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Malaria: Apicoplast and new therapeutic drug targets
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6.10.08
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This cellular organelle may possibly form a binding site for new drugs. Various metabolic reaction chains are present in this organelle. In 1998 it was demonstrated that in some Apicomplexa the “shikimate pathway” is present. The name “shikimate” comes from “shikimi no ki”, the Japanese name for star aniseed (Illicium religiosum), from which shikimic acid was first isolated. The shikimate pathway is a biochemical reaction chain which occurs in algae, higher plants, fungi and various micro-organisms. It does not occur in mammals, however. It is important for the synthesis of aromatic amino acids such as phenylalanine, tyrosine and tryptophan, as well as for the production of ubiquinone and other substances. In the Apicomplexa it possibly supplies folic acid precursors which are needed for growth. The herbicide glyphosate (“Round-up”) is a known inhibitor of an enzyme from this reaction chain and can block the growth of parasites. It also appears that the apicoplast synthesises isoprenoids in a manner which clearly differs from that of mammals. Isoprenoids are used for the production of cholesterol, steroid hormones, coenzyme Q and for enzyme prenylation. Humans synthesise these substances via what is called the “mevalonate pathway”, known as a target for cholesterol-lowering substances such as HMG-CoA reductase inhibitors (statins, e.g. simvastatin = Zocor®). The apicoplast on the other hand, uses what is called the “methylerythritol or DOXP pathway” (1-deoxy-D-xylulose-5-phosphate). Fosmidomycin is a substance which actively blocks these reaction chains in P. falciparum. It is hoped that better knowledge of the biochemical details will lead to new therapeutic products for the treatment of, for example, toxoplasmosis, cryptosporidiosis and malaria.
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