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Gene Review

G6PC  -  glucose-6-phosphatase, catalytic subunit

Homo sapiens

Synonyms: G-6-Pase, G6PC1, G6PT, G6Pase, G6Pase-alpha, ...
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Disease relevance of G6PC


Psychiatry related information on G6PC

  • Recent immunological studies have shown that G-6-Pase (which has conventionally been thought to be present only in the gluconeogenic organs) is present in minor cell types in a variety of human tissues and that its distribution changes dramatically during human development [6].
  • Since no structural modification occurs in the spermatozoon of Acrosternum aseadum after copulation, we used cytochemical studies to show the enzymatic activities variations of acid phosphatase, thiamine pyrophosphatase, glucose-6-phosphatase and cytochrome C oxidase, when the spermatozoon passes through the spermatheca [7].

High impact information on G6PC

  • Glucose-6-phosphatase dependent substrate transport in the glycogen storage disease type-1a mouse [8].
  • Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis [8].
  • By examining G6Pase in the liver and kidney, the primary gluconeogenic tissues, we demonstrate that glucose-6-P transport and hydrolysis are performed by separate proteins which are tightly coupled [8].
  • In these mutant mice, the amounts of glycogen synthase messenger RNA were 50 to 70 percent of normal and the transcriptional induction of the genes for two gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, was delayed [9].
  • These findings are consistent with the possibility that Foxo1 is involved in insulin regulation of glucose production by mediating the ability of insulin to decrease the glucocorticoid/cAMP response of G6p [2].

Chemical compound and disease context of G6PC


Biological context of G6PC

  • We observed the expression of hepatic G6Pase catalytic subunit, G6PC, in both tissues, although increased template inputs were required for its detection [15].
  • Some genotype-phenotype correlations exist, for example, homozygosity for one G6PC mutation, G188R, seems to be associated with a glycogen storage disease type I non-a phenotype and homozygosity for the 727G>T mutation may be associated with a milder phenotype but an increased risk for hepatocellular carcinoma [1].
  • We report on the molecular genetic analyses of G6PC and G6PT1 in 130 GSD Ia patients and 15 GSD I non-a patients, respectively, and provide an overview of the current literature pertaining to the molecular genetics of GSD I [1].
  • In HepG2 cells, the maximum repression of basal glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription by insulin requires two distinct promoter regions, designated A (located between -231 and -199) and B (located between -198 and -159), that together form an insulin response unit [16].
  • In addition, these data show that the binding of FOXO1a/3a to two adjacent IRSs in the G6Pase promoter is cooperative and that promoter context alters the specific IRS base requirements for FOXO1a-stimulated fusion gene expression [17].

Anatomical context of G6PC


Associations of G6PC with chemical compounds


Physical interactions of G6PC

  • These data strongly suggest that the mechanism by which PUFA suppress the glucose-6-phosphatase gene transcription involves an inhibition of the binding of HNF4 alpha to its cognate sites in the presence of polyunsaturated fatty acyl-CoA thioesters [24].

Enzymatic interactions of G6PC

  • 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].

