Hexokinase-4

Definition:

Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively). Compared to other hexokinases, has a weak affinity for D-glucose, and is effective only when glucose is abundant (By similarity). Mainly expressed in pancreatic beta cells and the liver and constitutes a rate-limiting step in glucose metabolism in these tissues. Since insulin secretion parallels glucose metabolism and the low glucose affinity of GCK ensures that it can change its enzymatic activity within the physiological range of glucose concentrations, GCK acts as a glucose sensor in the pancreatic beta cell (By similarity). In pancreas, plays an important role in modulating insulin secretion (By similarity). In liver, helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage (By similarity). Required to provide D-glucose 6-phosphate for the synthesis of glycogen. Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate.

References:

[1]. G Velho, et al. Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J Clin Invest. 1996 Oct 15;98(8):1755-61. [Content Brief]

[2]. Priya Pal, et al. Activating mutations in the human glucokinase gene revealed by genetic selection. Biochemistry. 2009 Feb 10;48(5):814-6. [Content Brief]

[3]. Antonio L Cuesta-Muñoz, et al. Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes. 2004 Aug;53(8):2164-8. [Content Brief]

[4]. L Z Xu, et al. Sugar specificity of human beta-cell glucokinase: correlation of molecular models with kinetic measurements. Biochemistry. 1995 May 9;34(18):6083-92. [Content Brief]

[5]. Henrik B T Christesen, et al. The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy. Diabetes. 2002 Apr;51(4):1240-6. [Content Brief]

[6]. Itziar Estalella, et al. Biochemical characterization of novel glucokinase mutations isolated from Spanish maturity-onset diabetes of the young (MODY2) patients. J Hum Genet. 2008;53(5):460-466. [Content Brief]

[7]. Vladi V Heredia, et al. Biochemical basis of glucokinase activation and the regulation by glucokinase regulatory protein in naturally occurring mutations. J Biol Chem. 2006 Dec 29;281(52):40201-7. [Content Brief]

[8]. Anne Raimondo, et al. Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability. Hum Mol Genet. 2014 Dec 15;23(24):6432-40. [Content Brief]

[9]. J Takeda, et al. Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants. J Biol Chem. 1993 Jul 15;268(20):15200-4. [Content Brief]

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