Glutamine:fructose-6-phosphate amidotransferase (GFAT) (GFAT)

Glutamine:fructose-6-phosphate amidotransferase (GFAT) is the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), converting fructose-6-phosphate and glutamine into glucosamine-6-phosphate (UniProt P41215). This pathway serves as a critical nutrient-sensing mechanism, as its end product, UDP-N-acetylglucosamine (UDP-GlcNAc), is the donor substrate for O-GlcNAcylation of nuclear and cytoplasmic proteins (PubMed: 22106267). GFAT exists in two isoforms, GFPT1 and GFPT2, which exhibit distinct tissue distribution and regulatory properties (NCBI Gene: 2673). Increased flux through GFAT is a major contributor to glucose-induced insulin resistance in skeletal muscle and adipose tissue, making it a target for type 2 diabetes research (PubMed: 10333050). Additionally, GFAT is upregulated in several cancers, such as pancreatic ductal adenocarcinoma, where it supports metabolic reprogramming and tumor growth (PubMed: 28844881). While inhibitors like azaserine and DON have been used in research, their lack of specificity for GFAT over other glutamine-utilizing enzymes presents a significant therapeutic challenge (PubChem CID: 115215).

Other names

GFPT1GFPT2GFAT1GFAT2Glutamine--fructose-6-phosphate aminotransferase [isomerizing]Hexosamine-fructose-6-phosphate aminotransferaseD-fructose-6-phosphate amidotransferase

Inhibition of the rate-limiting step in the hexosamine biosynthetic pathway, reducing the production of glucosamine-6-phosphate and subsequent O-GlcNAcylation of proteins.