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Gene Review

GFPT1  -  glutamine--fructose-6-phosphate...

Homo sapiens

Synonyms: CMSTA1, D-fructose-6-phosphate amidotransferase 1, GFA, GFAT, GFAT 1, ...
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Disease relevance of GFPT1

  • Expression of the cDNA in E. coli produced a protein of approximately 77 kDa and increased GFAT activity 4.5-fold over endogenous bacterial levels [1].
  • Overall, the development of cloned GFAT molecular probes should provide new insights into the development of insulin resistance by allowing quantitation of GFAT mRNA levels in pathophysiological states such as non-insulin-dependent diabetes mellitus and obesity [1].
  • GFAT1 and GFAT1Alt expressed by recombinant adenovirus infection in COS-7 cells displayed robust enzyme activity and kinetic differences [2].
  • To determine if GFAT is indeed regulated by PKA, we expressed the active form of the enzyme using a vaccinia virus expression system and showed that the activity of the enzyme was to decrease to undetectable levels by PKA phosphorylation [3].
  • The identification of a novel GFAT1 subtype possessing functional enzymatic activity and tissue-specific expression should provide additional insight into the mechanism of skeletal muscle insulin resistance and diabetes complications [4].

High impact information on GFPT1

  • Overall, our study indicates that the flux of glucose metabolism through the GFAT catalyzed hexosamine biosynthetic pathway is involved in the glucose-induced mesangial production of TGF-beta leading to increased matrix production [5].
  • We conclude that glucose and insulin regulate GFA activity in skeletal muscle [6].
  • However, the lower the GFA protein content of the astrocytoma, the more malignant it was [7].
  • GFA and S 100 protein levels as an index for malignancy in human gliomas and neurinomas [7].
  • The high glucose-induced activation of the GlRE is mediated by the HBP; increased flux through the HBP induced by high glucose concentrations, by glutamine, or by overexpression of the rate-limiting enzyme glutamine:fructose-6-phosphate aminotransferase (GFAT) particularly activated USF-2 expression [8].

Chemical compound and disease context of GFPT1


Biological context of GFPT1


Anatomical context of GFPT1

  • We measured allele specific levels of GFPT1 mRNA and we compared mRNA levels across diagnostic categories for each ethnic group using RNA derived from transformed lymphocytes [12].
  • Wild-type and mutated vectors were transfected into human embryonic kidney 293 cells and mesangial cells and GFAT enzyme activity was assessed by formation of glucosamine-6-phosphate [13].
  • Subsequent cloning and sequencing revealed two GFAT1 mRNAs in both mouse and human skeletal muscles [2].
  • GFAT1Alt is the predominant GFAT1 mRNA in mouse hindlimb muscle, is weakly expressed in the heart, and is undetectable in the brain, liver, kidney, lung, intestine, spleen, and 3T3-L1 adipocytes [2].
  • GFAT1 is ubiquitous, whereas GFAT2 is expressed mainly in the central nervous system [2].

Associations of GFPT1 with chemical compounds

  • RESULTS: Mutation of histidine 577 or lysine 676 to alanine led to a complete loss of GFAT enzyme activity [13].
  • Glutamine: fructose-6-phosphate amidotransferase 1 (GFPT1) acts as a rate-limiting enzyme in the hexosamine biosynthetic pathway, which is an alternative branch of glucose metabolism [15].
  • Therefore, we suggested that the hexosamine biosynthetic pathway (the key enzyme of which is glutamine:fructose-6-phosphate amidotransferase [GFAT]) contributes to the high glucose-induced TGF-beta1 production [5].
  • Inhibition of GFAT by the substrate analogue azaserine or by inhibition of GFAT protein synthesis with antisense oligonucleotide prevented the high glucose-induced increase in cellular glucosamine metabolites and TGF-beta1 expression and bioactivity and subsequent effects on mesangial cell proliferation and matrix production [5].
  • When total intracellular hexosamine products were measured, we found that hexosamine formation was unaltered by insulin or glucose (or a combination) but was elevated by greater than 4-fold in the presence of insulin, glucose, and glutamine (t1/2 of 22 min), a condition known to cause both desensitization and loss of GFAT activity [16].

