Abstract
Peroxiredoxin 6 (Prdx6) is a ubiquitously expressed 1-cysteine Peroxiredoxin found throughout all phyla. In mammals, under different physiological conditions, it has evolved from a peroxidase to a multifunctional enzyme. Among the mammalian Prdx6's, human and rat Prdx6's are the most extensively studied. Our study revealed that human and rat Prdx6's exhibit differences in their peroxidase activity. These two Prdx6's have only 8% difference in their primary sequence (with 19 amino acids) with no apparent modification at any of the key conserved residues. In the present communication, we have investigated the roles of thermodynamics, structure and internal flexibility of Prdx6 to account for the difference in their peroxidase activity. We discovered that these amino acid variations have led to structural alterations in human Prdx6 so that it shows enhanced intrinsic dynamics (or flexibility) than the rat protein. We could also identify the gain of intrinsic dynamics of the catalytic site in human Prdx6 due to relocation of an important active site residue (R132) to the loop region as the most plausible reason for high catalytic activity in the human protein as compared to rat variant. Since it is the thioredoxin fold that upholds the peroxidase function, certain structural alteration in the Prdx6 structure might help to regulate the efficiency of thioredoxin folds. Our results hint that Prdx6 might have a cis-acting regulatory sequence(s).
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