title: 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.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA. Arthur_Cooper@nymc.edu.
authors.forename: Arthur J L
authors.initials: AJ
authors.lastname: Cooper
authors.affiliation: Department of Neurology, The Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10021, USA.|A.N. Bach Institute of Biochemistry, Russian Academy of Sciences, 33 Leninsky Prospekt, Moscow, 119071, Russia.
authors.forename: Yevgeniya I
authors.initials: YI
authors.lastname: Shurubor
authors.affiliation: Department of Urology, New York Medical College, Valhalla, NY, 10595, USA.
authors.forename: Thambi
authors.initials: T
authors.lastname: Dorai
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Pinto
authors.affiliation: A.N. Bach Institute of Biochemistry, Russian Academy of Sciences, 33 Leninsky Prospekt, Moscow, 119071, Russia.
authors.forename: Elena P
authors.initials: EP
authors.lastname: Isakova
authors.affiliation: A.N. Bach Institute of Biochemistry, Russian Academy of Sciences, 33 Leninsky Prospekt, Moscow, 119071, Russia.
authors.forename: Yulia I
authors.initials: YI
authors.lastname: Deryabina
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, 99210, USA.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Denton
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA.|A.N. Bach Institute of Biochemistry, Russian Academy of Sciences, 33 Leninsky Prospekt, Moscow, 119071, Russia.
authors.forename: Boris F
authors.initials: BF
authors.lastname: Krasnikov
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001216:Asparagine / Q000737:chemistry / Q000378:metabolism*; D005973:Glutamine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D022124:Hyperammonemia / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism*; D013455:Sulfur / Q000378:metabolism*
chemical_list: D005973:Glutamine; D001216:Asparagine; D013455:Sulfur; D000581:Amidohydrolases; C047679:omega-amidase; D009584:Nitrogen
keywords: Asparagine transaminase; Glutamine transaminase; Kynurenine aminotransferase; Nitrilase-like protein (Nit2); α-Ketoglutaramate; α-Ketosuccinamate; ω-Amidase