Activating mutations in the human glucokinase gene revealed by genetic selection

Biochemistry. 2009 Feb 10;48(5):814-6. doi: 10.1021/bi802142q.


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.

Publication types

  • Comparative Study

MeSH terms

  • Allosteric Regulation / genetics
  • Amino Acid Substitution / genetics
  • Congenital Hyperinsulinism / enzymology
  • Congenital Hyperinsulinism / genetics
  • Crystallization
  • Genetic Variation
  • Glucokinase / chemistry*
  • Glucokinase / genetics*
  • Glucokinase / pharmacokinetics
  • Glucose / pharmacokinetics
  • Humans
  • Polymorphism, Single Nucleotide / genetics*
  • Protein Binding
  • Thermodynamics
  • Transcriptional Activation / genetics*


  • Glucokinase
  • Glucose