Comparative modeling of thioredoxin glutathione reductase from Schistosoma mansoni: A multifunctional target for antischistosomal therapy
Schistosoma mansoni, a trematode parasite, which causes schistosomiasis and affects more than 200 million people worldwide, lives in an aerobic environment and therefore needs an effective redox mechanism for surviving reactive oxygen species from its host. Although, the host has two different redox systems: glutaredoxin and thioredoxin, the parasite has only one unique multifunctional enzyme, thioredoxin glutathione reductase (TGR) involving a fusion of two proteins, glutaredoxin (Grx) and thioredoxin reductase (TR), for performing all the redox activities. This dependence of S. mansoni on a single protein, TGR, for its protection from oxidative stress, makes it a promising drug target. Here, we describe a suitably validated, homology model for S. mansoni TGR (SmTGR), developed using both TR and Grx templates, functionally complete in the dimeric form with cofactors NADP(H) and FAD. Comparative analysis of substrate and inhibitor binding pockets of our model with crystal structures of parent TR as well as with that of glutathione reductase (GR), which is an essential component of the Grx system, appears to provide greater insight into the functioning of TGR. This also augments recent observations reported on the basis of X-ray structure data on SmTGR monomer lacking the C-terminal selenocysteine tail.
who world health organization grx glutaredoxin trx thioredoxin gr glutathione reductase gsh glutathione gpx glutathione peroxidase gssg glutathione disulfide tr thioredoxin reductase tpx thioredoxin peroxidase sec selenocysteine motif tgr thioredoxin glutathione reductase smtgr schistosoma mansoni tgr fad flavin adenine dinucleotide nadp(h) nicotinamide adenine dinucleotide phosphate rms root mean square deviation ssm secondary structure method of superposition smd steered molecular dynamics