The human enzyme phosphoglucose isomerase (hPGI) is important in glycolysis. It is also a biomarker for several different types of cancer and is a target for anti-cancer therapy. The spatially extended active site in hPGI, predicted computationally by us, was subsequently established from kinetics assays of variants with single mutations in predicted distal positions. The K362A second shell variant shows no detectable activity, while the Q388A, E495Q, D511N second-shell variants, as well as the H100L and H396L third-shell variants, all show significantly diminished activity. While these distal residues contribute to catalysis through modulation of the electrostatic environment of the active site, they also participate in dynamic processes that may be critical to catalysis. We report on molecular dynamics simulations of wild-type and variant hPGI in solution. The role of the K362–D511 salt bridge will be clarified. Specifically, the preliminary studies of the motion of alpha-helix 23 will be explored to determine the importance of this motion for catalysis. These dynamic studies may reveal how distal residues modulate conformational changes that are important for catalysis.

Spatially extended active site: How distal residues contribute to catalysis in human phosphoglucose isomerase

253rd National Meeting (2017)

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