These reactions mediate the synthesis of aspartate and asparagine from glutamate, TCA cycle intermediates, and ammonia and and allow the utilization of carbon atoms from these amino acids for glucose synthesis under fasting conditions (Felig 1975; Owen et al. 1979).
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Martini F, Angelaccio S, Barra D, Pascarella S, Maras B, Doonan S, Bossa F.; ''The primary structure of mitochondrial aspartate aminotransferase from human heart.''; PubMedEurope PMCScholia
Raasakka A, Mahootchi E, Winge I, Luan W, Kursula P, Haavik J.; ''Structure of the mouse acidic amino acid decarboxylase GADL1.''; PubMedEurope PMCScholia
Pessentheiner AR, Pelzmann HJ, Walenta E, Schweiger M, Groschner LN, Graier WF, Kolb D, Uno K, Miyazaki T, Nitta A, Rieder D, Prokesch A, Bogner-Strauss JG.; ''NAT8L (N-acetyltransferase 8-like) accelerates lipid turnover and increases energy expenditure in brown adipocytes.''; PubMedEurope PMCScholia
Karamitros CS, Konrad M.; ''Human 60-kDa lysophospholipase contains an N-terminal L-asparaginase domain that is allosterically regulated by L-asparagine.''; PubMedEurope PMCScholia
Pangalos MN, Neefs JM, Somers M, Verhasselt P, Bekkers M, van der Helm L, Fraiponts E, Ashton D, Gordon RD.; ''Isolation and expression of novel human glutamate carboxypeptidases with N-acetylated alpha-linked acidic dipeptidase and dipeptidyl peptidase IV activity.''; PubMedEurope PMCScholia
Van Heeke G, Schuster SM.; ''Expression of human asparagine synthetase in Escherichia coli.''; PubMedEurope PMCScholia
Liu P, Torrens-Spence MP, Ding H, Christensen BM, Li J.; ''Mechanism of cysteine-dependent inactivation of aspartate/glutamate/cysteine sulfinic acid α-decarboxylases.''; PubMedEurope PMCScholia
Hlouchova K, Barinka C, Konvalinka J, Lubkowski J.; ''Structural insight into the evolutionary and pharmacologic homology of glutamate carboxypeptidases II and III.''; PubMedEurope PMCScholia
Owen OE, Reichard GA, Patel MS, Boden G.; ''Energy metabolism in feasting and fasting.''; PubMedEurope PMCScholia
Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, Yasuda T, Ikeda S, Hirano R, Terazono H, Crackower MA, Kondo I, Tsui LC, Scherer SW, Saheki T.; ''The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein.''; PubMedEurope PMCScholia
Herga S, Berrin JG, Perrier J, Puigserver A, Giardina T.; ''Identification of the zinc binding ligands and the catalytic residue in human aspartoacylase, an enzyme involved in Canavan disease.''; PubMedEurope PMCScholia
Del Arco A, Agudo M, Satrústegui J.; ''Characterization of a second member of the subfamily of calcium-binding mitochondrial carriers expressed in human non-excitable tissues.''; PubMedEurope PMCScholia
Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN.; ''Structure of aspartoacylase, the brain enzyme impaired in Canavan disease.''; PubMedEurope PMCScholia
Le Coq J, An HJ, Lebrilla C, Viola RE.; ''Characterization of human aspartoacylase: the brain enzyme responsible for Canavan disease.''; PubMedEurope PMCScholia
Liu P, Ge X, Ding H, Jiang H, Christensen BM, Li J.; ''Role of glutamate decarboxylase-like protein 1 (GADL1) in taurine biosynthesis.''; PubMedEurope PMCScholia
Saheki T, Kobayashi K, Iijima M, Nishi I, Yasuda T, Yamaguchi N, Gao HZ, Jalil MA, Begum L, Li MX.; ''Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency.''; PubMedEurope PMCScholia
Prokesch A, Pelzmann HJ, Pessentheiner AR, Huber K, Madreiter-Sokolowski CT, Drougard A, Schittmayer M, Kolb D, Magnes C, Trausinger G, Graier WF, Birner-Gruenberger R, Pospisilik JA, Bogner-Strauss JG.; ''N-acetylaspartate catabolism determines cytosolic acetyl-CoA levels and histone acetylation in brown adipocytes.''; PubMedEurope PMCScholia
Mesters JR, Barinka C, Li W, Tsukamoto T, Majer P, Slusher BS, Konvalinka J, Hilgenfeld R.; ''Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer.''; PubMedEurope PMCScholia
O'Keefe DS, Bacich DJ, Heston WD.; ''Comparative analysis of prostate-specific membrane antigen (PSMA) versus a prostate-specific membrane antigen-like gene.''; PubMedEurope PMCScholia
Palmieri L, Pardo B, Lasorsa FM, del Arco A, Kobayashi K, Iijima M, Runswick MJ, Walker JE, Saheki T, Satrústegui J, Palmieri F.; ''Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria.''; PubMedEurope PMCScholia
Wiame E, Tyteca D, Pierrot N, Collard F, Amyere M, Noel G, Desmedt J, Nassogne MC, Vikkula M, Octave JN, Vincent MF, Courtoy PJ, Boltshauser E, van Schaftingen E.; ''Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia.''; PubMedEurope PMCScholia
Doyle JM, Schininà ME, Bossa F, Doonan S.; ''The amino acid sequence of cytosolic aspartate aminotransferase from human liver.''; PubMedEurope PMCScholia
Wozniak KM, Rojas C, Wu Y, Slusher BS.; ''The role of glutamate signaling in pain processes and its regulation by GCP II inhibition.''; PubMedEurope PMCScholia
Calcium-binding mitochondrial carrier proteins Aralar1 and Aralar2 (SLC25A12 and SLC25A13 respectively), located in the inner mitochondrial membrane, mediate the exchange of cytosolic aspartate and mitochondrial glutamate (Palmieri et al. 2001). The exchange is physiologically irreversible because of the potential across the inner mitochondrial membrane (positive outside, negative inside). In the body, SLC25A12 is found mainly in heart, skeletal muscle, and brain, while SCL25A13 is widely expressed but most abundant in liver (del Arco et al. 2000; Palmieri et al. 2001). Defects in SLC25A13 are associated with type II citrullinemia, characterised by a liver-specific deficiency of the urea cycle enzyme argininosuccinate synthase (Kobayashi et al. 1999, Saheki et al. 2002).
