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GCK

Official Full Name
GCK
Background
Glucose is phosphorylated to glucose-6-phosphate by glucokinases. This gene is alternatively spliced to generate three different forms of the enzyme; one found in the pancreas and two found in the liver. The main function of this gene is to regulate carbohydrate metabolism. Recombinant human pancreatic Glucokinase has a C-terminal FLAG tag and has 470 amino acid residues. It can be useful for studies including enzyme kinetics, activator screening and kinase selectivity.
Synonyms
EC 2.7.1.2; glucokinase; glucokinase (phosphorylating); 9001-36-9; GCK; FGQTL3; GK; GLK; HHF3; HK4; HKIV; HXKP; LGLK; MODY2; Human pancreatic glucokinase; pancreatic glucokinase

Catalog
ProductName
EC No.
CAS No.
Source
Price
CatalogNATE-1903
EC No.EC 2.7.1.2
CAS No.9001-36-9
SourceZymomonas mobil...
CatalogNATE-1697
EC No.EC 2.7.1.2
CAS No.9001-36-9
SourceE. coli
CatalogNATE-1696
EC No.EC 2.7.1.2
CAS No.9001-36-9
SourceE. coli
CatalogNATE-1687
EC No.EC 2.7.1.2
CAS No.9001-36-9
SourceE. coli
CatalogNATE-1686
EC No.EC 2.7.1.2
CAS No.9001-36-9
SourceE. coli
CatalogEXWM-3033
ProductNameglucokinase
EC No.EC 2.7.1.2
CAS No.9001-36-9
Source
CatalogNATE-1571
EC No.EC 2.7.1.2
CAS No.9001-36-9
SourceE. coli
CatalogNATE-0282
EC No.EC 2.7.1.2
CAS No.9001-36-9
SourceBacillus stearo...
Related Services
Related Protocols
glucokinase -Enzymatic Assay Protocol
Related Reading

Glucokinase (GCK, EC 2.7.1.2) prevalently occurring in the liver and pancreas of humans and most other vertebrates is a hexokinase isozyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. It is of great importance in carbohydrate metabolism regulation by acting as a glucose sensor to induce shifts in metabolism or cell function that responds to the rising or falling levels of glucose, such as occur after a meal or when fasting. Mutagenesis of GCK could cause unusual forms of diabetes or hypoglycemia. GCK is homologously related to at least three other hexokinases, all of which can mediate phosphorylation of glucose, being the first step of both glycogen synthesis and glycolysis. However, GCK possesses a lower affinity for glucose in comparison with the other hexokinases, and its activity is limited to only a few cell types, making the other three hexokinases as more pivotal in glycolysis and glycogen synthesis for most tissues and organs. On account of this reduced affinity, the activity of GCK differs substantially along with the concentration of glucose under common physiological conditions. Additionally, GCK is encoded by a separate gene and has unique kinetic properties, thus allowi ng it to provide a different set of functions.

Nomenclature

GCK

There are some alternative names for this enzyme, such as human hexokinase IV, hexokinase D, and ATP:D-hexose 6-phosphotransferase. The usual name glucokinase is originated from its relative specificity for glucose under physiologic conditions. It has been disputed that the name glucokinase is misleading and should be abandoned, since this enzyme can also phosphorylate other hexoses under proper conditions, and some distantly related enzymes in bacteria with more absolute specificity for glucose match the name of glucokinase better. Nonetheless, glucokinase is still a preferred name in the contexts of medicine and mammalian physiology.

Structure

Glucokinase is a monomeric protein possessing 465 amino acids and a molecular weight of about 50 kD. At least two clefts exist in GCK, one for the active site to bind with glucose and MgATP, and the other for a putative allosteric activator that has not yet been identified. The size of GCK is about half of the other mammalian hexokinases retaining a degree of dimeric structure. The ATP binding domain is shared by hexokinases, bacterial GCKs, and other proteins, and the common structure is termed an actin fold.

Human GCK is coded by the single autosomal GCK gene with10 exons on chromosome 7 and genes for GCK in other animals are homologous to human GCK. The gene has a distinctive feature by commencing with two tissue-specific promoter regions contained in the first exon from the 5' end. Transcription initiated at either promoter could generate a slightly distinct molecule in liver and in other tissues. The two isoforms of GCK differ only by 13–15 amino acids at the N-terminal end of the molecule, thus resulting in only a negligible difference in structure, but the two GCK isoforms possess the same kinetic and functional characteristics. Another mammalian glucose kinase, ADP-specific GCK discovered in 2004 is coded by a gene that is distinct and similar to that of primitive organisms. It is dependent on ADP instead of ATP, suggesting a probability of more effective function during hypoxia.

Catalysis

The principal substrate with physiologic importance of GCK is glucose, and the most significant product is glucose-6-phosphate. Another necessary substrate to produce phosphate is ATP, which is converted to ADP by removing a phosphate. The reaction catalyzed by GCK is shown below:

GCKFigure 1. Phosphorylation of glucose catalyzed by glucokinase.

In this procedure, ATP is complexed to a cofactor, magnesium. Under certain conditions, GCK functions like other hexokinases to trigger phosphorylation of other hexoses and similar molecules, like mannose, fructose, and glucosamine. Hence, the general GCK reaction can be more precisely described as:

GCKFigure 2. General reaction catalyzed by glucokinase.

GCK is distinguished from other hexokinases through two important kinetic properties, which enables it to act as glucose sensor in a special role. The conformation and/or function of GCK could be changed in parallel with the rising concentrations of glucose in the physiologically important range of 4–10 mmol/L. It achieves a half-saturation state at a glucose concentration of about 8 mmol/L. The activity of GCK would not inhibited by its product of glucose-6-phosphate, thus allowing a continued signal output amid significant amounts of its product. These two characteristics permit it to perform the regulation of a "supply-driven" metabolic pathway, meaning that the reaction rate is determined by the supply of glucose, rather than the demand for end products.

The moderate cooperativity with glucose belongs to another distinctive property of GCK, which owns only a single binding site for glucose and is the only known monomeric regulatory enzyme exhibiting substrate cooperativity. It has been postulated that the nature of the cooperativity involves a "slow transition" between two different enzyme states with different activity rates.

Clinical Significance

Since insulin is one of the most important regulators of GCK synthesis, diabetes mellitus of all types inhibit the synthesis and activity of GCK by a variety of mechanisms. GCK activity is also sensitive to oxidative stress of cells, particularly the beta cells. About 200 mutations of the human GCK gene have been discovered, which could cause a change in the efficiency of glucose binding and phosphorylation, thus increasing or decreasing the sensitivity of beta cell to secret insulin in response to glucose, and leaving clinically significant hyperglycemia or hypoglycemia. More than 190 of these mutations show an adverse effect on the functional efficiency of GCK. Heterozygosity for alleles with reduced enzyme activity raises the threshold for insulin release and persistance, causing mild hyperglycemia, which is referred to as maturity onset diabetes of the young, type 2, while homozygosity for GCK alleles with reduced function would give rise to severe congenital insulin deficiency, which brings a problem of persistent neonatal diabete. Researches are ongoing to activate GCK in a hope of treating of type 2 diabetes.

Reference

  1. Heredia V V, Thomson J, Nettleton D, Sun S. Glucose-induced conformational changes in glucokinase mediate allosteric regulation: transient kinetic analysis. Biochem, 2006, 45(24):7553–7562.

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