Aspartate and asparagine metabolism (Homo sapiens)

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13, 225, 10, 12171, 4, 9, 156, 7, 162233, 8, 1811, 19-21, 24231416mitochondrial intermembrane spacecytosolmitochondrial matrixL-AsnGOT2 dimerPXLP-K333-GADL1 SLC25A12 Zn2+ TAU ASNS OANH3NAAGAc-CoANAALAD2 FOLH1B L-Asp NAT8LNAALADasesCoA-SHPXLP-K259-GOT1 dimerSLC25A13 FOLH1 GADL1 substratesH2OL-GluCYSA PXLP-K333-GADL1dimerHTAU 2OGb-Ala CO2PPiNAASPOAAASPA:Zn2+ dimerCH3COO-ASPGL-AspNAANAAH2OATP2OGH2OPXLP-K279-GOT2 ASPA ASNS dimerL-GlnCSA GADL1 productsPXLP-K259-GOT1 H+L-AspL-GluAMPSLC25A12,13172314


Description

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). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8963693
Reactome-version 
Reactome version: 73
Reactome Author 
Reactome Author: Jassal, Bijay

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Bibliography

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  1. Martini F, Angelaccio S, Barra D, Pascarella S, Maras B, Doonan S, Bossa F.; ''The primary structure of mitochondrial aspartate aminotransferase from human heart.''; PubMed Europe PMC Scholia
  2. Raasakka A, Mahootchi E, Winge I, Luan W, Kursula P, Haavik J.; ''Structure of the mouse acidic amino acid decarboxylase GADL1.''; PubMed Europe PMC Scholia
  3. 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.''; PubMed Europe PMC Scholia
  4. Karamitros CS, Konrad M.; ''Human 60-kDa lysophospholipase contains an N-terminal L-asparaginase domain that is allosterically regulated by L-asparagine.''; PubMed Europe PMC Scholia
  5. 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.''; PubMed Europe PMC Scholia
  6. Van Heeke G, Schuster SM.; ''Expression of human asparagine synthetase in Escherichia coli.''; PubMed Europe PMC Scholia
  7. Liu P, Torrens-Spence MP, Ding H, Christensen BM, Li J.; ''Mechanism of cysteine-dependent inactivation of aspartate/glutamate/cysteine sulfinic acid α-decarboxylases.''; PubMed Europe PMC Scholia
  8. Hlouchova K, Barinka C, Konvalinka J, Lubkowski J.; ''Structural insight into the evolutionary and pharmacologic homology of glutamate carboxypeptidases II and III.''; PubMed Europe PMC Scholia
  9. Owen OE, Reichard GA, Patel MS, Boden G.; ''Energy metabolism in feasting and fasting.''; PubMed Europe PMC Scholia
  10. Felig P.; ''Amino acid metabolism in man.''; PubMed Europe PMC Scholia
  11. 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.''; PubMed Europe PMC Scholia
  12. 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.''; PubMed Europe PMC Scholia
  13. 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.''; PubMed Europe PMC Scholia
  14. Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN.; ''Structure of aspartoacylase, the brain enzyme impaired in Canavan disease.''; PubMed Europe PMC Scholia
  15. Le Coq J, An HJ, Lebrilla C, Viola RE.; ''Characterization of human aspartoacylase: the brain enzyme responsible for Canavan disease.''; PubMed Europe PMC Scholia
  16. Liu P, Ge X, Ding H, Jiang H, Christensen BM, Li J.; ''Role of glutamate decarboxylase-like protein 1 (GADL1) in taurine biosynthesis.''; PubMed Europe PMC Scholia