Regulatory relationships of GFPT1


Other interactions of GFPT1

  • Molecular screening of the human glutamine-fructose-6-phosphate amidotransferase 1 (GFPT1) gene and association studies with diabetes and diabetic nephropathy [12].
  • Glutamine:fructose-6-phosphate amidotransferase (GFPT), the rate limiting enzyme in hexosamine biosynthesis, is encoded by the unlinked but highly homologous genes GFPT1 and GFPT2 [17].
  • Instead, they were linked to the coordinated upregulation in gastrocnemius of genes that govern glucose uptake and the hexosamine pathway, namely, GLUT1 and GFAT1, which might contribute to insulin resistance [18].
  • In a second assay method that measures the stimulation of glutaminase activity, a K(d) of 2 microm was measured for Fru-6-P binding to hGFAT1 [19].

Analytical, diagnostic and therapeutic context of GFPT1


  1. Molecular cloning, cDNA sequence, and bacterial expression of human glutamine:fructose-6-phosphate amidotransferase. McKnight, G.L., Mudri, S.L., Mathewes, S.L., Traxinger, R.R., Marshall, S., Sheppard, P.O., O'Hara, P.J. J. Biol. Chem. (1992) [Pubmed]
  2. A novel variant of glutamine: fructose-6-phosphate amidotransferase-1 (GFAT1) mRNA is selectively expressed in striated muscle. DeHaven, J.E., Robinson, K.A., Nelson, B.A., Buse, M.G. Diabetes (2001) [Pubmed]
  3. Phosphorylation of human glutamine:fructose-6-phosphate amidotransferase by cAMP-dependent protein kinase at serine 205 blocks the enzyme activity. Chang, Q., Su, K., Baker, J.R., Yang, X., Paterson, A.J., Kudlow, J.E. J. Biol. Chem. (2000) [Pubmed]
  4. Identification of GFAT1-L, a novel splice variant of human glutamine: fructose-6-phosphate amidotransferase (GFAT1) that is expressed abundantly in skeletal muscle. Niimi, M., Ogawara, T., Yamashita, T., Yamamoto, Y., Ueyama, A., Kambe, T., Okamoto, T., Ban, T., Tamanoi, H., Ozaki, K., Fujiwara, T., Fukui, H., Takahashi, E.I., Kyushiki, H., Tanigami, A. J. Hum. Genet. (2001) [Pubmed]
  5. High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. Kolm-Litty, V., Sauer, U., Nerlich, A., Lehmann, R., Schleicher, E.D. J. Clin. Invest. (1998) [Pubmed]
  6. Glutamine:fructose-6-phosphate amidotransferase activity in cultured human skeletal muscle cells: relationship to glucose disposal rate in control and non-insulin-dependent diabetes mellitus subjects and regulation by glucose and insulin. Daniels, M.C., Ciaraldi, T.P., Nikoulina, S., Henry, R.R., McClain, D.A. J. Clin. Invest. (1996) [Pubmed]
  7. GFA and S 100 protein levels as an index for malignancy in human gliomas and neurinomas. Jacque, C.M., Kujas, M., Poreau, A., Raoul, M., Collier, P., Racadot, J., Baumann, N. J. Natl. Cancer Inst. (1979) [Pubmed]
  8. Upstream stimulatory factor (USF) proteins induce human TGF-beta1 gene activation via the glucose-response element-1013/-1002 in mesangial cells: up-regulation of USF activity by the hexosamine biosynthetic pathway. Weigert, C., Brodbeck, K., Sawadogo, M., Häring, H.U., Schleicher, E.D. J. Biol. Chem. (2004) [Pubmed]
  9. Increased glutamine:fructose-6-phosphate amidotransferase activity in skeletal muscle of patients with NIDDM. Yki-Järvinen, H., Daniels, M.C., Virkamäki, A., Mäkimattila, S., DeFronzo, R.A., McClain, D. Diabetes (1996) [Pubmed]
