The trypanothione system and its implications in the therapy of trypanosomatid diseases.
Biosynthesis and the use of trypanothione, a redox metabolite of parasitic trypanosomatids, are reviewed here with special emphasis on the development of trypanocidal drugs. This metabolic system is unique to and essential for the protozoal parasites. Selective inhibition of key elements of trypanothione metabolism, therefore, promises eradication of the parasites without affecting the host. Considering the metabolic importance and drugability of system components, inhibition of the enzymes for regeneration and de novo synthesis of trypanothione is rated as the most promising approach, while related peroxidases and redoxins are disregarded as targets because of limited chances to achieve selective inhibition. The organizational need to exploit the accumulating knowledge of trypanosomatid metabolism for medical practice is briefly addressed.
Department of Chemistry, Otto-von-Guericke-Universität, Universitätsplatz 2, 39106 Magdeburg, Germany. l.flohe@t-online.de
Leopold
L
Flohé
D019732:Amide Synthases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055808:Drug Discovery / Q000379:methods; D056986:Euglenozoa Infections / Q000188:drug therapy* / Q000469:parasitology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013095:Spermidine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014351:Trypanosomatina / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
D015800:Protozoan Proteins; D014344:Trypanocidal Agents; C114110:tryparedoxin; D013879:Thioredoxins; C044809:trypanothione; D010544:Peroxidases; C110959:tryparedoxin peroxidase; D054464:Peroxiredoxins; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D019732:Amide Synthases; C064407:trypanothione synthetase; D005978:Glutathione; D013095:Spermidine