Disease relevance of Gfpt1

• Immunization with PC, PS-liposomes containing unconjugated Gfpt1 and MPL stimulated the highest titers observed, thereby effectively preventing tumor growth in Balbc nu/nu-mice challenged with human small cell lung cancer cells [1].
• Glutamine:fructose-6-phosphate amidotransferase (GFAT) is the first and rate-limiting enzyme of the hexosamine biosynthesis pathway, which plays an important role in glucose toxicity and cellular insulin resistance [2].
• A 2.4-fold increase of GFA activity in muscle of the transgenic mice led to weight-dependent hyperinsulinemia in random-fed mice [3].
• Increased flux through the hexosamine biosynthetic pathway with glutamine:fructose-6-phosphate-amidotransferase (GFAT) as rate-limiting enzyme has been linked to the enhanced bioactivity of the prosclerotic cytokine transforming growth factor beta1 (TGF-beta1) in fibrotic complications, particularly in diabetic kidney disease [4].
• Astroglia-specific protein (GFA) in clonal cell lines derived from the G26 mouse glioma [5].

High impact information on Gfpt1

• Glutamine:fructose-6-phosphate amidotransferase (GFA), the first and rate limiting enzyme of the hexosamine biosynthetic pathway, was overexpressed in skeletal muscle and adipose tissue of transgenic mice [3].
• A protein encoded by a new gene with approximately 75% homology to glutamine-fructose-6-phosphate amidotransferase (GFAT) was termed GFAT2 on the basis of this similarity [6].
• The Km values for the two substrates of reaction, fructose 6-phosphate and glutamine, were determined to be 0.8 mm for fructose 6-phosphate and 1.2 mm for glutamine, which are within the ranges determined for GFAT1 [6].
• Previously we showed that phosphorylation of serine 205 in GFAT1 by the catalytic subunit of cAMP-dependent protein kinase (PKA) inhibits its activity [6].
• To examine the effect of increased hexosamine flux in liver, the rate-limiting enzyme in hexosamine biosynthesis (glutamine:fructose-6-phosphate amidotransferase [GFA]) was overexpressed in transgenic mice using the PEPCK promoter [7].

Biological context of Gfpt1

• The mouse GFAT promoter lacks a canonical TATA box and has several GC boxes within a highly GC-rich region [8].
• GFAT and nucleotide sugars were unchanged in liver, where the transgene is not expressed [9].
• Here, we investigate in a stable transfection system the effect of overexpression of GFAT on TGF-beta1 synthesis in NIH-3T3 fibroblasts [4].

Anatomical context of Gfpt1

• We also compared the promoter activities of mouse GFAT1 and GFAT2 in several cell lines [2].
• Precursor cells of GFA (glial fibrillary acidic) protein-positive astrocytes were cultured in a chemically defined medium as a homogeneous population [10].
• For example, insulin resistance results when the rate-limiting enzyme for hexosamine synthesis, glutamine:fructose-6-phosphate amidotransferase (GFA), is overexpressed in muscle and adipose tissue of transgenic mice [11].
• This study points out 1) the capacity of astrocytes to synthesize surprisingly high amounts of soluble GFA at periods of intense metabolic activity, and 2) the reactivity of astrocytes in relation to the degree of deficiency of the myelinating oligodendrocytes [12].
• In the jimpy mutant, practically devoid of myelin, the increase of GFA occurs but does not stop until death, at 25 days postnatal [12].

Associations of Gfpt1 with chemical compounds

• Glutamine:fructose-6-phosphate amidotransferase (GFAT) is the enzyme that is rate limiting in the synthesis of glucosamine and hexosamines [8].
• The enzyme glutamine:fructose 6-phosphate amidotransferase (L-glutamine:D-fructose-6-phosphate amidotransferase; EC 2.6.1.16, GFAT) catalyzes the formation of glucosamine 6-phosphate from fructose 6-phosphate and glutamine [13].
• Overexpression of GFA in skeletal muscle thus leads to defects in glucose transport similar to those seen in type 2 diabetes [11].
• Increased levels of UDP-N-acetylglucosamine, the principal end-product of the hexosamine pathway were seen in transgenic fat, consistent with the overexpression of GFA [14].
• Treatment of the transgenic animals with the thiazolidinedione troglitazone completely reversed the defect in glucose disposal without changing GFA activity or the levels of uridine 5'-diphosphate-N-acetylglucosamine [11].

Analytical, diagnostic and therapeutic context of Gfpt1

• Since it was considered that an active immunization against ganglioside Gfpt1 (IV2Fuc-, II3NeuAc-Gg4Cer) expressed by human small cell lung cancer cells may be beneficial in the treatment of this neoplasm in humans, an optimal mode of vaccination in model mice was investigated [1].
• Both populations of GFA protein and vimentin-positive astrocytes express N-CAM and the L2/HNK-1 epitope, but not tetanus toxin receptors or A2B5 antigen, at levels detectable by indirect immunofluorescence procedures [15].
• The differentiation of tanycytes during development of the mouse hypothalamus has been followed by immunohistochemistry with a GFA protein antiserum [16].
• Blockade of GFAT was confirmed by using Western blotting with the RL2 antibody, which recognizes an epitope on proteins containing N-acetylglucosamine [17].

References