The Metabolic Importance of the Glutaminase II Pathway in Normal and Cancerous Cells

Authors

Thambi Dorai, 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. Electronic address: TDorai@northwell.edu.
John T. Pinto, Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA.Follow
Travis T. Denton, Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, WA, 99210, USA; Department of Translational Medicine & Physiology, Elson S. Floyd College of Medicine, Washington State University Health Sciences, Spokane, WA, 99210, USA; Steve Gleason Institute for Neuroscience, Washington State University Health Sciences, Spokane, WA, 99210, USA.
Boris F. Krasnikov, Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA.
Arthur J. Cooper, Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA.Follow

Author Type(s)

Faculty

Journal Title

Analytical Biochemistry

First Page

114083

Document Type

Article

Publication Date

5-1-2022

Department

Biochemistry and Molecular Biology

Abstract

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.

Recommended Citation

Dorai, T., Pinto, J. T., Denton, T. T., Krasnikov, B. F., & Cooper, A. J. (2022). The Metabolic Importance of the Glutaminase II Pathway in Normal and Cancerous Cells. Analytical Biochemistry, 644, 114083. https://doi.org/10.1016/j.ab.2020.114083