Small-Molecule Allosteric Activation of Human Glucokinase in the Absence of Glucose.

ABSTRACT: Synthetic allosteric activators of human glucokinase are receiving considerable attention as potential diabetes therapeutic agents. Although their mechanism of action is not fully understood, structural studies suggest that activator association requires prior formation of a binary enzyme-glucose complex. Here, we demonstrate that three previously described activators associate with glucokinase in a glucose-independent fashion. Transient-state kinetic assays reveal a lag in enzyme progress curves that is systematically reduced when the enzyme is preincubated with activators. Isothermal titration calorimetry demonstrates that activator binding is enthalpically driven for all three compounds, whereas the entropic changes accompanying activator binding can be favorable or unfavorable. Viscosi

SUBMITTER: Bowler JM 

PROVIDER: S-EPMC3840467 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature