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GCK  -  glucokinase (hexokinase 4)

Homo sapiens

 
 
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Disease relevance of GCK

  • We studied the GCK V62M mutation identified in two families and co-segregating with hyperglycemia to understand how this mutation resulted in reduced function [1].
  • Heterozygous inactivating GCK mutations cause hyperglycemia, whereas activating mutations cause hypoglycemia [1].
  • Mutations in the GCK/MODY2 gene are the most common cause of MODY in our population as recruited from pediatric and adolescent index patients [2].
  • Birth weight was lower in the presence of a GCK fetal mutation when the mutation was of paternal origin [2].
  • Likewise, the role of the GCK 3' variant in the reduced insulin sensitivity of obesity will require further study [3].
 

Psychiatry related information on GCK

 

High impact information on GCK

 

Chemical compound and disease context of GCK

 

Biological context of GCK

 

Anatomical context of GCK

 

Associations of GCK with chemical compounds

  • Recombinant glutathionyl S-transferase-V62M GCK is paradoxically activated rather than inactivated due to a decreased S0.5 for glucose compared with wild type (4.88 versus 7.55 mM) [1].
  • Functional characterisation of these mutations revealed that insertion of asparagine residue N161 fully inactivates GCK, whereas the M235V and R308W mutations only partially impair enzymatic activity [15].
  • The inhibition of GCK by GCKR is relieved by the binding of fructose-1-phosphate (F-1-P) to GCKR [22].
  • At higher glucose concentrations or in the presence of low concentrations of fructose, GK translocated to the cytoplasm [16].
  • We identified a small molecule GK activator, compound A, that increased the glucose affinity and maximal velocity (V(max)) of GK [20].
 

Physical interactions of GCK

 

Enzymatic interactions of GCK

  • The substrate cycle enzyme glucose-6-phosphatase catalyzes the terminal step in both the gluconeogenic and glycogenolytic pathways and is opposed by the glycolytic enzyme glucokinase [25].
  • Controlled proteolysis of wild-type glucokinase by proteinase K revealed that the SH group oxidizing agent alloxan can induce the formation of multiple intramolecular disulfide bridges corresponding to a double-band pattern of glucokinase protein in nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis [26].
 

Regulatory relationships of GCK

 

Other interactions of GCK

  • In contrast to the glucokinase and HNF-1alpha genes, mutations in the HNF-4alpha gene are a relatively uncommon cause of MODY, and our understanding of the MODY1 form of diabetes is based on studies of only a single family, the R-W pedigree [30].
  • Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP [20].
  • The relative proportions classified as diabetic depended on whether fasting (38 % vs 22 %, glucokinase vs HNF-1 alpha) or 2-h values (19 % vs 44 %) were used [31].
  • Of 67 French MODY families that we have now studied, 42 (63%) have mutations in the glucokinase gene, 14 (21%) have mutations in the HNF-1alpha gene, and 11 (16%) have no mutations in the HNF-4alpha, IPF1 and HNF-1beta genes [32].
  • Although none of these mutations affected the interaction of GCK with PFKFB1, we found that the R308W mutation caused protein instability and increased the strength of interaction with GCKR [15].
 

