Hemozoin

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Hemozoin , and malaria - pigment called, is produced in the digestion of hemoglobin by the malaria parasite Plasmodium falciparum in its asexual reproductive cycle intraerythrozytischen.

Emergence

Unlike most infectious diseases , malaria is not caused by viruses or bacteria , but by parasites . After infection by the mosquito Anopheles, the parasites first attack the hepathocytes and then the red blood cells . They digest the hemoglobin within their approximately 48-hour reproductive cycle; About 75% of the erythrocytic hemoglobin is broken down by the parasite. By hydrolysis of the parasite gains from amino acids for its own metabolism, at the same time but also creates free heme , which is toxic to both the host and the parasite. As the decomposition of hemoglobin progresses, a measure against this toxin becomes necessary. Since the parasite has no heme oxygenase activity, it converts the heme into insoluble crystalline hemozoin with the help of the heme detoxification protein (HDP) in the vacuoles of the erythrocytes. A lot about this process is still unknown and is the subject of research (as of 2020), but the protein differs in many ways from all other proteins of the Plasmodium: It can neither be modified nor broken down into functional components. HDP converts in an acidic environment, is thermostable and also the most efficient known hemozoin-forming protein. Its path into the vacuole of the erythrocytes via cellular transport vesicles is also unique and cannot be blocked. Its molecular mass and position in the vacuole are also not yet known.

After a few cycles, the dark spots characteristic of malaria form within the infected cell. At various stages of development in the body, the parasites contain traces of the pigment; It enables medical professionals to make a relatively quick light microscopic diagnosis, because the parasite contains the pigment at all stages of its development. It is not possible to determine the location of this biocrystallization ; only statements can be made about the storage location of the end product. Some researchers postulate that the process already begins in the transport vesicles, the proof of this assumption is still pending.

The actual process of conversion has not yet been researched well enough and is controversial, but it is widely considered to be the parasites' greatest weakness. A drug that attacks these factors and thus combats malaria has not yet been developed and the modes of action of common drugs such as chloroquine are not yet fully understood. It is now clear, however, that the accumulation of hemozoin by blocking the release of pyrogenic cytokines , such as TNF , is responsible for the characteristic fever attacks and malaria anemia .

discovery

In 1847, a black-brown pigment by JF Meckel was observed in the blood and spleen of a patient. Long after its discovery, it was controversial as the malaria pigment. Even after much recorded research on numerous patients, it was not definitively proven where the pigment came from. The connection to malaria was quickly established around 1850, but for a long time it was believed that the body itself produced this pigment as a reaction to the disease. After the malaria parasites were discovered, it was assumed that hemozoin was a melanin . In 1880 it turned out that the malaria pigment is instead produced by the parasites themselves as they multiply in the erythrocytes. Because of the differences between hemozoin and melanin in terms of solubility and reactions to bleaching within many experiments, the outdated view was eventually abandoned. In 1891, T. Carbone and WH Brown published a paper which linked the breakdown of hemoglobin with the production of the pigment and described the malaria pigment as a form of hematin . In the 1930s, several authors presented hemozoin as the pure crystalline form of α-hematin and showed that the crystals did not contain any proteins. An explanation for the different solution properties between the malaria pigment and the α-hematin crystals was not found at this time. There followed numerous, predominantly Indian studies, which for the first time looked at the pigment detached from the parasites. Due to the researchers' drastic isolation processes , the results were falsified and confirmed the great similarity to hematin. This view persisted for years until the falsification of the results came to light. Since then, hemozoin has been viewed as a waste product of a decomposed hemoglobin molecule. Even today, neither the malaria pigment nor its formation nor the function of the proteins involved are sufficiently understood, but they are viewed as a very promising therapeutic approach.

structure

The generally accepted structural model has a central high-spin iron in the middle of a porphyrin ring . The carboxy group of the propionyl radical forms a weak bond with the neighboring ring. Furthermore, hydrogen bonds between free propionyl radicals are considered likely. The resulting polymeric β-hematin grows in length as many of these individual heme disks are stacked on top of one another to form a pseudocrystal. The structure itself makes the hemozoin difficult to break down and the proteins do not play into the stability. Before agreeing on a structure, the structure of hemozoin was discussed for a long time; for example, Claude Brémard proposed the monomeric high-spin ferriporphyrin model in 1993.

Inhibition

The formation of hemozoin is a good approach to therapy development. If the protein hematin, which is beyond the control of the parasite, is stopped, the formation of hemozoin is prevented and the toxic heme is not broken down. Many drugs that have already been used aim to prevent the formation of hemozoin by inhibition and thus kill the parasites. The best understood drugs with hematin biocrystallization inhibitors are quinolines, such as chloroquine (a quinine derivative ) and mefloquine . They bind the free heme and the hemozoin crystals and thus prevent additional units from docking.

Individual evidence

  1. ↑ a b c d e f g h i Electron microscopic examinations on the question of the intraerythrocytic iron distribution in the context of the initial hemozoin formation in malaria tropica. Dissertation .
  2. ↑ a b c d e f g h Alessandro Esposito, Teresa Tiffert, Jakob MA Mauritz, Simon Schlachter, Lawrence H. Bannister, Clemens F. Kaminski, Virgilio L. Lew: FRET Imaging of Hemoglobin Concentration in Plasmodium falciparum-Infected Red Cells . In: PLoS ONE . tape 3 , no. 11 , November 21, 2008, p. e3780 , doi : 10.1371 / journal.pone.0003780 ( PDF ).
  3. ↑ a b c d e f g h i j Malaria pigment hemozoin and the functional inhibition of monocytes. Habilitation thesis .
  4. ↑ a b c d Daniel E. Goldberg: Complex nature of malaria parasite hemoglobin degradation . In: Proceedings of the National Academy of Sciences . tape 110 , no. 14 , April 2, 2013, p. 5283-5284 , doi : 10.1073 / pnas.1303299110 ( PDF ).
  5. ↑ H. Meckel von Helmsbach: About black pigment in the spleen and the blood of a mentally ill . In: Allg. Z. Psychiatry Psy.-judicial. Medicine . tape 4 , 1847, p. 198-226 .
  6. ↑ a b c W. H. Brown: Malarial Pigment (so-called Melanin): Its Nature and Mode of Production . In: Journal of Experimental Medicine . tape 13 , no. 2 , February 1911, p. 290–299 , doi : 10.1084 / jem.13.2.290 ( PDF ).
  7. ↑ a b c d e Theodor von Brand: Glimpses at the Early Days of Parasite Biochemistry. In: H. Van den Bossche (Ed.): Comparative Biochemistry of Parasites. Academic Press, New York / London 1972, ISBN 0-12-711050-X , pp. 9-11.
  8. ↑ T. Carbone: Sulla natura chimica del pigmento malarico. In: GR Accad Med Torino. 39, 1891, pp. 901-906.
  9. ↑ a b J. A. Sinton, BN Ghosh: Studies of malarial pigment (hemozoin). Part I. Investigation of the action of solvents on haemozoin and the spectroscopic appearances observed in the solutions. In: Records of the malaria survey of India. 4, 1934, pp. 15-42.4.