Thioredoxin glutathione reductase-dependent redox networks in platyhelminth parasites.
CONCLUSIONS
Platyhelminth parasites cause chronic infections that are a major cause of disability, mortality, and economic losses in developing countries. Maintaining redox homeostasis is a major adaptive problem faced by parasites and its disruption can shift the biochemical balance toward the host. Platyhelminth parasites possess a streamlined thiol-based redox system in which a single enzyme, thioredoxin glutathione reductase (TGR), a fusion of a glutaredoxin (Grx) domain to canonical thioredoxin reductase (TR) domains, supplies electrons to oxidized glutathione (GSSG) and thioredoxin (Trx). TGR has been validated as a drug target for schistosomiasis.


BACKGROUND
In addition to glutathione (GSH) and Trx reduction, TGR supports GSH-independent deglutathionylation conferring an additional advantage to the TGR redox array. Biochemical and structural studies have shown that the TR activity does not require the Grx domain, while the glutathione reductase and deglutathionylase activities depend on the Grx domain, which receives electrons from the TR domains. The search for TGR inhibitors has identified promising drug leads, notably oxadiazole N-oxides.


RESULTS
A conspicuous feature of platyhelminth TGRs is that their Grx-dependent activities are temporarily inhibited at high GSSG concentrations. The mechanism underlying the phenomenon and its biological relevance are not completely understood.


CONCLUSIONS
The functional diversity of Trxs and Grxs encoded in platyhelminth genomes remains to be further assessed to thoroughly understand the TGR-dependent redox network. Optimization of TGR inhibitors and identification of compounds targeting other parasite redox enzymes are good options to clinically develop relevant drugs for these neglected, but important diseases.
Department of Immunology-Microbiology, Rush University Medical Center, Chicago, IL 60612, USA. david_l_williams@rush.edu
David L
DL
Williams
Mariana
M
Bonilla
Vadim N
VN
Gladyshev
Gustavo
G
Salinas
D000818:Animals; D002590:Cestode Infections / Q000276:immunology / Q000469:parasitology*; D015801:Helminth Proteins / Q000378:metabolism*; D006790:Host-Parasite Interactions; D006801:Humans; D053858:Metabolic Networks and Pathways; D009097:Multienzyme Complexes / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010986:Platyhelminths / Q000201:enzymology* / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism
D015801:Helminth Proteins; D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase