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Review
. 2009 Jan;66(1):27-42.
doi: 10.1007/s00018-008-8322-9.

Molecular physiology of mammalian glucokinase

P B Iynedjian  1
Affiliations
Review

Molecular physiology of mammalian glucokinase

P B Iynedjian. Cell Mol Life Sci. 2009 Jan.

Abstract

The glucokinase (GCK) gene was one of the first candidate genes to be identified as a human "diabetes gene". Subsequently, important advances were made in understanding the impact of GCK in the regulation of glucose metabolism. Structure elucidation by crystallography provided insight into the kinetic properties of GCK. Protein interaction partners of GCK were discovered. Gene expression studies revealed new facets of the tissue distribution of GCK, including in the brain, and its regulation by insulin in the liver. Metabolic control analysis coupled to gene overexpression and knockout experiments highlighted the unique impact of GCK as a regulator of glucose metabolism. Human GCK mutants were studied biochemically to understand disease mechanisms. Drug development programs identified small molecule activators of GCK as potential antidiabetics. These advances are summarized here, with the aim of offering an integrated view of the role of GCK in the molecular physiology and medicine of glucose homeostasis.

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Figures

Figure 1
Figure 1
Regulation of GCK activity and subcellular localization by interaction with GCKR. The scheme depicts hepatocytes after an overnight fast (postabsorptive) and during the ingestive phase after a carbohydrate containing meal (postprandial). The nuclear compartment (circle) communicates with the cytoplasmic space by nuclear pores. The blue and cyan ovals represent the large and small lobes of GCK respectively. After carbohydrate ingestion, the glucose concentration in plasma and hepatocytes rises, as does the concentration of fructose-1-phosphate. As a result, the GCKR (red)-GCK interaction is loosened, allowing GCK to bind glucose, adopt the closed (catalytically active) conformation and exit from the nucleus to generate glucose-6-phosphate for glycogen synthesis and glycolysis.
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