Chemistry, biochemistry and clinical relevance of the glutamine metabolite α-ketoglutaramate/2-hydroxy-5-oxoproline

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.