Role of Glutamine Transaminases in Nitrogen, Sulfur, Selenium, and 1-Carbon Metabolism

Cooper, Arthur J. L.; Dorai, Thambi; Dorai, Bhuvaneswari; Krasnikov, Boris F.; Li, Jianyong; Hallen, André; Pinto, John T.

doi:10.1007/978-1-4939-1932-1_3

Cited by 12 publications

(29 citation statements)

References 46 publications

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“…All magnifications are ×20.) Reproduced from Cooper et al (2015) with permission used in the cancer treatment (Parmentier et al 2015). We suggest that part of the effectiveness of asparaginase treatment may result from inhibiting the asparaginase II and glutaminase II pathways for the provision of anaplerotic oxaloacetate and α-ketoglutarate to the cancer cells.…”

Section: An Important Role For ω-Amidase In Rapidly Dividing Cellsmentioning

confidence: 96%

“…The above discussion has prompted us to posit the following hypothesis, which has been published previously (Cooper et al 2015): GTK and ω-amidase are enriched and centrally located in epithelial cells from a wide variety of tissues and are thus poised to metabolize a variety of α-keto acids transported from body fluids. Our preliminary evidence has provided support for this hypothesis.…”

Section: An Important Role For ω-Amidase In Rapidly Dividing Cellsmentioning

confidence: 97%

“…It is now increasingly recognized that repair enzymes have evolved to correct the "mistakes" of other enzymes Linster et al 2013). In this context, one of the current authors (AJLC) had previously suggested that an important role of the glutamine transaminases is to act as repair enzymes to salvage α-keto acids generated through nonspecific transamination reactions (Cooper 1988, 2004, Cooper and Meister 1981, Cooper et al 2015. For example, the aromatic amino acids are substrates of both the cytosolic and mitochondrial forms of AspAT, and methionine and cysteine are substrates of the mitochondrial isozyme (Miller and Litwack 1971;Shrawder and Martinez-Carrion 1972).…”

Section: Salvage Of α-Keto Acidsmentioning

confidence: 98%

“…As a result, the gene for KAT I/GTK is annotated in mammalian gene data banks as cysteine S-conjugate beta-lyase isozyme 1 (CCBL1). This annotation is somewhat unfortunate because many PLPcontaining enzymes (including several aminotransferases) are now known to catalyze these β-lyase reactions as side reactions (Cooper et al 2011(Cooper et al , 2015. A closely related gene annotated as CCBL2 in mammalian gene data banks codes for KAT III/GTL (Pinto et al 2014).…”

Section: Glutamine Transaminases and Cysteine S-conjugate β-Lyasesmentioning

confidence: 98%

“…8) may be physiologically as critical as the PAG pathway (Eq. 1) for the metabolism of l-glutamine and possibly even more so (Cooper et al 2015).…”

Section: Identity Of Mammalian Glutamine Transaminasesmentioning

confidence: 99%

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ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

et al. 2015

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In mammals, two major routes exist for the metabolic conversion of L-glutamine to α-ketoglutarate. The most widely studied pathway involves the hydrolysis of L-glutamine to L-glutamate catalyzed by glutaminases, followed by the conversion of L-glutamate to α-ketoglutarate by the action of an L-glutamate-linked aminotransferase or via the glutamate dehydrogenase reaction. However, another major pathway exists in mammals for the conversion of L-glutamine to α-ketoglutarate (the glutaminase II pathway) in which L-glutamine is first transaminated to α-ketoglutaramate (KGM) followed by hydrolysis of KGM to α-ketoglutarate and ammonia catalyzed by an amidase known as ω-amidase. In mammals, the glutaminase II pathway is present in both cytosolic and mitochondrial compartments and is most prominent in liver and kidney. Similarly, two routes exist for the conversion of L-asparagine to oxaloacetate. In the most extensively studied pathway, L-asparagine is hydrolyzed to L-aspartate by the action of asparaginase, followed by transamination of L-aspartate to oxaloacetate. However, another pathway also exists for the conversion of L-asparagine to oxaloacetate (the asparaginase II pathway). In this pathway, L-asparagine is first transaminated to α-ketosuccinamate (KSM), followed by hydrolysis of KSM to oxaloacetate by the action of ω-amidase. One advantage of both the glutaminase II and the asparaginase II pathways is that they are irreversible, and thus are important in anaplerosis by shuttling 5-C (α-ketoglutarate) and 4-C (oxaloacetate) units into the TCA cycle. In this review, we briefly mention the importance of the glutaminase II and asparaginase II pathways in microorganisms and plants. However, the major emphasis of the review is related to the importance of these pathways (especially the common enzyme component of both pathways--ω-amidase) in nitrogen and sulfur metabolism in mammals and as a source of anaplerotic carbon moieties in rapidly dividing cells. The review also discusses a potential dichotomous function of ω-amidase as having a role in tumor progression. Finally, the possible role of KGM as a biomarker for hyperammonemic diseases is discussed.

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Section: An Important Role For ω-Amidase In Rapidly Dividing Cellsmentioning

confidence: 96%

Section: An Important Role For ω-Amidase In Rapidly Dividing Cellsmentioning

confidence: 97%

Section: Salvage Of α-Keto Acidsmentioning

confidence: 98%

Section: Glutamine Transaminases and Cysteine S-conjugate β-Lyasesmentioning

confidence: 98%

“…8) may be physiologically as critical as the PAG pathway (Eq. 1) for the metabolism of l-glutamine and possibly even more so (Cooper et al 2015).…”

Section: Identity Of Mammalian Glutamine Transaminasesmentioning

confidence: 99%

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ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

et al. 2015

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Erratum to: ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

et al. 2015

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

Cooper

Kuhara

2013

Metab Brain Dis

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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.

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Role of Glutamine Transaminases in Nitrogen, Sulfur, Selenium, and 1-Carbon Metabolism

Cited by 12 publications

References 46 publications

ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

Erratum to: ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

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

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