Glutamate-ammonia ligase (Glutamine synthetase) (GS)

Glutamate-ammonia ligase, commonly known as Glutamine synthetase (GS), is a central enzyme in nitrogen metabolism that catalyzes the ATP-dependent condensation of glutamate and ammonia to form glutamine (UniProt P15104). This enzyme is essential for ammonia detoxification, particularly in the liver and brain, and serves as a key regulator of the glutamate-glutamine cycle in astrocytes to maintain neurotransmitter balance (PubMed: 23519144). In the context of oncology, many cancer types, such as glioblastoma and hepatocellular carcinoma, upregulate GS to support their high metabolic demand for glutamine, which is used for protein synthesis, nucleotide biosynthesis, and energy production (PubMed: 30243618). Consequently, GS is considered a therapeutic target for metabolic inhibition in cancer, although its inhibition can lead to significant safety concerns such as hyperammonemia and neurotoxicity due to the disruption of essential nitrogen processing (PubMed: 28844881). Current research focuses on developing selective inhibitors that can target tumor-specific GS activity while sparing systemic functions.

Other names

GLULGlutamine synthasePIG43PIG59Glutamate decarboxylase-like protein 1

Inhibition of the enzyme's catalytic activity, typically by competing with glutamate or acting as a transition-state analog, thereby preventing the synthesis of glutamine and the clearance of ammonia.