Glutamine synthetase

Glutamine synthetase (GS, encoded by GLUL) catalyzes the ATP-dependent conversion of glutamate and ammonia to glutamine, a reaction essential for ammonia detoxification and neurotransmitter regulation (UniProt: P15104). In the brain, the enzyme plays a crucial role in removing neurotoxic glutamate and toxic ammonia, converting them to harmless glutamine. Beyond catalytic function, GS also acts as a palmitoyltransferase regulating endothelial GTPase signaling and contributes to ribosomal biogenesis and ion channel modulation through BEST2 interaction.

GS is widely expressed and its loss-of-function causes severe neurological disease. Pathogenic GLUL mutations result in congenital glutamine deficiency (GLND) and developmental epileptic encephalopathy 116 (DEE116), characterized by brain malformations, seizures, and developmental delay (UniProt: P15104). These monogenic disorders underscore the protein's critical role in neural development and function.

In Alzheimer's Disease, glutamine synthetase is significantly downregulated in post-mortem brain tissue compared to age-matched controls (mean log2FC: −0.692; Chaparral AD proteomics). This reduction may compromise ammonia and glutamate detoxification in AD brain, potentially exacerbating excitotoxic stress and neuroinflammation characteristic of the disease pathology.