Background: Metabolic reprogramming of tumours is a hallmark of cancer. Among the changes in the metabolic network of cancer cells, glutaminolysis is a key reaction altered in neoplasms. Glutaminase proteins control the first step in glutamine metabolism and their expression correlates with malignancy and growth rate of a great variety of cancers. The two types of glutaminase isoenzymes, GLS and GLS2, differ in their expression patterns and functional roles: GLS has oncogenic properties and GLS2 has been described as a tumour suppressor factor.

Results: We have focused on glutaminase connections with key oncogenes and tumour suppressor genes. Targeting glutaminase isoenzymes includes different strategies aimed at deactivating the rewiring of cancer metabolism. In addition, we found a long list of metabolic enzymes, transcription factors and signalling pathways dealing with glutaminase. On the other hand, a number of chemicals have been described as isoenzyme-specific inhibitors of GLS and/or GLS2 isoforms. These molecules are being characterized as synergic and therapeutic agents in many types of tumours.

Conclusion: This review states the metabolic pathways that are rewired in cancer, the roles of glutaminase isoforms in cancer, as well as the metabolic circuits regulated by glutaminases. We also show the plethora of anticancer drugs that specifically inhibit glutaminase isoenzymes for treating several sets of cancer.

背景：肿瘤的代谢重编程是癌症的标志。在癌细胞代谢网络的变化中，谷氨酰胺分解是肿瘤中改变的关键反应。谷氨酰胺酶蛋白控制着谷氨酰胺代谢的第一步，它们的表达与多种癌症的恶性程度和生长率相关。两种类型的谷氨酰胺酶同工酶GLS和GLS2在表达方式和功能上有所不同：GLS具有致癌性，而GLS2被描述为肿瘤抑制因子。

结果：我们集中研究了谷氨酰胺酶与关键癌基因和抑癌基因的联系。靶向谷氨酰胺酶同工酶包括旨在使癌症新陈代谢失活的不同策略。此外，我们发现了与谷氨酰胺酶相关的代谢酶，转录因子和信号传导途径的清单。另一方面，许多化学品已被描述为GLS和/或GLS2同工型的同功酶特异性抑制剂。这些分子在许多类型的肿瘤中被表征为协同和治疗剂。

结论：本综述阐述了在癌症中重新建立的代谢途径，谷氨酰胺酶同工型在癌症中的作用以及谷氨酰胺酶调节的代谢回路。我们还显示了过多的抗癌药物，它们能特异性抑制谷氨酰胺酶同工酶来治疗几种癌症。