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

Glucosamine-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 (Source: nih.gov, tandfonline.com). This pathway is a critical nutrient-sensing mechanism that produces UDP-GlcNAc, the essential substrate for O-GlcNAcylation and N-glycosylation of proteins (Source: nih.gov). GFAT exists in two primary isoforms, GFAT1 and GFAT2, which exhibit tissue-specific expression and distinct regulatory roles (Source: nih.gov). Overactivity of GFAT is strongly linked to the development of insulin resistance and type 2 diabetes, while its upregulation in various cancers, such as pancreatic and lung cancer, promotes tumor growth, survival, and immune evasion (Source: nih.gov). Conversely, loss-of-function mutations in the GFPT1 gene cause congenital myasthenic syndrome, a neuromuscular disorder (Source: nih.gov). Therapeutic strategies targeting GFAT include glutamine analogs and competitive inhibitors, though achieving selectivity and avoiding systemic toxicity remain significant challenges in drug development (Source: tandfonline.com, nih.gov).

Other names

GFPTGFPT1GFPT2Glucosamine-6-phosphate synthaseD-fructose-6-phosphate amidotransferaseHexosephosphate aminotransferaseL-glutamine-D-fructose-6-phosphate amidotransferaseGlmS

Competitive or irreversible inhibition of the glutaminase or isomerase domains, or allosteric feedback inhibition by the end-product UDP-GlcNAc.