Activating mutations in the human glucokinase gene revealed by genetic selection

Biochemistry
Priya Pal, Brian G Miller

Abstract

We describe the discovery of 11 new activating mutations in the human glk gene associated with the disease persistent hyperinsulinemic hypoglycemia of infancy (PHHI). Three of the newly identified substitutions colocalize to a region of the glucokinase polypeptide where a synthetic allosteric activator binds. Of these substitutions, I211F is the most active variant identified to date, with a k(cat)/K(0.5,glucose) value (6.6 x 10(4) M(-1) s(-1)) that is 12-fold higher than that of wild-type glucokinase. The stimulatory mutations described herein represent surreptitious genetic determinants of PHHI. They also identify novel features of the glucokinase scaffold that could be targeted during the development of diabetes therapeutics.

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Citations

Aug 19, 2015·Proceedings of the National Academy of Sciences of the United States of America·A Carl WhittingtonBrian G Miller
Nov 24, 2011·Archives of Biochemistry and Biophysics·Mioara Larion, Brian G Miller
Apr 12, 2014·Protein Science : a Publication of the Protein Society·Juliana A MartinezBrian G Miller
Dec 3, 2013·ACS Medicinal Chemistry Letters·Joseph M BowlerBrian G Miller

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