Aspartoacylase (ASPA) is a cytosolic zinc metalloenzyme highly expressed in brain white matter, skeletal muscle, kidney, adrenal glands, lung and liver. ASPA catalyses the hydrolysis of N-acetylaspartic acid (NAA) to produce acetate (CH3COO-) and L-aspartate (L-Asp). NAA occurs in high concentration in brain and is thought to play a significant part in the maintenance of intact white matter. In other tissues it acts as a scavenger of NAA from body fluids. Defects in ASPA lead to Canavan disease (CAND; MIM:271900), a fatal neurological disorder of infants characterised by white matter vacuolisation and demyelination (Herga et al. 2006, Le Coq et al. 2006, Bitto et al. 2007).
Excessive glutamate has been implicated in neurodegenerative disorders and stroke. One source of glutamate is from the hydrolysis of N-acetylaspartylglutamate (NAAG), a neurotransmitter found in the brain. NAAG can he hydrolysed by glutamate carboxypeptidase 2 (FOLH1), a membrane-bound, homodimeric enzyme which possesses both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity (Mesters et al. 2006). Inhibition of FOLH1 could have neuroprotective effects (Wozniak et al. 2012). Other dipeptidases able to hydrolyse NAAG are N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2) (Pangalos et al. 1999, Hlouchova et al. 2009) and putative N-acetylated-alpha-linked acidic dipeptidase (FOLH1B) (O'Keefe et al. 2004).
Acidic amino acid decarboxylase GADL1 (GADL1) can decarboxylate aspartate, cysteine sulfinic acid, and cysteic acid to beta-alanine, hypotaurine and taurine, respectively but does not exhibit any decarboxylation activity toward glutamate (Liu et al. 2012, 2013). The dimeric structure of the enzyme is inferred from studies of its mouse homolog (Raasakka et al. 2018).
L-Asparaginases can catalyse the hydrolysis of L-asparagine (L-Asn) to L-aspartic acid (L-Asp) and ammonia (NH3) in organisms ranging from bacteria to humans. Bacterial type II versions of the enzyme serve as therapeutics for the treatment of acute lymphoblastic leukemia despite adverse side effects. The human equivalent (60 kDa lysophospholipase, ASPG) has shown to possess L-Asparaginase activity and may be a potential alternative replacement for bacterial enzymes as a leukemia therapeutic in the future (Karamitros & Konrad 2014).
Cytosolic aspartate aminotransferase (glutamate oxaloacetate transaminase 1 - GOT1) catalyzes the reversible reaction of oxaloacetate and glutamate to form aspartate and 2-oxoglutarate (alpha-ketoglutarate) (Doyle et al. 1990). Unpublished crystallographic data (PBD 3IIO) suggest the enzyme is a homodimer.
Cytosolic aspartate aminotransferase (glutamate oxaloacetate transaminase 1 - GOT1) catalyzes the reversible reaction of aspartate and 2-oxoglutarate (alpha-ketoglutarate) to form oxaloacetate and glutamate (Doyle et al. 1990). Unpublished crystallographic data (PBD 3IIO) suggest the enzyme is a homodimer).
Mitochondrial glutamate oxaloacetate transaminase 2 (aspartate aminotransferase 2 - GOT2) catalyzes the reversible reaction of aspartate and 2-oxoglutarate (alpha-ketoglutarate) to form oxaloacetate and glutamate (Martini et al. 1985). The active form of the enzyme is inferred to be a dimer with one molecule of pyridoxal phosphate associated with each monomer.
Cytosolic asparagine synthase (ASNS) catalyzes the reaction of aspartate, glutamine, and ATP to form asparagine, glutamate, AMP, and pyrophosphate. Studies of the recombinant protein expressed in E. coli suggest that the active form of the enzyme is a dimer (Van Heeke and Schuster 1989).
N-acetylaspartate (NAA) is a highly abundant brain metabolite which delivers the acetate moiety for synthesis of acetyl-CoA, further utilised for fatty acid generation. In the mitochondrial matrix of neuronal cells, N-acetylaspartate synthetase (NAT8L) catalyses the formation of NAA from acetyl-CoA (Ac-CoA) and L-aspartatic acid (L-Asp) (Wiame et al. 2009, Pessentheiner et al. 2013, Prokesch et al. 2016).
Cytosolic acetyl-CoA (Ac-CoA) is used for lipid synthesis in adipocytes. N-acetylaspartate (NAA) is a source of Ac-CoA when catabolised in the cytosol. As no known specific NAA transporters have yet been identified, NAA translocates from the mitochondrial matrix to the cytosol by an unknown mechanism (Prokesch et al. 2016).
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