Glutathione and trypanothione in parasitic hydroperoxide metabolism

Thiol-dependent hydroperoxide metabolism in parasites is reviewed in respec t to potential therapeutic strategies. The hydroperoxide- metabolism of Cri thidia fasciculata has been characterized to comprise a cascade of three en zymes, trypanothione reductase, tryparedoxin, and tryparedoxin peroxidase, plus two supportive enzymes to synthesize the redox mediator trypanothione from glutathione and spermidine. The essentiality of the system in respect to parasite vitality and virulence has been verified by genetic approaches. The system appears to be common to all genera of the Kinetoplastida. The t erminal peroxidase of the system belongs to the protein family of peroxired oxins which is also represented in Entamoeba and a variety of metazoan para sites. Plasmodial hydroperoxide metabolism displays similarities to the mam malian system in comprising glutathione biosynthesis, glutathione reductase , and at least one glutathione peroxidase homolog having the active site se lenocysteine replaced by cysteine. Nothing precise is known about the antio xidant defence systems of Giardia, Toxoplasma, and Trichomonas species. Als o, the role of ovothiols and mycothiols reportedly present in several paras ites remains to be established. Scrutinizing known enzymes of parasitic ant ioxidant defence for suitability as drug targets leaves only those of the t rypanosomatid system as directly or indirectly validated. By generally acce pted criteria of target selection and feasibility considerations tryparedox in and tryparedoxin peroxidase can at present be rated as the most appealin g target structures for the development of antiparasitic drugs. (C) 1999 El sevier Science Inc.