glutaminefructose6phosphate

Glutamine-fructose-6-phosphate amidotransferase (GFAT) is the enzyme that catalyzes the first and rate-limiting step of the hexosamine biosynthetic pathway, converting fructose-6-phosphate and glutamine into glucosamine-6-phosphate and glutamate. This reaction sets the flux through the pathway that ultimately generates UDP-N-acetylglucosamine (UDP-GlcNAc), a key donor substrate for protein and lipid glycosylation.

In humans there are two GFAT isoforms, GFAT1 and GFAT2, encoded by the GFPT1 and GFPT2 genes. The enzyme generally functions in the cytosol and consists of two catalytic domains: an N-terminal glutaminase domain that provides ammonia, and a C-terminal sugar isomerase domain that transfers the amide group to fructose-6-phosphate to form glucosamine-6-phosphate.

Regulation of GFAT activity integrates nutrient and energy status. Flux through the hexosamine pathway increases with high glucose and other nutrients, enhancing protein O-GlcNAcylation. UDP-GlcNAc levels can feedback regulate GFAT, and activity is further modulated by phosphorylation, allosteric effectors, and cellular signaling pathways. Tissue distribution and isoform expression contribute to the regulation of hexosamine flux in different physiological contexts.

Clinical and research relevance: Altered GFAT activity and hexosamine pathway flux have been implicated in metabolic disorders such as insulin resistance and type 2 diabetes, as well as in cancer and neurodegenerative diseases where changes in glycosylation affect protein function and signaling. GFAT remains a focus of studies on nutrient sensing, metabolic regulation, and glycosylation-dependent cellular processes.