Glutamine-utilizing enzyme (GATase)

Glutamine-utilizing enzymes, primarily represented by the glutamine amidotransferase (GATase) family, are essential catalysts that facilitate the transfer of the amide nitrogen from L-glutamine to a variety of acceptor substrates. This enzymatic activity is critical for the de novo biosynthesis of purine and pyrimidine nucleotides, amino acids such as asparagine, and amino sugars required for glycoprotein synthesis (Massière & Badet-Denisot, 1998). In many pathological states, particularly in oncology, cells undergo metabolic reprogramming to become "glutamine addicted," utilizing these enzymes to support rapid proliferation, redox balance, and the replenishment of tricarboxylic acid (TCA) cycle intermediates (Altman et al., 2016). Therapeutic targeting of these enzymes has historically focused on glutamine antimetabolites like 6-diazo-5-oxo-L-norleucine (DON) and acivicin, which act as irreversible inhibitors by mimicking glutamine and covalently binding to the enzyme's active site (Lemberg et al., 2018). While these broad-spectrum inhibitors showed potent anti-tumor activity, their clinical development was hindered by significant systemic toxicities, including severe gastrointestinal distress and neurotoxicity. Modern drug development efforts now focus on more selective inhibitors, such as those targeting glutaminase (GLS1), or the use of tumor-targeted prodrugs like JHU-083 to improve the therapeutic index (Rais et al., 2016).

Other names

Glutamine amidotransferaseGATaseGlutamine-dependent amidotransferaseGlutamine-dependent enzymeGlutamine-utilizing enzymes

Inhibition of nitrogen transfer or hydrolysis of glutamine, often through covalent modification of active site residues by glutamine analogs or through allosteric inhibition of specific enzymes like glutaminase (Massière & Badet-Denisot, 1998; Altman et al., 2016).