Glutathione and trypanothione in parasitic hydroperoxide metabolism.
Thiol-dependent hydroperoxide metabolism in parasites is reviewed in respect to potential therapeutic strategies. The hydroperoxide metabolism of Crithidia fasciculata has been characterized to comprise a cascade of three enzymes, 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 terminal peroxidase of the system belongs to the protein family of peroxiredoxins which is also represented in Entamoeba and a variety of metazoan parasites. Plasmodial hydroperoxide metabolism displays similarities to the mammalian system in comprising glutathione biosynthesis, glutathione reductase, and at least one glutathione peroxidase homolog having the active site selenocysteine replaced by cysteine. Nothing precise is known about the antioxidant defence systems of Giardia, Toxoplasma, and Trichomonas species. Also, the role of ovothiols and mycothiols reportedly present in several parasites remains to be established. Scrutinizing known enzymes of parasitic antioxidant defence for suitability as drug targets leaves only those of the trypanosomatid system as directly or indirectly validated. By generally accepted criteria of target selection and feasibility considerations tryparedoxin and tryparedoxin peroxidase can at present be rated as the most appealing target structures for the development of antiparasitic drugs.
Flohé
L
L
Department of Biochemistry, Technical University of Braunschweig, Germany. lfl@gbf.de
Hecht
H J
HJ
Steinert
P
P
D000595:Amino Acid Sequence; D000818:Animals; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D016830:Kinetoplastida / Q000235:genetics / Q000378:metabolism; D008288:Malaria / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000378:metabolism; D010272:Parasitic Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000469:parasitology; D010544:Peroxidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism*; D054464:Peroxiredoxins; D015800:Protozoan Proteins; D017386:Sequence Homology, Amino Acid; D013095:Spermidine / Q000031:analogs & derivatives* / Q000378:metabolism; D013879:Thioredoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D010545:Peroxides; D015800:Protozoan Proteins; C114110:tryparedoxin; D013879:Thioredoxins; C044809:trypanothione; D010544:Peroxidases; C110959:tryparedoxin peroxidase; D054464:Peroxiredoxins; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005978:Glutathione; D013095:Spermidine