Glutaminase, which converts glutamine to glutamate, is involved in Warburg effect in cancer cells. Two human glutaminase genes have been identified, GLS (GLS1) and GLS2. Two alternative transcripts arise from each glutaminase gene: first, the kidney isoform (KGA) and glutaminase C (GAC) for GLS; and, second, the liver isoform (LGA) and glutaminase B (GAB) for GLS2. While GLS1 is considered as a cancer therapeutic target, the potential role of GLS2 in cancer remains unclear. Here, we discovered a series of alkyl benzoquinones that preferentially inhibit glutaminase B isoform (GAB, GLS2) rather than the kidney isoform of glutaminase (KGA, GLS1). We identified amino acid residues in an allosteric binding pocket responsible for the selectivity. Treatment with the alkyl benzoquinones decreased intracellular glutaminase activity and glutamate levels. GLS2 inhibition by either alkyl benzoquinones or GLS2 siRNA reduced carcinoma cell proliferation and anchorage-independent colony formation, and induced autophagy via AMPK mediated mTORC1 inhibition. Our findings demonstrate amino acid sequences for selective inhibition of glutaminase isozymes and validate GLS2 as a potential anti-cancer target.
Cancer cells tend to exhibit the Warburg effect, in which cellular metabolisms proceed via: 1) an altered glucose metabolism characterized by a high rate of glycolysis followed by lactic acid fermentation; and 2) up-regulated glutaminolysis by increasing glutaminase activity. Glutamine is essential for cancer cell proliferation, especially in the context of tricarboxylic acid (TCA) cycle anaplerosis. Glutaminase plays an essential role converting glutamine to glutamate, which is converted by glutamate dehydrogenase into α-ketoglutarate. This α-ketoglutarate enters the TCA cycle where it is involved in the production of ATP, nucleotides, certain amino acids, lipids, and glutathione in mitochondria [1]. Recently, glutaminase has emerged as a drug target for the development of glutaminase inhibitors for the treatment of cancerous disease [2]. However, only a few series of glutaminase inhibitors for GLS1 have been identified, and only partial in vivo anti-cancer efficacy has been demonstrated [3-6].
Recombinant protein corresponding to active human GLS2 with a His-Tag expressed in E. coli
Applications:Suitable for use in the study of enzyme kinetics, screening inhibitors and selectivity profiling.
Storage and Stability:Aliquot to avoid repeated freezing and thawing and store at -70°C. Aliquots are stable for 6 months after receipt. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap.
仕様
Size：1mg
Source Antigen：Recombinant, E. coli
Grade：Purified
Purity：≥90% (SDS-PAGE)
Form：Supplied as a lyophilized powder from PBS. Reconstitute with sterile ddH2O.
