Chemistry Faculty Work
Title
Small-Molecule Allosteric Activation of Human Glucokinase in the Absence of Glucose
Document Type
Article
Publication Date
2013
Publication Title
ACS Medicinal Chemistry Letters
Volume Number
4
Issue Number
7
DOI
10.1021/ml400061x
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. Viscosity variation experiments indicate that the kcat value of glucokinase is almost fully limited by product release, both in the presence and absence of activators, suggesting that activators impact a step preceding product release. The observation of glucose-independent allosteric activation of glucokinase has important implications for the refinement of future diabetes therapeutics and for the mechanism of kinetic cooperativity of mammalian glucokinase.
ISSN
1948-5875
First Page
580
Last Page
584
Recommended Citation
Hervert, Katherine; Bowler, Joseph; Kearley, Mark; and Miller, Brian, "Small-Molecule Allosteric Activation of Human Glucokinase in the Absence of Glucose" (2013). Chemistry Faculty Work. 9.
https://digitalcommons.owu.edu/chem_pubs/9
Link Out URL
https://doi.org/10.1021/ml400061x