  17. 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.''; PubMed Europe PMC Scholia
  18. 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.''; PubMed Europe PMC Scholia
  19. 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.''; PubMed Europe PMC Scholia
  20. O'Keefe DS, Bacich DJ, Heston WD.; ''Comparative analysis of prostate-specific membrane antigen (PSMA) versus a prostate-specific membrane antigen-like gene.''; PubMed Europe PMC Scholia
  21. 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.''; PubMed Europe PMC Scholia
  22. 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.''; PubMed Europe PMC Scholia
  23. Doyle JM, Schininà ME, Bossa F, Doonan S.; ''The amino acid sequence of cytosolic aspartate aminotransferase from human liver.''; PubMed Europe PMC Scholia
  24. Wozniak KM, Rojas C, Wu Y, Slusher BS.; ''The role of glutamate signaling in pain processes and its regulation by GCP II inhibition.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114747view16:23, 25 January 2021ReactomeTeamReactome version 75
113191view11:25, 2 November 2020ReactomeTeamReactome version 74
112793view17:49, 9 October 2020DeSlOntology Term : 'alanine, aspartate and glutamate metabolic pathway' added !
112792view17:48, 9 October 2020DeSlOntology Term : 'asparagine metabolic pathway' added !
112791view17:48, 9 October 2020DeSlOntology Term : 'PW:0001082' removed !
112790view17:48, 9 October 2020DeSlOntology Term : 'arginine metabolic pathway' added !
112745view16:15, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2OGMetaboliteCHEBI:16810 (ChEBI)
AMPMetaboliteCHEBI:16027 (ChEBI)
ASNS ProteinP08243 (Uniprot-TrEMBL)
ASNS dimerComplexR-HSA-507865 (Reactome)
ASPA ProteinP45381 (Uniprot-TrEMBL)
ASPA:Zn2+ dimerComplexR-HSA-5692213 (Reactome)
ASPGProteinQ86U10 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
CH3COO-MetaboliteCHEBI:15366 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
CSA MetaboliteCHEBI:16345 (ChEBI)
CYSA MetaboliteCHEBI:17285 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
FOLH1 ProteinQ04609 (Uniprot-TrEMBL)
FOLH1B ProteinQ9HBA9 (Uniprot-TrEMBL)
GADL1 productsComplexR-ALL-6787762 (Reactome)
GADL1 substratesComplexR-ALL-6787759 (Reactome)
GOT2 dimerComplexR-HSA-70594 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HTAU MetaboliteCHEBI:16668 (ChEBI)
L-AsnMetaboliteCHEBI:58048 (ChEBI)
L-Asp MetaboliteCHEBI:29991 (ChEBI)
L-AspMetaboliteCHEBI:29991 (ChEBI)
L-GlnMetaboliteCHEBI:58359 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
NAAMetaboliteCHEBI:21547 (ChEBI)
NAAGMetaboliteCHEBI:76931 (ChEBI)
NAALAD2 ProteinQ9Y3Q0 (Uniprot-TrEMBL)
NAALADasesComplexR-HSA-6787341 (Reactome)
NAASPMetaboliteCHEBI:16953 (ChEBI)
NAT8LProteinQ8N9F0 (Uniprot-TrEMBL)
NH3MetaboliteCHEBI:16134 (ChEBI)
OAAMetaboliteCHEBI:30744 (ChEBI)
OAMetaboliteCHEBI:30744 (ChEBI)
PPiMetaboliteCHEBI:29888 (ChEBI)
PXLP-K259-GOT1 ProteinP17174 (Uniprot-TrEMBL)
PXLP-K259-GOT1 dimerComplexR-HSA-70579 (Reactome)
PXLP-K279-GOT2 ProteinP00505 (Uniprot-TrEMBL)
PXLP-K333-GADL1 dimerComplexR-HSA-6787755 (Reactome)
PXLP-K333-GADL1 ProteinQ6ZQY3 (Uniprot-TrEMBL)