Analytical, diagnostic and therapeutic context of GCK

References

  1. Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young. Gloyn, A.L., Odili, S., Zelent, D., Buettger, C., Castleden, H.A., Steele, A.M., Stride, A., Shiota, C., Magnuson, M.A., Lorini, R., d'Annunzio, G., Stanley, C.A., Kwagh, J., van Schaftingen, E., Veiga-da-Cunha, M., Barbetti, F., Dunten, P., Han, Y., Grimsby, J., Taub, R., Ellard, S., Hattersley, A.T., Matschinsky, F.M. J. Biol. Chem. (2005) [Pubmed]
  2. Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. Barrio, R., Bellanné-Chantelot, C., Moreno, J.C., Morel, V., Calle, H., Alonso, M., Mustieles, C. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  3. Role of common sequence variants in insulin secretion in familial type 2 diabetic kindreds: the sulfonylurea receptor, glucokinase, and hepatocyte nuclear factor 1alpha genes. Elbein, S.C., Sun, J., Scroggin, E., Teng, K., Hasstedt, S.J. Diabetes Care (2001) [Pubmed]
  4. Site-directed mutagenesis studies on the determinants of sugar specificity and cooperative behavior of human beta-cell glucokinase. Xu, L.Z., Zhang, W., Weber, I.T., Harrison, R.W., Pilkis, S.J. J. Biol. Chem. (1994) [Pubmed]
  5. High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetes (SIEDP). Massa, O., Meschi, F., Cuesta-Munoz, A., Caumo, A., Cerutti, F., Toni, S., Cherubini, V., Guazzarotti, L., Sulli, N., Matschinsky, F.M., Lorini, R., Iafusco, D., Barbetti, F. Diabetologia (2001) [Pubmed]
  6. Metabolic coupling factors in pancreatic beta-cell signal transduction. Newgard, C.B., McGarry, J.D. Annu. Rev. Biochem. (1995) [Pubmed]
  7. Neonatal diabetes mellitus due to complete glucokinase deficiency. Njølstad, P.R., Søvik, O., Cuesta-Muñoz, A., Bjørkhaug, L., Massa, O., Barbetti, F., Undlien, D.E., Shiota, C., Magnuson, M.A., Molven, A., Matschinsky, F.M., Bell, G.I. N. Engl. J. Med. (2001) [Pubmed]
  8. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Hattersley, A.T., Beards, F., Ballantyne, E., Appleton, M., Harvey, R., Ellard, S. Nat. Genet. (1998) [Pubmed]
  9. Familial hyperinsulinism caused by an activating glucokinase mutation. Glaser, B., Kesavan, P., Heyman, M., Davis, E., Cuesta, A., Buchs, A., Stanley, C.A., Thornton, P.S., Permutt, M.A., Matschinsky, F.M., Herold, K.C. N. Engl. J. Med. (1998) [Pubmed]
  10. Three novel missense mutations in the glucokinase gene (G80S; E221K; G227C) in Italian subjects with maturity-onset diabetes of the young (MODY). Mutations in brief no. 162. Online. Guazzini, B., Gaffi, D., Mainieri, D., Multari, G., Cordera, R., Bertolini, S., Pozza, G., Meschi, F., Barbetti, F. Hum. Mutat. (1998) [Pubmed]
  11. Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. Stoffel, M., Patel, P., Lo, Y.M., Hattersley, A.T., Lucassen, A.M., Page, R., Bell, J.I., Bell, G.I., Turner, R.C., Wainscoat, J.S. Nat. Genet. (1992) [Pubmed]
  12. Hyperinsulinism of the newborn. Glaser, B. Semin. Perinatol. (2000) [Pubmed]
  13. Modulation of glucose responsiveness of insulinoma beta-cells by graded overexpression of glucokinase. Wang, H., Iynedjian, P.B. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  14. Fructose improves the ability of hyperglycemia per se to regulate glucose production in type 2 diabetes. Hawkins, M., Gabriely, I., Wozniak, R., Vilcu, C., Shamoon, H., Rossetti, L. Diabetes (2002) [Pubmed]
  15. Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity. Garc??a-Herrero, C.M., Gal??n, M., Vincent, O., Fl??ndez, B., Gargallo, M., Delgado-Alvarez, E., Bl??zquez, E., Navas, M.A. Diabetologia (2007) [Pubmed]
  16. Glucokinase regulatory protein may interact with glucokinase in the hepatocyte nucleus. Brown, K.S., Kalinowski, S.S., Megill, J.R., Durham, S.K., Mookhtiar, K.A. Diabetes (1997) [Pubmed]
  17. Localization of MODY3 to a 5-cM region of human chromosome 12. Menzel, S., Yamagata, K., Trabb, J.B., Nerup, J., Permutt, M.A., Fajans, S.S., Menzel, R., Iwasaki, N., Omori, Y., Cox, N.J. Diabetes (1995) [Pubmed]
  18. From clinicogenetic studies of maturity-onset diabetes of the young to unraveling complex mechanisms of glucokinase regulation. Sagen, J.V., Odili, S., Bjørkhaug, L., Zelent, D., Buettger, C., Kwagh, J., Stanley, C., Dahl-Jørgensen, K., de Beaufort, C., Bell, G.I., Han, Y., Grimsby, J., Taub, R., Molven, A., Søvik, O., Njølstad, P.R., Matschinsky, F.M. Diabetes (2006) [Pubmed]
