However, glucokinase is coded by a separate gene and its distinctive kinetic properties allow it to serve a different set of functions.

Because of this reduced affinity, the activity of glucokinase, under usual physiological conditions, varies substantially according to the concentration of glucose.

It is dependent on ADP rather than ATP (suggesting the possibility of more effective function during hypoxia), and the metabolic role and importance remain to be elucidated.

[9] Three important kinetic properties distinguish glucokinase from the other hexokinases, allowing it to function in a special role as glucose sensor.

Rather than a Km for glucose, it is more accurate to describe a half-saturation level S0.5, the concentration at which the enzyme is 50% saturated and active.

[19] A "minimal mathematical model" has been devised based on the above kinetic information to predict the beta cell glucose phosphorylation rate (BGPR) of normal ("wild type") glucokinase and the known mutations.

All except cys 230 are essential for the catalytic process, forming multiple disulfide bridges during interaction with the substrates and regulators.

At least in the beta cells, the ratio of active to inactive glucokinase molecules is at least partly determined by the balance of oxidation of sulfhydryl groups or reduction of disulfide bridges.

Several sequences and the three-dimensional structure of the key active sites are highly conserved both in intra-species homologs and across species from mammals to yeast.

[23] The ATP binding domain, for example, are shared with hexokinases, bacterial glucokinases, and other proteins, and the common structure is termed an actin fold.

[5] The two promoters are functionally exclusive and governed by distinct sets of regulatory factors, so that glucokinase expression can be regulated separately in different tissue types.

[5] The two promoters correspond to two broad categories of glucokinase function: In liver, glucokinase acts as the gateway for the "bulk processing" of available glucose, while, in the neuroendocrine cells, it acts as a sensor, triggering cell responses that affect body-wide carbohydrate metabolism.

Glucokinase has been discovered in specific cells in four types of mammalian tissue: liver, pancreas, small intestine, and brain.

The gene structure and amino acid sequence are highly conserved among most mammals (e.g., rat and human glucokinase is more than 80% homologous).

Glucokinase activity can be rapidly amplified or damped in response to changes in the glucose supply, typically resulting from eating and fasting.

Regulation occurs at several levels and speeds, and is influenced by many factors that affect mainly two general mechanisms: Insulin acting via the sterol regulatory element binding protein-1c (SREBP1c) is thought to be the most important direct activator of glucokinase gene transcription in hepatocytes.

Glucokinase transcription becomes nearly undetectable in prolonged starvation, severe carbohydrate deprivation, or untreated insulin-deficient diabetes.

However, as would be expected given its antagonistic effect on glycogen synthesis, glucagon and its intracellular second messenger cAMP suppresses glucokinase transcription and activity, even in the presence of insulin.

Fatty acids in significant amounts amplify GK activity in the liver, while long chain acyl CoA inhibits it.

In islet beta cells, glucokinase activity serves as a principal control for the secretion of insulin in response to rising levels of blood glucose.

One of the immediate consequences of increased cellular respiration is a rise in the NADH and NADPH concentrations (collectively referred to as NAD(P)H).

This shift in the redox status of the beta cells results in rising intracellular calcium levels, closing of the KATP channels, depolarization of the cell membrane, merging of the insulin secretory granules with the membrane, and release of insulin into the blood.

It is as a signal for insulin release that glucokinase exerts the largest effect on blood sugar levels and overall direction of carbohydrate metabolism.

This physical association stabilizes glucokinase in a catalytically favorable conformation (somewhat opposite the effect of GKRP binding) that enhances its activity.

When blood glucose concentration falls to hypoglycemic levels, α cells release glucagon.

While glucokinase has been shown to occur in certain cells (enterocytes) of the small intestine and stomach, its function and regulation have not been worked out.

It has been suggested that here, also, glucokinase serves as a glucose sensor, allowing these cells to provide one of the earliest metabolic responses to incoming carbohydrates.

At least 497 mutations of the human glucokinase gene GCK have been discovered, that can change the efficiency of glucose binding and phosphorylation, increasing or decreasing the sensitivity of beta cell insulin secretion in response to glucose, and producing clinically significant hyperglycemia or hypoglycemia.

Heterozygosity for alleles with reduced enzyme activity results in a higher threshold for insulin release and persistent, mild hyperglycemia.

[35] Homozygosity for GCK alleles with reduced function can cause severe congenital insulin deficiency, resulting in persistent neonatal diabetes.