Hexokinase-4

Function

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.

Classification

Family (Pfam)

PF00349 Hexokinase_1, PF03727 Hexokinase_2

InterPro

ATPase_NBD, Hexokinase, Hexokinase_BS, Hexokinase_C, Hexokinase_N

Functional cluster

Tubulins & Mitochondrial Metabolic Enzymes

Experimental structures · PDB · 35

• 1V4S X-ray 2.30A
• 1V4T X-ray 3.40A
• 3A0I X-ray 2.20A
• 3F9M X-ray 1.50A
• 3FGU X-ray 2.15A
• 3FR0 X-ray 2.70A
• 3GOI X-ray 2.52A
• 3H1V X-ray 2.11A
• 3ID8 X-ray 2.40A
• 3IDH X-ray 2.14A
• 3IMX X-ray 2.00A
• 3QIC X-ray 2.20A
• … and 23 more

A predicted model is available from AlphaFold.

Gene Ontology · 25

• GO:0005829 cytosol
• GO:0005739 mitochondrion
• GO:0005654 nucleoplasm
• GO:0005524 ATP binding
• GO:0005536 D-glucose binding
• GO:0008865 fructokinase activity
• GO:0004340 glucokinase activity
• GO:0141089 glucose sensor activity
• GO:0019158 mannokinase activity
• GO:0070509 calcium ion import
• GO:0061621 canonical glycolysis
• GO:0032869 cellular response to insulin stimulus
• GO:0044320 cellular response to leptin stimulus
• GO:0051156 glucose 6-phosphate metabolic process
• GO:0006007 glucose catabolic process
• GO:0042593 glucose homeostasis
• GO:0006006 glucose metabolic process
• GO:0006096 glycolytic process
• GO:0001678 intracellular glucose homeostasis
• GO:0045721 negative regulation of gluconeogenesis
• GO:0045725 positive regulation of glycogen biosynthetic process
• GO:0032024 positive regulation of insulin secretion
• GO:0006110 regulation of glycolytic process
• GO:0050796 regulation of insulin secretion
• GO:0009749 response to glucose

Disease associations

• maturity-onset diabetes of the young type 2 MONDO:0007453
• type 2 diabetes mellitus MONDO:0005148
• hyperinsulinemic hypoglycemia, familial, 3 MONDO:0011236
• permanent neonatal diabetes mellitus 1 MONDO:0100165

Drugs targeting this protein · 6

• NERIGLIATIN activator
• PF-04991532 activator
• AZD-1656 activator
• MK-0941 activator
• LY-2608204 activator
• DORZAGLIATIN activator

Related proteins · sequence + function similarity

• Hexokinase-4 1.00
• Hexokinase-4 0.99
• Hexokinase 0.86
• Hexokinase-1 0.84
• Hexokinase-1 0.84
• Hexokinase-2 0.83
• Hexokinase-2 0.83
• Hexokinase-8 0.83
• Hexokinase-6 0.82
• Hexokinase-1 0.81
• Hexokinase-2 0.81
• Hexokinase-9 0.80

Co-cited proteins · studied together in the literature

• Hepatocyte nuclear factor 1-alpha 2 shared papers
• Glucokinase regulatory protein 2 shared papers
• Hexokinase-4 2 shared papers
• Glucokinase regulatory protein 1 shared papers
• Midnolin 1 shared papers
• Midnolin 1 shared papers
• Midnolin 1 shared papers
• Hexokinase-4 1 shared papers

Literature · 47 cited papers

• Heterogeneity in phenotype of hyperinsulinism caused by activating glucokinase mutations: a novel mutation and its functional characterization. Clin. Endocrinol. (Oxf.) · 2017
• Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability. Hum. Mol. Genet. · 2014
• Identification of the ubiquitin-like domain of midnolin as a new glucokinase interaction partner. J. Biol. Chem. · 2013
• Structural basis for regulation of human glucokinase by glucokinase regulatory protein. Biochemistry · 2013
• Insights into the pathogenicity of rare missense GCK variants from the identification and functional characterization of compound heterozygous and double mutations inherited in cis. Diabetes Care · 2012
• The active conformation of human glucokinase is not altered by allosteric activators. Acta Crystallogr. D · 2011
• The previously reported T342P GCK missense variant is not a pathogenic mutation causing MODY. Diabetologia · 2011
• Large islets, beta-cell proliferation, and a glucokinase mutation. N. Engl. J. Med. · 2010
• Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene. Mol. Endocrinol. · 2009
• Discovery of novel 3,6-disubstituted 2-pyridinecarboxamide derivatives as GK activators. Bioorg. Med. Chem. Lett. · 2009
• Activating mutations in the human glucokinase gene revealed by genetic selection. Biochemistry · 2009
• Biochemical characterization of novel glucokinase mutations isolated from Spanish maturity-onset diabetes of the young (MODY2) patients. J. Hum. Genet. · 2008
• … and 35 more in the literature graph