Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA; Department of Urology, New York Medical College, Valhalla, NY, 10595, USA.
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA.
Anal Biochem. 2022 May 1;644:114083. doi: 10.1016/j.ab.2020.114083. Epub 2020 Dec 23.
In rapidly dividing cells, including many cancer cells, l-glutamine is a major energy source. Utilization of glutamine is usually depicted as: l-glutamine → l-glutamate (catalyzed by glutaminase isozymes; GLS1 and GLS2), followed by l-glutamate → α-ketoglutarate [catalyzed by glutamate-linked aminotransferases or by glutamate dehydrogenase (GDH)]. α-Ketoglutarate is a major anaplerotic component of the tricarboxylic acid (TCA) cycle. However, the glutaminase II pathway also converts l-glutamine to α-ketoglutarate. This pathway consists of a glutamine transaminase coupled to ω-amidase [Net reaction: l-Glutamine + α-keto acid + HO → α-ketoglutarate + l-amino acid + NH]. This review focuses on the biological importance of the glutaminase II pathway, especially in relation to metabolism of cancer cells. Our studies suggest a component enzyme of the glutaminase II pathway, ω-amidase, is utilized by tumor cells to provide anaplerotic carbon. Inhibitors of GLS1 are currently in clinical trials as anti-cancer agents. However, this treatment will not prevent the glutaminase II pathway from providing anaplerotic carbon derived from glutamine. Specific inhibitors of ω-amidase, perhaps in combination with a GLS1 inhibitor, may provide greater therapeutic efficacy.
在快速分裂的细胞中，包括许多癌细胞，L-谷氨酰胺是一种主要的能量来源。谷氨酰胺的利用通常描述为：L-谷氨酰胺→L-谷氨酸（由谷氨酰胺酶同工酶；GLS1 和 GLS2 催化），然后 L-谷氨酸→α-酮戊二酸[由谷氨酸连接氨基转移酶或谷氨酸脱氢酶（GDH）催化]。α-酮戊二酸是三羧酸（TCA）循环的主要补料成分。然而，谷氨酰胺酶 II 途径也将 L-谷氨酰胺转化为α-酮戊二酸。该途径由谷氨酰胺转氨酶与ω-酰胺酶组成[净反应：L-谷氨酰胺+α-酮酸+HO→α-酮戊二酸+L-氨基酸+NH]。这篇综述重点介绍了谷氨酰胺酶 II 途径的生物学重要性，特别是与癌细胞代谢的关系。我们的研究表明，谷氨酰胺酶 II 途径的一种酶成分，ω-酰胺酶，被肿瘤细胞用来提供补料碳。目前，GLS1 的抑制剂正在临床试验中作为抗癌药物。然而，这种治疗方法并不能阻止谷氨酰胺酶 II 途径提供来自谷氨酰胺的补料碳。ω-酰胺酶的特异性抑制剂，也许与 GLS1 抑制剂联合使用，可能会提供更大的治疗效果。
