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

In the glutaminase II pathway (which we now refer to as the glutamine transaminase-omega-amidase (GT omega A) pathway), L-glutamine is transaminated to a-ketoglutaramate (KGM), which, in turn, is hydrolyzed to a-ketoglutarate and ammonia by an enzyme known as omega-amidase. Despite the fact that the GT omega A 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/a-keto acid specificity of the glutamine transaminases, which has led to confusion over nomenclature and in assigning precise biological roles. Secondly, the a-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 GT omega A 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 GT omega A 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 beta-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 GT omega A pathway in mammalian and human tissues and in agricultural research; and (2) potent and selective inhibitors of omega-amidase, both as anti-cancer agents and as a means for investigating the detailed enzyme mechanism.