Chemistry, biochemistry and clinical relevance of the glutamine metabolite α-ketoglutaramate/2-hydroxy-5-oxoproline
Travis T. Denton
A B C * and Arthur J. L. Cooper D *
A Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University Health Sciences Spokane, Spokane, WA, USA.
B Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University Health Sciences Spokane, Spokane, WA, USA.
C Steve Gleason Institute for Neuroscience, Washington State University Health Sciences Spokane, Spokane, WA, USA.
D Department of Biochemistry and Molecular Biology, New York Medical College, 15 Dana Road, Valhalla, NY 10595, USA.
Dr. Denton obtained his BS degree in chemistry from Central Washington University and a PhD in chemistry from the University of Montana. Dr Denton performed a postdoctoral fellowship at the Human BioMolecular Research Institute in San Diego, CA, followed by a second postdoctoral fellowship at the Shafizadeh Rocky Mountain Center for Wood and Carbohydrate Chemistry at the University of Montana. He then moved on to become an Assistant Professor of chemistry at Eastern Washington University where he taught organic chemistry and performed medicinal chemistry research. Currently, Dr. Denton is an Assistant Professor at Washington State University Health Sciences Spokane in the College of Pharmacy and Pharmaceutical Sciences. Dr. Denton is an inaugural fellow in the Steve Gleason Institute for Neuroscience at Washington State University and is an affiliate Assistant Professor in the Elson S. Floyd College of Medicine at WSU Health Sciences Spokane. Dr. Denton leads medicinal chemistry/molecular biology efforts in the fields of glutamine addicted cancers, modulation of free radical biology at the level of the TCA cycle, development of small molecules for the treatment of neurological disorders, design and synthesis of small molecule inhibitors of CYP2A6 as smoking cessation agents, and preparation of carbohydrate-based polyhydroxypolyamides (polymers) for biomedical applications. |
Dr. Cooper obtained BSc (chemistry and zoology) and DSc (biochemistry) degrees from London University, an MSc degree (Biochemistry) from Imperial College, a PhD degree (biochemistry) from Weill Cornell Medicine (WCM) and a postdoctoral fellowship at Brandeis University (biochemistry). He has held professorships at WCM and New York Medical College (NYMC). He is currently Emeritus Professor of Biochemistry and Molecular Biology at NYMC and an Adjunct Professor at WCM. He is on the editorial board of several journals and is Editor-in-Chief of Analytical Biochemistry. His research interests include pyridoxal 5′-phosphate enzymes, enzyme mechanisms, bioactivation mechanisms, neurochemistry, neurodegenerative diseases, cancer biochemistry, chemoprevention, and 1-C, nitrogen, sulfur and selenium biochemistry. |
Australian Journal of Chemistry 76(8) 361-371 https://doi.org/10.1071/CH22264
Submitted: 16 December 2022 Accepted: 5 May 2023 Published: 11 July 2023
© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing.
Abstract
In the glutaminase II pathway (which we now refer to as the glutamine transaminase-ω-amidase (GTωA) pathway), l-glutamine is transaminated to α-ketoglutaramate (KGM), which, in turn, is hydrolyzed to α-ketoglutarate and ammonia by an enzyme known as ω-amidase. Despite the fact that the GTωA pathway was discovered more than 70 years ago, and is widespread in nature, the pathway has received limited attention. This is partly due to the broad amino acid/α-keto acid specificity of the glutamine transaminases, which has led to confusion over nomenclature and in assigning precise biological roles. Secondly, the α-keto acid product of glutamine transaminases – KGM – has not, until recently, become available in pure form. Here, we briefly discuss the metabolic importance of the GTωA pathway in microorganisms, plants and mammals. We pay special attention to the chemistry of KGM and methods for its synthesis. We discuss the importance of KGM as a biomarker for hyperammonemic diseases. We provide evidence that the GTωA pathway satisfies, in part, ‘glutamine addiction’ in a variety of cancer cells. We show that the anti-cancer drugs 6-diazo-5-oxo-l-norleucine and l-azaserine are transaminase and β-lyase substrates of glutamine transaminase K, respectively. We suggest that there is a pressing need for the development of: (1) inexpensive and scaled-up procedures for the synthesis of KGM to facilitate research on the biological importance of the GTωA pathway in mammalian and human tissues and in agricultural research; and (2) potent and selective inhibitors of ω-amidase, both as anti-cancer agents and as a means for investigating the detailed enzyme mechanism.
Keywords: 2-Hydroxy-5-oxoproline, glutaminase 1 (GLS1), glutaminase 2 (GLS2), glutaminase II pathway, glutamine transaminases, α-ketoglutaramate, α-ketoglutarate, α-keto-γ-methiolbutyrate, ω-amidase.
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