Hexosamine biosynthetic pathway and protein O-GlcNAcylation. Cancer cells compensate for energy metabolism by the hexosamine biosynthetic pathway. While most of the glucose is metabolized through glycolysis, approximately 3–5% of glucose enters the HBP. Glutamine-fructose-6-phosphate aminotransferase, the rate-limiting enzyme of the HBP, converts fructose-6-phosphate into glucosamine-6-phosphate. Subsequently, Glucosamine-6-P is acetylated and uridylation of Glucosamine-1-phosphate generates UDP-N-acetylglucosamine. UDP-GlcNAc acts a substrate, and O-GlcNAc-transferase and O-GlcNAcase add and remove GlcNAc to serine or threonine residues of target proteins, respectively. TCA, Tricarboxylic acid cycle; OXPHOS, Oxidative phosphorylation; HBP, hexosamine biosynthetic pathway GFAT1, hexosamine biosynthetic pathway; GNAT, N-acetyltransferase; AGM, N-acetylphosphoglucosamine mutase; AGX, UDP-N-acetylhexosamine pyrophosphorylase; OGA, O-GlcNAcase; OGT, O-GlcNAc-transferase.