Short‐term control of glucokinase activity: role of a regulatory protein

Abstract

Glucokinase is one of the four hexokinases present in mammalian tissues. It is expressed in two cell types that have to respond to changes in the blood glucose concentration, the liver parenchymal cell and the β‐cells of pancreatic islets. The former are responsible for the metabolism and storage of an important part of the ingested glucose, whereas the latter secrete insulin in response to an increase in the blood glucose level. One major characteristic of glucokinase is that it has a relatively low affinity for glucose and displays positive cooperativity for this substrate, despite the fact that it is a monometic enzyme. Furthermore, unlike other hexokinases, it is not inhibited by micromolar (physiological) concentrations of glucose 6‐phosphate but by a regulatory protein that transduces the effect of fructose 6‐phosphate and of fructose 1‐phosphate. The purpose of this review is to describe these aspects of the regulation of glucokinase.— Van Schaftingen, E., Detheux, M., Veiga da Cunha, M. Short‐term control of glucokinase activity; role of a regulatory protein. FASEB J. 8: 414‐419; 1994.

Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators

“…As a first step toward a novel therapeutic strategy for the control of glycemia in type 2 diabetes, our aim was to identify potent activators of GK that increase the affinity of liver cells for glucose and thereby lower the hepatic glucose threshold. Although there are various known competitive inhibitors of GK, both physiological and pharmacological (6,16), there are as yet no clearly established physiological activators of GK other than fructose 1-phosphate, which indirectly activates GK by causing its dissociation from GKRP. We report here the structures of two chemically distinct direct activators of GK that potently stimulate hepatic glucose metabolism with a generally similar profile as physiological activation by precursors of fructose 1-phosphate but by a mechanism that is independent of GKRP.…”

“…In the liver, GK activity is regulated by hormonal control of gene expression (15) and by a 68-kDa GK regulatory protein (GKRP), which inhibits GK competitively with respect to glucose (16). The binding affinity of GKRP for GK is increased by fructose 6-phosphate and decreased by fructose 1-phosphate, which binds to the same site on GKRP (17).…”

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

“…2). Since the interaction of GCK with GCKR has been shown to be potentiated by F6P and counteracted by F1P [7], we tested the effect of the mutation R308W in the presence of either F1P plus high glucose or F6P plus low glucose in the buffer. Increased interaction of GCKR with the GCK (R308W) mutant was observed in both of the two conditions, although it was slightly better detectable when F1P plus high glucose was present in the buffer (Fig.…”

“…This specific function of GCK is based on the particular kinetic characteristics of this enzyme, which include a low affinity for glucose, cooperativity with this substrate, and a lack of end-product inhibition at physiological concentrations. In addition, GCK activity is regulated through protein-protein interactions by the glucokinase (hexokinase 4) regulator (GCKR, also known as glucokinase regulatory protein [GKRP]), which acts as a competitive inhibitor with respect to glucose and also regulates the nucleo-cytoplasmic localisation of the enzyme [7][8][9]. In addition, GCK has been shown to associate with other partners, such as the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1, also known as PFK2) [10,11], a dual specificity phosphatase [12], the neuronal isoform of nitric oxide synthase [13], the proapoptotic Bcell leukaemia/lymphoma 2 (BCL2) family member BCL2-antagonist of cell death (BAD) [14] and the precursor of the propionyl-CoA carboxylase beta subunit [15].…”

Identification, characterization of levoglucosan kinase, and cloning and expression of levoglucosan kinase cDNA from Aspergillus niger CBX-209 in Escherichia coli

“…For general hexokinases, their K m values ranged from only several millimolars in bacteria or fungi [34,45] up to 20 mM in mammals [35,46]. In the latter case, the glucokinase was suggested to regulate the blood sugar concentration with a high K m [47,48]. Compared with much lower K m values of glucokinase (0.063 mM) and hexokinase (0.35 mM) for glucose in A. niger [49,50], K m value of LG kinase at about 71 mM for levoglucosan indicated that A. niger cells might accumulate levoglucosan in vivo at a rate higher than that of glucose to produce enough amount of glucose 6-phosphate and then convert it into high yield of citric acid.…”