Metabolic Brain Disease

, Volume 29, Issue 4, pp 991–1006 | Cite as

α-Ketoglutaramate: an overlooked metabolite of glutamine and a biomarker for hepatic encephalopathy and inborn errors of the urea cycle

  • Arthur J. L. Cooper
  • Tomiko Kuhara
Original Paper


Glutamine metabolism is generally regarded as proceeding via glutaminase-catalyzed hydrolysis to glutamate and ammonia, followed by conversion of glutamate to α-ketoglutarate catalyzed by glutamate dehydrogenase or by a glutamate-linked aminotransferase (transaminase). However, another pathway exists for the conversion of glutamine to α-ketoglutarate that is often overlooked, but is widely distributed in nature. This pathway, referred to as the glutaminase II pathway, consists of a glutamine transaminase coupled to ω-amidase. Transamination of glutamine results in formation of the corresponding α-keto acid, namely, α-ketoglutaramate (KGM). KGM is hydrolyzed by ω-amidase to α-ketoglutarate and ammonia. The net glutaminase II reaction is: L ‐ Glutamine + α ‐ keto acid + H2O → α ‐ ketoglutarate + L ‐ amino acid + ammonia. In this mini-review the biochemical importance of the glutaminase II pathway is summarized, with emphasis on the key component KGM. Forty years ago it was noted that the concentration of KGM is increased in the cerebrospinal fluid (CSF) of patients with hepatic encephalopathy (HE) and that the level of KGM in the CSF correlates well with the degree of encephalopathy. In more recent work, we have shown that KGM is markedly elevated in the urine of patients with inborn errors of the urea cycle. It is suggested that KGM may be a useful biomarker for many hyperammonemic diseases including hepatic encephalopathy, inborn errors of the urea cycle, citrin deficiency and lysinuric protein intolerance.


ω-Amidase Ammonia Glutaminase II Hepatic encephalopathy α-ketoglutaramate Urea cycle disorders 





Argininosuccinate synthase


Branched-chain amino acid aminotransferase


Cerebrospinal fluid


Carbamyl phosphate synthetase I


Gas chromatography-mass spectrometry




Glutamine transaminase K


Glutamine transaminase L


Hepatic encephalopathy


Kynurenine aminotransferase


Kidney type glutaminase






Liver type glutaminase


Lysinuric protein intolerance




Neonatal intrahepatic cholestasis

Nit 1

Nitrilase-like protein 1

Nit 2

Nitrilase-like protein 2


Phosphate-activated glutaminase


Ornithine transcarbamylase



Some of the author’s work mentioned in this review was supported by NIH grant DK 16739.

Conflict of interest

No potential conflict of interest relevant to this article is presented.


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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyNew York Medical CollegeValhallaUSA
  2. 2.Department of Biochemistry, Division of Human Genetics, Medical Research InstituteKanazawa Medical UniversityKahoku-gunJapan
  3. 3.Japan Clinical Metabolomics InstituteKahokuJapan

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