GLUL (glutamine synthetase) catalyzes the ATP-dependent conversion of glutamate and ammonia to glutamine 1. Its primary function involves ammonia detoxification across multiple tissues: in the brain it converts neurotoxic glutamate to glutamine, while in liver it removes ammonia 2. During erythropoiesis, GLUL activity is essential to detoxify ammonium generated during heme biosynthesis, preventing oxidative stress and supporting red blood cell maturation 2. Beyond glutamine synthesis, GLUL exhibits non-canonical functions. In endothelial cells, it acts as a palmitoyltransferase to promote RHOJ palmitoylation and membrane localization, regulating endothelial cell migration during vascular development independent of glutamine synthetase activity 1. GLUL also regulates osteogenic differentiation by preventing FOXO3 degradation through altered O-GlcNAcylation 3. GLUL expression is dysregulated in multiple cancers, including clear cell renal cell carcinoma and intrahepatic cholangiocarcinoma, where it promotes lipid deposition and tumor growth through enhanced glutamine metabolism 45. Loss-of-function mutations cause developmental and epileptic encephalopathy and congenital glutamine deficiency. These findings reveal GLUL as a multifunctional enzyme essential for metabolic homeostasis, vascular development, erythropoiesis, and bone health, with significant implications for cancer and neurodevelopmental disease pathogenesis.