ω-Amidase and Its Substrate α-Ketoglutaramate (the α-Keto Acid Analogue of Glutamine) as Biomarkers in Health and Disease.

A large literature exists on the biochemistry, chemistry, metabolism, and clinical importance of the α-keto acid analogues of many amino acids. However, although glutamine is the most abundant amino acid in human tissues, and transamination of glutamine to its α-keto acid analogue (α-ketoglutaramate; KGM) was described more than seventy years ago, little information is available on the biological importance of KGM. Herein, we summarize the metabolic importance of KGM as an intermediate in the glutamine transaminase - ω-amidase (GTωA) pathway for the conversion of glutamine to anaplerotic α-ketoglutarate. We describe some properties of KGM, notably its occurrence as a lactam (2-hydroxy-5-oxoproline; 99.7% at pH 7.2), and its presence in normal tissues and body fluids. We note that the concentration of KGM is elevated in the cerebrospinal fluid of liver disease patients and that the urinary KGM/creatinine ratio is elevated in patients with an inborn error of the urea cycle and in patients with citrin deficiency. Recently, of the 607 urinary metabolites measured in a kidney disease study, KGM was noted to be one of five metabolites that was most significantly associated with uromodulin (a potential biomarker for tubular functional mass). Finally, we note that KGM is an intermediate in the breakdown of nicotine in certain organisms and is an important factor in nitrogen homeostasis in some microorganisms and plants. In conclusion, we suggest that biochemists and clinicians should consider KGM as (i) a key intermediate in nitrogen metabolism in all branches of life, and (ii) a biomarker, along with ω-amidase, in several diseases.