SLC25A12 ProteinO75746 (Uniprot-TrEMBL)
SLC25A12,13ComplexR-HSA-372469 (Reactome)
SLC25A13 ProteinQ9UJS0 (Uniprot-TrEMBL)
TAU MetaboliteCHEBI:15891 (ChEBI)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
b-Ala MetaboliteCHEBI:16958 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2OGArrowR-HSA-70581 (Reactome)
2OGR-HSA-70592 (Reactome)
2OGR-HSA-70596 (Reactome)
AMPArrowR-HSA-70599 (Reactome)
ASNS dimermim-catalysisR-HSA-70599 (Reactome)
ASPA:Zn2+ dimermim-catalysisR-HSA-5691507 (Reactome)
ASPGmim-catalysisR-HSA-6797627 (Reactome)
ATPR-HSA-70599 (Reactome)
Ac-CoAR-HSA-8954468 (Reactome)
CH3COO-ArrowR-HSA-5691507 (Reactome)
CO2ArrowR-HSA-6787757 (Reactome)
CoA-SHArrowR-HSA-8954468 (Reactome)
GADL1 productsArrowR-HSA-6787757 (Reactome)
GADL1 substratesR-HSA-6787757 (Reactome)
GOT2 dimermim-catalysisR-HSA-70596 (Reactome)
H+ArrowR-HSA-8954468 (Reactome)
H2OR-HSA-5691507 (Reactome)
H2OR-HSA-6797627 (Reactome)
H2OR-HSA-70599 (Reactome)
L-AsnArrowR-HSA-70599 (Reactome)
L-AsnR-HSA-6797627 (Reactome)
L-AspArrowR-HSA-372448 (Reactome)
L-AspArrowR-HSA-5691507 (Reactome)
L-AspArrowR-HSA-6797627 (Reactome)
L-AspArrowR-HSA-70581 (Reactome)
L-AspR-HSA-372448 (Reactome)
L-AspR-HSA-70592 (Reactome)
L-AspR-HSA-70596 (Reactome)
L-AspR-HSA-70599 (Reactome)
L-AspR-HSA-8954468 (Reactome)
L-GlnR-HSA-70599 (Reactome)
L-GluArrowR-HSA-372448 (Reactome)
L-GluArrowR-HSA-5693783 (Reactome)
L-GluArrowR-HSA-70592 (Reactome)
L-GluArrowR-HSA-70596 (Reactome)
L-GluArrowR-HSA-70599 (Reactome)
L-GluR-HSA-372448 (Reactome)
L-GluR-HSA-70581 (Reactome)
NAAArrowR-HSA-8954468 (Reactome)
NAAArrowR-HSA-8954513 (Reactome)
NAAGR-HSA-5693783 (Reactome)
NAALADasesmim-catalysisR-HSA-5693783 (Reactome)
NAAR-HSA-5691507 (Reactome)
NAAR-HSA-8954513 (Reactome)
NAASPArrowR-HSA-5693783 (Reactome)
NAT8Lmim-catalysisR-HSA-8954468 (Reactome)
NH3ArrowR-HSA-6797627 (Reactome)
OAAArrowR-HSA-70596 (Reactome)
OAArrowR-HSA-70592 (Reactome)
OAR-HSA-70581 (Reactome)
PPiArrowR-HSA-70599 (Reactome)
PXLP-K259-GOT1 dimermim-catalysisR-HSA-70581 (Reactome)
PXLP-K259-GOT1 dimermim-catalysisR-HSA-70592 (Reactome)
PXLP-K333-GADL1 dimermim-catalysisR-HSA-6787757 (Reactome)
R-HSA-372448 (Reactome) 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).
R-HSA-5691507 (Reactome) 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).
R-HSA-5693783 (Reactome) 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).
R-HSA-6787757 (Reactome) 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).
R-HSA-6797627 (Reactome) 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).
R-HSA-70581 (Reactome) 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.
R-HSA-70592 (Reactome) 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).
R-HSA-70596 (Reactome) 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.
R-HSA-70599 (Reactome) 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).
R-HSA-8954468 (Reactome) 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).
R-HSA-8954513 (Reactome) 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).
SLC25A12,13mim-catalysisR-HSA-372448 (Reactome)
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