Fig. 1

The hexosamine biosynthetic pathway. Glucose enters the cell and undergoes two-step conversion to fructose-6P (fructose-6-phosphate), after which approximately 95% of it proceeds to glycolysis and 3–5% of it is converted to glucosamine-6P (glucosamine-6-phosphate) by the enzyme GFAT (glutamine:fructose-6-phosphate amidotransferase), utilizing glutamine that enters the cell. GFAT catalyzes the first and rate-limiting step in the formation of hexosamine products and thus is a key regulator of HBP. GNA1/GNPNAT1 (glucosamine-6-phosphate N-acetyltransferase) then converts glucosamine-6P (which can also be made by glucosamine entering the cell) into GlcNAc-6P (N-acetylglucosamine-6-Phosphate), also utilizing acetyl-CoA that is made from fatty acid metabolism. This is then converted to GlcNAc-1P (N-acetylglucosamine 1-phosphate) by PGM3/AGM1 (phosphoglucomutase) and further to UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) by UAP/AGX1 (UDP-N-acetylhexosamine pyrophosphorylase), utilizing UTP from the nucleotide metabolism pathway. UDP-GlcNAc is then used for N-linked and O-linked glycosylation in the ER and Golgi and for O-GlcNAc modification of nuclear and cytoplasmic proteins by OGT (O-GlcNAc transferase). OGA (O-GlcNAcase) catalyzes the removal of O-GlcNAc and adds back GlcNAc to the HBP pool for re-cycling through salvage pathway (Fig. 3)