  19. Diagnostic heterogeneity of diabetes in lean young adults: classification based on immunological and genetic parameters. Dussoix, P., Vaxillaire, M., Iynedjian, P.B., Tiercy, J.M., Ruiz, J., Spinas, G.A., Berger, W., Zahnd, G., Froguel, P., Philippe, J. Diabetes (1997) [Pubmed]
  20. An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism. Futamura, M., Hosaka, H., Kadotani, A., Shimazaki, H., Sasaki, K., Ohyama, S., Nishimura, T., Eiki, J., Nagata, Y. J. Biol. Chem. (2006) [Pubmed]
  21. Mutations in the glucokinase regulatory protein gene in 2p23 in obese French caucasians. Veiga-da-Cunha, M., Delplanque, J., Gillain, A., Bonthron, D.T., Boutin, P., Van Schaftingen, E., Froguel, P. Diabetologia (2003) [Pubmed]
  22. Co-localization of the ketohexokinase and glucokinase regulator genes to a 500-kb region of chromosome 2p23. Hayward, B.E., Fantes, J.A., Warner, J.P., Intody, S., Leek, J.P., Markham, A.F., Bonthron, D.T. Mamm. Genome (1996) [Pubmed]
  23. Stat 5B, activated by insulin in a Jak-independent fashion, plays a role in glucokinase gene transcription. Sawka-Verhelle, D., Tartare-Deckert, S., Decaux, J.F., Girard, J., Van Obberghen, E. Endocrinology (2000) [Pubmed]
  24. Enzymatic assay of magnesium through glucokinase activation. Fossati, P., Sirtoli, M., Tarenghi, G., Giachetti, M., Berti, G. Clin. Chem. (1989) [Pubmed]
  25. Regulation of glucose production by the liver. Nordlie, R.C., Foster, J.D., Lange, A.J. Annu. Rev. Nutr. (1999) [Pubmed]
  26. Importance of cysteine residues for the stability and catalytic activity of human pancreatic beta cell glucokinase. Tiedge, M., Richter, T., Lenzen, S. Arch. Biochem. Biophys. (2000) [Pubmed]
  27. PDX-1 induces insulin and glucokinase gene expressions in alphaTC1 clone 6 cells in the presence of betacellulin. Watada, H., Kajimoto, Y., Miyagawa, J., Hanafusa, T., Hamaguchi, K., Matsuoka, T., Yamamoto, K., Matsuzawa, Y., Kawamori, R., Yamasaki, Y. Diabetes (1996) [Pubmed]
  28. BETA2 activates transcription from the upstream glucokinase gene promoter in islet beta-cells and gut endocrine cells. Moates, J.M., Nanda, S., Cissell, M.A., Tsai, M.J., Stein, R. Diabetes (2003) [Pubmed]
  29. Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus. Mevorach, M., Giacca, A., Aharon, Y., Hawkins, M., Shamoon, H., Rossetti, L. J. Clin. Invest. (1998) [Pubmed]
  30. Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4alpha/MODY1 gene. Lindner, T., Gragnoli, C., Furuta, H., Cockburn, B.N., Petzold, C., Rietzsch, H., Weiss, U., Schulze, J., Bell, G.I. J. Clin. Invest. (1997) [Pubmed]
  31. The genetic abnormality in the beta cell determines the response to an oral glucose load. Stride, A., Vaxillaire, M., Tuomi, T., Barbetti, F., Njølstad, P.R., Hansen, T., Costa, A., Conget, I., Pedersen, O., Søvik, O., Lorini, R., Groop, L., Froguel, P., Hattersley, A.T. Diabetologia (2002) [Pubmed]
  32. Mutation screening in 18 Caucasian families suggest the existence of other MODY genes. Chèvre, J.C., Hani, E.H., Boutin, P., Vaxillaire, M., Blanché, H., Vionnet, N., Pardini, V.C., Timsit, J., Larger, E., Charpentier, G., Beckers, D., Maes, M., Bellanné-Chantelot, C., Velho, G., Froguel, P. Diabetologia (1998) [Pubmed]
  33. Routine mutation screening of HNF-1alpha and GCK genes in MODY diagnosis: how effective are the techniques of DHPLC and direct sequencing used in combination? Boutin, P., Vasseur, F., Samson, C., Wahl, C., Froguel, P. Diabetologia (2001) [Pubmed]
  34. Identification of glucokinase mutation in subjects with post-renal transplantation diabetes mellitus. Nam, J.H., Lee, H.C., Kim, Y.H., Cha, B.S., Song, Y.D., Lim, S.K., Kim, K.R., Huh, K.B. Diabetes Res. Clin. Pract. (2000) [Pubmed]
  35. Insulin induction of glucokinase and fatty acid synthase in hepatocytes: analysis of the roles of sterol-regulatory-element-binding protein-1c and liver X receptor. Hansmannel, F., Mordier, S., Iynedjian, P.B. Biochem. J. (2006) [Pubmed]
  36. Human liver glucokinase gene: cloning and sequence determination of two alternatively spliced cDNAs. Tanizawa, Y., Koranyi, L.I., Welling, C.M., Permutt, M.A. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
 
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