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Structural Analysis of the Charge Transfer Mechanism in Thioredoxin Glutathione ReductaseAuthors: Parshvika Sharma,Gopal Krishnan Bulusu,Abhijit Mitra Conference: The 3rd Indo-German Conference on Modeling Chemical & Biological Reactivity (MCBR3 2013) (MCBR3, February 2013 2013) Location NIPER, Mohali Date: 2013-02-26 Report no: IIIT/TR/2013/38 AbstractSchistosomiasis is a disease caused by a trematode parasite, Schistosoma mansoni. The host consists of two different redox systems: Glutaredoxin (Grx) and Thioredoxin (Trx), but the parasite has only one multifunctional enzyme Thioredoxin Glutathione Reductase (TGR), which is responsible for carrying out all the redox activities, necessary for protecting the parasite against oxidative stress inside the host. TGR is a fusion of Thioredoxin Reductase (TR) with Glutaredoxin (Grx) at its N-terminus. The dependence of S. mansoni on a single protein for all its redox functions makes it a potential drug target. We have carried out structural analysis of Glutathione Reductase (GR), Thioredoxin Reductase (TR) and Thioredoxin Glutathione Reductase (TGR) using available crystal structures from PDB to understand the catalytic mechanism in these oxidoreductases. NADPH plays a major role as an electron carrier and transfers the electrons to the oxidized cofactor, FAD, which is non-covalently attached to the enzyme. This initiates further steps of the catalytic process. Here, we investigate how the interplay of conformations of these cofactors and those of the neighbouring residues facilitate the charge transfer process. TR, GR and TGR share similarity in their respective active site regions. Several conserved residues and non covalent interactions, play a major role during the electron transfer process. We hypothesise the function of NADPH during the entire charge transfer process as follows: a Tyr residue moves and facilitates the binding of NADPH to FAD in pi-stacking conformation. Two Arg residues reorient to interact with 2'-phosphate group and adenine ring of NADPH for effective binding. Lys, Glu and His residues near the active site regions form salt bridges and possibly aid the charge transfer mechanism in these redox enzymes. Full paper: pdf Centre for Computational Natural Sciences and Bioinformatics |
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