Regulatory relationships of G6PC


Other interactions of G6PC


Analytical, diagnostic and therapeutic context of G6PC


  1. Glycogen storage disease type I: diagnosis and phenotype/genotype correlation. Matern, D., Seydewitz, H.H., Bali, D., Lang, C., Chen, Y.T. Eur. J. Pediatr. (2002) [Pubmed]
  2. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. Nakae, J., Kitamura, T., Silver, D.L., Accili, D. J. Clin. Invest. (2001) [Pubmed]
  3. Cloning and sequencing of the 5' region of the human glucose-6-phosphatase gene: transcriptional regulation by cAMP, insulin and glucocorticoids in H4IIE hepatoma cells. Schmoll, D., Allan, B.B., Burchell, A. FEBS Lett. (1996) [Pubmed]
  4. Diabetes affects similarly the catalytic subunit and putative glucose-6-phosphate translocase of glucose-6-phosphatase. Li, Y., Méchin, M.C., van de Werve, G. J. Biol. Chem. (1999) [Pubmed]
  5. A new model for the membrane topology of glucose-6-phosphatase: the enzyme involved in von Gierke disease. Hemrika, W., Wever, R. FEBS Lett. (1997) [Pubmed]
  6. Glucose-6-phosphatase proteins of the endoplasmic reticulum. Burchell, A., Allan, B.B., Hume, R. Mol. Membr. Biol. (1994) [Pubmed]
  7. Ultrastructural and cytochemical studies of the spermatozoa of Acrosternum aseadum (Hemiptera: Pentatomidae) after copulation. Fernandes, A.P., Báo, S.N. J. Submicrosc. Cytol. Pathol. (2000) [Pubmed]
  8. Glucose-6-phosphatase dependent substrate transport in the glycogen storage disease type-1a mouse. Lei, K.J., Chen, H., Pan, C.J., Ward, J.M., Mosinger, B., Lee, E.J., Westphal, H., Mansfield, B.C., Chou, J.Y. Nat. Genet. (1996) [Pubmed]
  9. Impaired energy homeostasis in C/EBP alpha knockout mice. Wang, N.D., Finegold, M.J., Bradley, A., Ou, C.N., Abdelsayed, S.V., Wilde, M.D., Taylor, L.R., Wilson, D.R., Darlington, G.J. Science (1995) [Pubmed]
  10. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Lei, K.J., Shelly, L.L., Pan, C.J., Sidbury, J.B., Chou, J.Y. Science (1993) [Pubmed]
  11. Asparagine-linked oligosaccharides are localized to a luminal hydrophilic loop in human glucose-6-phosphatase. Pan, C.J., Lei, K.J., Chou, J.Y. J. Biol. Chem. (1998) [Pubmed]
  12. Silencing of the human microsomal glucose-6-phosphate translocase induces glioma cell death: potential new anticancer target for curcumin. Belkaid, A., Copland, I.B., Massillon, D., Annabi, B. FEBS Lett. (2006) [Pubmed]
  13. Disturbed lipid metabolism in glycogen storage disease type 1. Bandsma, R.H., Smit, G.P., Kuipers, F. Eur. J. Pediatr. (2002) [Pubmed]
  14. Effects of dehydroepiandrosterone on gluconeogenic enzymes and glucose uptake in human hepatoma cell line, HepG2. Yamashita, R., Saito, T., Satoh, S., Aoki, K., Kaburagi, Y., Sekihara, H. Endocr. J. (2005) [Pubmed]
  15. Expression of glucose-6-phosphatase system genes in murine cortex and hypothalamus. Goh, B.H., Khan, A., Efendić, S., Portwood, N. Horm. Metab. Res. (2006) [Pubmed]
  16. The three insulin response sequences in the glucose-6-phosphatase catalytic subunit gene promoter are functionally distinct. Vander Kooi, B.T., Streeper, R.S., Svitek, C.A., Oeser, J.K., Powell, D.R., O'Brien, R.M. J. Biol. Chem. (2003) [Pubmed]
  17. Correlation between FOXO1a (FKHR) and FOXO3a (FKHRL1) Binding and the Inhibition of Basal Glucose-6-Phosphatase Catalytic Subunit Gene Transcription by Insulin. Onuma, H., Vander Kooi, B.T., Boustead, J.N., Oeser, J.K., O'brien, R.M. Mol. Endocrinol. (2006) [Pubmed]
  18. Structure-function analysis of the glucose-6-phosphate transporter deficient in glycogen storage disease type Ib. Chen, L.Y., Pan, C.J., Shieh, J.J., Chou, J.Y. Hum. Mol. Genet. (2002) [Pubmed]
  19. The catalytic center of glucose-6-phosphatase. HIS176 is the nucleophile forming the phosphohistidine-enzyme intermediate during catalysis. Ghosh, A., Shieh, J.J., Pan, C.J., Sun, M.S., Chou, J.Y. J. Biol. Chem. (2002) [Pubmed]
  20. The glucose-6-phosphatase system. van Schaftingen, E., Gerin, I. Biochem. J. (2002) [Pubmed]
  21. The fine structural localization of testicular phosphatases in man: the control testis. Barham, S.S., Berlin, J.D., Brackeen, R.B. Cell Tissue Res. (1976) [Pubmed]
  22. Molecular genetics of type 1 glycogen storage disease. Janecke, A.R., Mayatepek, E., Utermann, G. Mol. Genet. Metab. (2001) [Pubmed]
  23. Historical highlights and unsolved problems in glycogen storage disease type 1. Moses, S.W. Eur. J. Pediatr. (2002) [Pubmed]
  24. Polyunsaturated fatty acyl coenzyme A suppress the glucose-6-phosphatase promoter activity by modulating the DNA binding of hepatocyte nuclear factor 4 alpha. Rajas, F., Gautier, A., Bady, I., Montano, S., Mithieux, G. J. Biol. Chem. (2002) [Pubmed]
  25. Regulation of glucose production by the liver. Nordlie, R.C., Foster, J.D., Lange, A.J. Annu. Rev. Nutr. (1999) [Pubmed]
  26. cAMP response element binding protein (CREB) activates transcription via two distinct genetic elements of the human glucose-6-phosphatase gene. Thiel, G., Al Sarraj, J., Stefano, L. BMC Mol. Biol. (2005) [Pubmed]
  27. Mineralocorticoid receptor is involved in the regulation of genes responsible for hepatic glucose production. Liu, G., Grifman, M., Keily, B., Chatterton, J.E., Staal, F.W., Li, Q.X. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  28. 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]
  29. Effect of tumor necrosis factor on enzymes of gluconeogenesis in the rat. Yasmineh, W.G., Theologides, A. Proc. Soc. Exp. Biol. Med. (1992) [Pubmed]
  30. Vanadate but not tungstate prevents the fructose-induced increase in GLUT5 expression and fructose uptake by neonatal rat intestine. Kirchner, S., Kwon, E., Muduli, A., Cerqueira, C., Cui, X.L., Ferraris, R.P. J. Nutr. (2006) [Pubmed]
  31. Insulin-regulated gene expression. O'Brien, R.M., Streeper, R.S., Ayala, J.E., Stadelmaier, B.T., Hornbuckle, L.A. Biochem. Soc. Trans. (2001) [Pubmed]
  32. Identification and characterisation of a new human glucose-6-phosphatase isoform. Guionie, O., Clottes, E., Stafford, K., Burchell, A. FEBS Lett. (2003) [Pubmed]
  33. Glucose-6-phosphatase structure, regulation, and function: an update. Foster, J.D., Pederson, B.A., Nordlie, R.C. Proc. Soc. Exp. Biol. Med. (1997) [Pubmed]
  34. The signature motif in human glucose-6-phosphate transporter is essential for microsomal transport of glucose-6-phosphate. Pan, C.J., Chen, L.Y., Mansfield, B.C., Salani, B., Varesio, L., Chou, J.Y. Hum. Genet. (2003) [Pubmed]
  35. Genetic analysis of the glucose-6-phosphatase mutation of type 1a glycogen storage disease in a Chinese family. Lee, W.J., Lee, H.M., Chi, C.S., Shu, S.G., Lin, L.Y., Lin, W.H. Clin. Genet. (1996) [Pubmed]
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