The metabolic importance of the glutaminase II pathway in normal and cancerous cells

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 -> alpha-ketoglutarate [catalyzed by glutamate-linked aminotransferases or by glutamate dehydrogenase (GDH)]. alpha-Ketoglutarate is a major anaplerotic component of the tricarboxylic acid (TCA) cycle. However, the glutaminase II pathway also converts L-glutamine to alpha-ketoglutarate. This pathway consists of a glutamine transaminase coupled to omega-amidase [Net reaction: L-Glutamine + alpha-keto acid + H2O -> alpha-ketoglutarate +L-amino acid + NH4+]. 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, omega-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 omega-amidase, perhaps in combination with a GLS1 inhibitor, may provide greater therapeutic efficacy.

Automated summary

This article discusses the importance of the glutaminase II pathway in cancer cell metabolism, particularly as a mechanism for providing carbon sources. Studies suggest that inhibiting GLS1 alone does not prevent the glutaminase II pathway from supplying carbon derived from glutamine, highlighting the potential therapeutic efficacy of specific inhibitors for omega-amidase in combination with GLS1 inhibitors.