Glutamine-fructose-6-phosphate aminotransferase [isomerizing] (GFAT) (GFAT)

Glutamine-fructose-6-phosphate aminotransferase (GFAT) is the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), which converts fructose-6-phosphate and glutamine into glucosamine-6-phosphate [UniProt: Q06210]. This enzyme acts as a key nutrient sensor by regulating the production of UDP-N-acetylglucosamine (UDP-GlcNAc), the substrate required for O-GlcNAcylation, a post-translational modification that modulates protein function in response to cellular glucose levels [PubMed: 11595664]. GFAT exists in two primary isoforms, GFPT1 and GFPT2, which are involved in maintaining metabolic homeostasis and cellular signaling [NCBI Gene: 2673]. Clinically, elevated GFAT activity is associated with insulin resistance and the pathogenesis of type 2 diabetes, as increased flux through the HBP interferes with insulin receptor signaling [PubMed: 11595664]. In oncology, GFAT is often overexpressed to meet the high metabolic requirements of tumor cells, particularly in pancreatic and lung cancers [PubMed: 29107099]. Conversely, mutations in the GFPT1 gene are linked to congenital myasthenic syndrome, highlighting its importance in neuromuscular junction maintenance [PubMed: 21296103]. While pharmacological inhibitors like azaserine and 6-diazo-5-oxo-L-norleucine (DON) can block GFAT, their lack of specificity poses significant safety concerns, making the development of selective inhibitors a primary focus for therapeutic intervention [PubChem: CID 115110].

Other names

GFPT1GFPT2GFAT1GFAT2Hexosephosphate aminotransferaseD-fructose-6-phosphate amidotransferase [isomerizing]

Inhibition of the hexosamine biosynthetic pathway by blocking the conversion of fructose-6-phosphate and glutamine to glucosamine-6-phosphate, thereby reducing the production of UDP-N-acetylglucosamine and subsequent protein O-GlcNAcylation.