Department of Biología Molecular y Bioquímica, Facultad de Ciencias, Campus de Teatinos, Universidad de Málaga, Málaga, Spain.
Curr Mol Med. 2013 May;13(4):514-34. doi: 10.2174/1566524011313040005.
Cancer cells require a robust supply of reduced nitrogen to produce nucleotides, non-essential amino acids and a high cellular redox activity. Glutamine provides a major substrate for respiration as well as nitrogen for the production of proteins, hexosamines, and macromolecules. Therefore, glutamine is one of key molecules in cancer metabolism during cell proliferation. The notion of targeting glutamine metabolism in cancer, originally rationalized by the number of pathways fed by this nutrient, has been reinforced by more recent studies demonstrating that its metabolism is regulated by oncogenes. Glutamine can exert its effects by modulating redox homeostasis, bioenergetics, nitrogen balance or other functions, including by being a precursor of glutathione, the major nonenzymatic cellular antioxidant. Glutaminase (GA) is the first enzyme that converts glutamine to glutamate, which is in turn converted to alpha-ketoglutarate for further metabolism in the tricarboxylic acid cycle. Different GA isoforms in mammals are encoded by two genes, Gls and Gls2. As each enzymatic form of GA has distinct kinetic and molecular characteristics, it has been speculated that the differential regulation of GA isoforms may reflect distinct functions or requirements in different tissues or cell states. GA encoded by Gls gene (GLS) has been demonstrated to be regulated by oncogenes and to support tumor cell growth. GA encoded by Gls2 gene (GLS2) reduces cellular sensitivity to reactive oxygen species associated apoptosis possibly through glutathione-dependent antioxidant defense, and therefore to behave more like a tumor suppressor. Thus, modulation of GA function may be a new therapeutic target for cancer treatment.
癌细胞需要大量还原态氮来合成核苷酸、非必需氨基酸和维持高细胞氧化还原活性。谷氨酰胺是呼吸作用的主要底物，也是合成蛋白质、己糖胺和大分子的氮源。因此，谷氨酰胺是细胞增殖过程中癌症代谢的关键分子之一。最初，由于有许多代谢途径依赖于这种营养物质，人们认为可以靶向谷氨酰胺代谢来治疗癌症，而最近的研究则进一步证实，其代谢受到致癌基因的调控。谷氨酰胺可以通过调节氧化还原平衡、生物能量学、氮平衡或其他功能发挥作用，包括作为谷胱甘肽的前体，谷胱甘肽是主要的非酶细胞抗氧化剂。谷氨酰胺酶 (GA) 是将谷氨酰胺转化为谷氨酸的第一酶，谷氨酸又转化为α-酮戊二酸，进一步在三羧酸循环中代谢。哺乳动物中的不同 GA 同工酶由两个基因 Gls 和 Gls2 编码。由于每种 GA 酶形式都具有独特的动力学和分子特征，因此有人推测 GA 同工酶的差异调节可能反映了不同组织或细胞状态的不同功能或需求。由 Gls 基因编码的 GA（GLS）已被证明受到致癌基因的调节，并支持肿瘤细胞生长。由 Gls2 基因编码的 GA（GLS2）通过谷胱甘肽依赖的抗氧化防御降低细胞对与活性氧相关的凋亡的敏感性，因此更像是一种肿瘤抑制因子。因此，GA 功能的调节可能成为癌症治疗的新靶点。
