The Metabolic Importance of the Overlooked Asparaginase II Pathway

Authors

Arthur J. Cooper, Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA.Follow
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; Departments of Urology and Medical Oncology, Phelps Hospital, Northwell Health System, Sleepy Hollow, NY, 10591, USA. Electronic address: t_dorai@hotmail.com.
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 Biomedical Sciences, 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. Electronic address: travis.denton@wsu.edu.

Author Type(s)

Faculty

Journal Title

Analytical Biochemistry

First Page

114084

Document Type

Article

Publication Date

5-1-2022

Department

Biochemistry and Molecular Biology

Abstract

The asparaginase II pathway consists of an asparagine transaminase [l-asparagine + α-keto acid ⇆ α-ketosuccinamate + l-amino acid] coupled to ω-amidase [α-ketosuccinamate + HO → oxaloacetate + NH]. The net reaction is: l-asparagine + α-keto acid + HO → oxaloacetate + l-amino acid + NH. Thus, in the presence of a suitable α-keto acid substrate, the asparaginase II pathway generates anaplerotic oxaloacetate at the expense of readily dispensable asparagine. Several studies have shown that the asparaginase II pathway is important in photorespiration in plants. However, since its discovery in rat tissues in the 1950s, this pathway has been almost completely ignored as a conduit for asparagine metabolism in mammals. Several mammalian transaminases can catalyze transamination of asparagine, one of which - alanine-glyoxylate aminotransferase type 1 (AGT1) - is important in glyoxylate metabolism. Glyoxylate is a precursor of oxalate which, in the form of its calcium salt, is a major contributor to the formation of kidney stones. Thus, transamination of glyoxylate with asparagine may be physiologically important for the removal of potentially toxic glyoxylate. Asparaginase has been the mainstay treatment for certain childhood leukemias. We suggest that an inhibitor of ω-amidase may potentiate the therapeutic benefits of asparaginase treatment.

Recommended Citation

Cooper, A. J., Dorai, T., Pinto, J. T., & Denton, T. T. (2022). The Metabolic Importance of the Overlooked Asparaginase II Pathway. Analytical Biochemistry, 644, 114084. https://doi.org/10.1016/j.ab.2020.114084