louis Westenra Sambon.^[7] In the 1930s several authors identified hemozoin as a pure crystalline form of α-hematin and showed that the substance did not contain proteins within the crystals,^[4] but no explanation for the solubility differences between malaria pigment and α-hematin crystals was given.^{[citation needed]}

Formation

During its intraerythrocytic asexual reproduction cycle Plasmodium falciparum consumes up to 80% of the host cell

Several mechanisms have been proposed for the production of hemozoin in Plasmodium, and the area is highly controversial, with membrane lipids,^[17][18] histidine-rich proteins,^[19] or even a combination of the two,^[20] being proposed to catalyse the formation of hemozoin. Other authors have described a heme detoxification protein, which is claimed to be more potent than either lipids or histidine-rich proteins.^[12] It is possible that many processes contribute to the formation of hemozoin.^[21] The formation of hemozoin in other blood-feeding organisms is not as well-studied as in Plasmodium.^[22] However, studies on Schistosoma mansoni have revealed that this parasitic worm produces large amounts of hemozoin during its growth in the human bloodstream. Although the shapes of the crystals are different from those produced by malaria parasites,^[23] chemical analysis of the pigment showed that it is made of hemozoin.^[24][25] In a similar manner, the crystals formed in the gut of the kissing bug Rhodnius prolixus during digestion of the blood meal also have a unique shape, but are composed of hemozoin.^[26] Hz formation in R. prolixus midgut occurs at physiologically relevant physico-chemical conditions and lipids play an important role in heme biocrystallization. Autocatalytic heme crystallization to Hz is revealed to be an inefficient process and this conversion is further reduced as the Hz concentration increases.^[27]

Several other mechanisms have been developed to protect a large variety of

Although β-hematin can be produced in assays spontaneously at low pH, the development of a simple and reliable method to measure the production of hemozoin has been difficult. This is in part due to the continued uncertainty over what molecules are involved in producing hemozoin, and partly from the difficulty in measuring the difference between aggregated or precipitated heme, and genuine hemozoin.^[29] Current assays are sensitive and accurate, but require multiple washing steps so are slow and not ideal for high-throughput screening.^[29] However, some screens have been performed with these assays.^[30]

Structure

β-Hematin crystals are made of

Hemozoin formation is an excellent drug target, since it is essential to malaria parasite survival and absent from the human host. The drug target hematin is host-derived and largely outside the genetic control of the parasite, which makes the development of drug resistance more difficult. Many clinically used drugs are thought to act by inhibiting the formation of hemozoin in the food vacuole.^[37] This prevents the detoxification of the heme released in this compartment, and kills the parasite.^[38]

The best-understood examples of such hematin biocrystallization inhibitors are quinoline drugs such as chloroquine and mefloquine. These drugs bind to both free heme and hemozoin crystals,^[39] and therefore block the addition of new heme units onto the growing crystals. The small, most rapidly growing face is the face to which inhibitors are believed to bind.^[40][41]

Role in pathophysiology

Hemozoin is released into the circulation during reinfection and phagocytosed in vivo and in vitro by host phagocytes and alters important functions in those cells. Most functional alterations were long-term postphagocytic effects,^[42][43] including erythropoiesis inhibition shown in vitro.^[44][45][46] In contrast, a powerful, short-term stimulation of oxidative burst by human monocytes was also shown to occur during phagocytosis of nHZ.^[47] Lipid peroxidation non-enzymatically catalysed by hemozoin iron was described in immune cells.^[48][49] Lipoperoxidation products, as hydroxyeicosatetraenoic acids (HETEs) and 4-hydroxynonenal (4-HNE), are functionally involved in immunomodulation.^{[43][46][49][50][51]}

See also

• Biocrystallization
• Drug discovery
• History of malaria
• Parasitic diseases

References