Glucokinase

• OMIM: 138079
• UniProt: P35557

Glucokinase ( GCK ) ( hexokinase IV) is the name for an enzyme selected from the group consisting of hexokinases, the phosphorylated in vertebrates (among other hexoses ) D- glucose to glucose-6 -phosphate.

In humans, there are three isoforms of the enzyme; in the liver, the storage of glucose as glycogen is initiated; in the pancreas, the reaction regulates the release of insulin. Mutations in the GCK gene can cause a specific form of early diabetes ( MODY 2) and a congenital hypoglycemia ( HHF3 ).

( Accept the other hexoses as a substrate, EC 2.7.1.1 ) further hexokinases are in the brain, muscles, eyes, kidneys, and localized in the intestine.

Function

ATP ADP

Entering glycolysis glucose is phosphorylated to glucose -6-phosphate (G -6P ) (Glc ) in the C6 atom. For the catalysis of this reaction, there are several enzymes, hexokinases and glucokinase. Glucokinase is found exclusively in the liver (hepatocytes ), and pancreas, in the rest of the body, the phosphorylation of glucose is performed by the hexokinases.

Hexokinases

The hexokinases Glc bind with high affinity corresponding to a K m value of 0.01 mM and is inhibited by its end product. In erythrocytes that functions in Rapoport Luebering cycle, a minor route of glycolysis, formed by the enzyme Bisphosphoglyceratmutase intermediate 2,3- diphosphoglycerate also as an inhibitor of hexokinases.

Due to the low Km value hexokinases the work with respect to glucose, both with a blood glucose concentration of 4 mmol / l in between meals and in 8-10 mmol / l of glucose during the absorption in the saturation region. Thus the hexokinases have a Km value for glucose, which is far below the lowest blood glucose concentration. This ensures that muscle, brain, etc. can inject glucose into glycolysis independent of the metabolic state, if required from the blood.

Glucokinase

Glucokinase has a lower affinity to their Km value is in the range of serum glucose concentration, it is not inhibited by G -6P and shows (positive) cooperative binding behavior. This is for her role in blood glucose sensor system of the pancreas is crucial.

The regulation of glucokinase occurs by reversible complexation with the glucokinase regulatory protein ( GKRP ). Binding is stimulated by fructose -6-phosphate, and sorbitol -6-phosphate, but inhibited by fructose-1 -phosphate. So latter increases glucokinase activity. After translocation into the nucleus, the complex is separated at high glucose levels, and again made ​​the glucokinase to the cytosol.

Comparison

The following figure shows the saturation curves of glucokinase and hexokinase are compared

Figure: glucose saturation curves for hexokinase (yellow upper hyperbola according Km = 0.01 mM) and a hypothetical kinase with Km = 5.5 mM (yellow, flat extending lower hyperbola ). The glucokinase of the pancreas follows the measurement points between these extremes, it has the following cooperativity according to Hill: Km ( av) = 5.5 mM (mean Michaelis constant); nH = 3 ( Hill coefficient); The blue highlighted area indicates the range of variation of blood glucose concentration, ie, blood glucose.

Accordingly, the curve of the glucokinase has a linear gradient in the range of physiological glucose levels, ie wherein Glc- Glc more increase in G -6P is proportionally converted and thereby removed from the bloodstream.

Recently, an activator (RO -28- 1675) of glucokinase was discovered by systematic screening of synthetic compounds, which affects both the liver and the pancreas enzyme. This could allow a new therapeutic principle for diabetes mellitus ( type 2).