Metabolic Heterogeneity, Plasticity, and Adaptation to “Glutamine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase—ω-Amidase (Glutaminase II)] Pathway

SIMPLE SUMMARY: Many types of cancer cells utilize the common amino acid l-glutamine to maintain their metabolic demands for energy and the nitrogen required for DNA synthesis. Versatility to control energy metabolism from l-glutamine (anaplerosis) is promoted by the use of two distinct pathways. The first (pathway 1; the canonical pathway) is as follows: [l-glutamine → l-glutamate ⇆ α-ketoglutarate → tricarboxylic acid (TCA) cycle]. This pathway contrasts with the much less studied GTωA (glutamine transaminase—ω-amidase or glutaminase II) pathway (pathway 2): [l-glutamine ⇆ α-ketoglutaramate (KGM) → α-ketoglutarate → TCA cycle]. Our prior publications have emphasized the importance of regulation of both pathways, which enables cancer cells to maintain selective metabolic advantages and to conserve their reliance on glucose. This review summarizes the metabolic importance of the GTωA pathway in both cancerous and normal tissues and proposes that anti-cancer strategies, based on inhibition of l-glutamine metabolism, require consideration of both the canonical and GTωA pathways. ABSTRACT: Many cancers utilize l-glutamine as a major energy source. Often cited in the literature as “l-glutamine addiction”, this well-characterized pathway involves hydrolysis of l-glutamine by a glutaminase to l-glutamate, followed by oxidative deamination, or transamination, to α-ketoglutarate, which enters the tricarboxylic acid cycle. However, mammalian tissues/cancers possess a rarely mentioned, alternative pathway (the glutaminase II pathway): l-glutamine is transaminated to α-ketoglutaramate (KGM), followed by ω-amidase (ωA)-catalyzed hydrolysis of KGM to α-ketoglutarate. The name glutaminase II may be confused with the glutaminase 2 (GLS2) isozyme. Thus, we recently renamed the glutaminase II pathway the “glutamine transaminase—ω-amidase (GTωA)” pathway. Herein, we summarize the metabolic importance of the GTωA pathway, including its role in closing the methionine salvage pathway, and as a source of anaplerotic α-ketoglutarate. An advantage of the GTωA pathway is that there is no net change in redox status, permitting α-ketoglutarate production during hypoxia, diminishing cellular energy demands. We suggest that the ability to coordinate control of both pathways bestows a metabolic advantage to cancer cells. Finally, we discuss possible benefits of GTωA pathway inhibitors, not only as aids to studying the normal biological roles of the pathway but also as possible useful anticancer agents.