Glucokinase

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in theliver, pancreas, gut, and brain of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting.

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Background


Glucokinase (GK) plays a major role in regulating glucose levels in the blood. A glucose affinity tailored to physiologic set point concentrations, and positive cooperativity with glucose binding, allows this enzyme to rapidly respond to small changes in blood glucose concentration with exquisite sensitivity. Several synthetic small molecules that allosterically activate GK are currently in clinical development; however, the hypoglycemic risk intrinsic to their activation mechanism has stimulated interest in alternative strategies for modulating glucokinase activity. GK is predominantly expressed in the liver and the b-islet cells of the pancreas, where it metabolizes glucose to G6P, resulting in increased glucose uptake (liver) or insulin secretion (pancreas), both of which decrease blood glucose levels. GK's role as a glucose sensor was validated in humans based on the association of deregulated glucose homeostasis with discrete mutations in GK. Mutations that abrogate the catalytic activity of GK can result in maturity onset diabetes of the young (MODY) and permanent neonatal diabetes mellitus (PNDM). Conversely, GK activating mutations have been linked to the development of persistent hyperinsulinemic hypoglycemia in infants (PHHI).

Glucokinase catalizes the ATP-dependent conversion of glucose into glucose-6-phosphate. The entry compound of glycolysis. In some bacteria, like E. coli. glucokinase seems to be important for metabolic pathway only because it phosphorylates intracellular glucose originating, e.g. from disaccharide hydrolysis. Unphosphorylated glucose can be obtained by glucose-containing disaccharides hydrolysiss: maltose, maltodextrin, lactose and trehalose metabolism. In E. coli, the existence of internal glucose has been concluded that it may originate from UDP-glucose in analogy to the formation of free galactose from UDP-galactose, or by a sugar phosphate transferase. In contrast, in Streptomyces coelicolor glucokinase is essential for catabolite repression. Even in Staphylococcus xylosus. in which catabolite repression is mainly exerted by the CcpA-dependent pathway. Inactivation of glk1. which encodes glucokinase. Leads to reduced catabolite repression of several genes. Spath discussed the potential contribution of glucokinase epression to catabolite repression in bacillus megasterium.

GK remains monomeric throughout its catalytic cycle. The positive cooperativity with glucose has therefore been the subject of much debate since its discovery, as this phenomenon is relatively rare among enzymes that do not function as homo-multimeric complexes. As GK has been shown to contain a single glucose binding site, the mechanism of cooperativity is consistent with a "mnemonical" model. In such a model, GK exists in equilibrium between a catalytically active conformation (E*) with high glucose affinity, and an inactive conformation (E) with a glucose affinity several orders of magnitude lower than that of E*. In the absence of glucose, GK is believed to exist predominantly in the E conformation, while glucose stabilizes the E* state. GK effectively "remembers" the E* state after ejecting G6P. Assuming that the transition between E and E* is much slower than the catalytic cycle, a second glucose molecule can then bind and enter the catalytic cycle before conversion back to the inactive form. Cooperativity arises from the fact that E* will revert to E before a second glucose molecule can bind if substrate concentrations are low, resulting in two kinetically distinct glucose-dependent phases of GK catalysis. To date, crystal structures of the putative E and E* states, as well as a potential intermediate structure, have been reported.

Reference:

Braun, C. R. (2013). Structural Characterization of BCL-2 Family Protein Interactions Using Photoreactive Stapled Peptides and Mass Spectrometry (Doctoral dissertation).