  10. The role of glial fibrillary acidic protein in the diagnosis of central nervous system tumors. Deck, J.H., Eng, L.F., Bigbee, J., Woodcock, S.M. Acta Neuropathol. (1978) [Pubmed]
  11. High-throughput functional genomics identifies genes that ameliorate toxicity due to oxidative stress in neuronal HT-22 cells: GFPT2 protects cells against peroxide. Zitzler, J., Link, D., Schäfer, R., Liebetrau, W., Kazinski, M., Bonin-Debs, A., Behl, C., Buckel, P., Brinkmann, U. Mol. Cell Proteomics (2004) [Pubmed]
  12. Molecular screening of the human glutamine-fructose-6-phosphate amidotransferase 1 (GFPT1) gene and association studies with diabetes and diabetic nephropathy. Elbein, S.C., Zheng, H., Jia, Y., Chu, W., Cooper, J.J., Hale, T., Zhang, Z. Mol. Genet. Metab. (2004) [Pubmed]
  13. Glutamine:fructose-6-phosphate aminotransferase enzyme activity is necessary for the induction of TGF-beta1 and fibronectin expression in mesangial cells. Weigert, C., Friess, U., Brodbeck, K., Häring, H.U., Schleicher, E.D. Diabetologia (2003) [Pubmed]
  14. Scrutiny of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) locus reveals conserved haplotype block structure not associated with diabetic nephropathy. Ng, D.P., Walker, W.H., Chia, K.S., Choo, S., Warram, J.H., Krolewski, A.S. Diabetes (2004) [Pubmed]
  15. Effect of +36T > C in intron 1 on the glutamine: fructose-6-phosphate amidotransferase 1 gene and its contribution to type 2 diabetes in different populations. Kunika, K., Tanahashi, T., Kudo, E., Mizusawa, N., Ichiishi, E., Nakamura, N., Yoshikawa, T., Yamaoka, T., Yasumo, H., Tsugawa, K., Moritani, M., Inoue, H., Itakura, M. J. Hum. Genet. (2006) [Pubmed]
  16. Coordinated regulation of glutamine:fructose-6-phosphate amidotransferase activity by insulin, glucose, and glutamine. Role of hexosamine biosynthesis in enzyme regulation. Traxinger, R.R., Marshall, S. J. Biol. Chem. (1991) [Pubmed]
  17. Common variants in glutamine:fructose-6-phosphate amidotransferase 2 (GFPT2) gene are associated with type 2 diabetes, diabetic nephropathy, and increased GFPT2 mRNA levels. Zhang, H., Jia, Y., Cooper, J.J., Hale, T., Zhang, Z., Elbein, S.C. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  18. Effect of sucrose and saturated-fat diets on mRNA levels of genes limiting muscle fatty acid and glucose supply in rats. Ferrer-Martínez, A., Marotta, M., Turini, M., Macé, K., Gómez-Foix, A.M. Lipids (2006) [Pubmed]
  19. Kinetic characterization of human glutamine-fructose-6-phosphate amidotransferase I: potent feedback inhibition by glucosamine 6-phosphate. Broschat, K.O., Gorka, C., Page, J.D., Martin-Berger, C.L., Davies, M.S., Huang Hc, H.C., Gulve, E.A., Salsgiver, W.J., Kasten, T.P. J. Biol. Chem. (2002) [Pubmed]
  20. Expression of glutamine:fructose-6-phosphate amidotransferase in human tissues: evidence for high variability and distinct regulation in diabetes. Nerlich, A.G., Sauer, U., Kolm-Litty, V., Wagner, E., Koch, M., Schleicher, E.D. Diabetes (1998) [Pubmed]
  21. Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Schleicher, E.D., Weigert, C. Kidney Int. Suppl. (2000) [Pubmed]
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