Urea cycle (Homo sapiens)

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168, 15, 184, 101, 2, 63, 12, 17, 20, 219, 115, 147, 13cytosolmitochondrial matrixCoA-SHH2OUreaARG1 ARSUAATPMn2+ ARG2 OTC trimerATPNADPH ASL Mn2+ L-ArgPPiASL tetramerSLC25A15 ADPNH4+L-GluL-ArgASS1 tetramer:NMRAL1dimer:NADPHCAPMitochondrialornithinetransportersARG1 trimerARG2 trimerPiSLC25A2 NMRAL1 NAGS(19-534)L-CitPiCPS1L-OrnNAcGluL-AspL-ArgAMPOTC ASS1 L-OrnFUMAHCO3-L-CitAc-CoAUreaH2OL-Orn492111551913


Description

The urea cycle yields urea, the major form in which excess nitrogen is excreted from the human body, and the amino acid arginine (Brusilow and Horwich 2001). It consists of four reactions: that of ornithine and carbamoyl phosphate to form citrulline, of citrulline and aspartate to form argininosuccinate, the cleavage of argininosuccinate to yield fumarate and arginine, and the cleavage of arginine to yield urea and re-form ornithine. The carbamoyl phosphate consumed in this cycle is synthesized in the mitochondria from bicarbonate and ammonia, and this synthesis in turn is dependent on the presence of N-acetylglutamate, which allosterically activates carbamoyl synthetase I enzyme. The synthesis of N-acetylglutamate is stimulated by high levels of arginine. Increased levels of free amino acids, indicated by elevated arginine levels, thus stimulate urea synthesis.

Two enzymes catalyze the hydrolysis of arginine to yield ornithine and urea. Cytosolic ARG1 is the canonical urea cycle enzyme. Mitochondrial ARG2 likewise catalyzes urea production from arginine and may have a substantial sparing effect in patients lacking ARG1 enzyme, so its reaction is annotated here although the role of ARG2 under normal physiological conditions remains unclear. View original pathway at Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 70635
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: D'Eustachio, Peter

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Bibliography

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  1. Cama E, Colleluori DM, Emig FA, Shin H, Kim SW, Kim NN, Traish AM, Ash DE, Christianson DW.; ''Human arginase II: crystal structure and physiological role in male and female sexual arousal.''; PubMed Europe PMC Scholia
  2. Gotoh T, Sonoki T, Nagasaki A, Terada K, Takiguchi M, Mori M.; ''Molecular cloning of cDNA for nonhepatic mitochondrial arginase (arginase II) and comparison of its induction with nitric oxide synthase in a murine macrophage-like cell line.''; PubMed Europe PMC Scholia
  3. Engel K, Höhne W, Häberle J.; ''Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene.''; PubMed Europe PMC Scholia
  4. Walker DC, McCloskey DA, Simard LR, McInnes RR.; ''Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region.''; PubMed Europe PMC Scholia
  5. Caldovic L, Morizono H, Gracia Panglao M, Gallegos R, Yu X, Shi D, Malamy MH, Allewell NM, Tuchman M.; ''Cloning and expression of the human N-acetylglutamate synthase gene.''; PubMed Europe PMC Scholia
  6. Iyer R, Jenkinson CP, Vockley JG, Kern RM, Grody WW, Cederbaum S.; ''The human arginases and arginase deficiency.''; PubMed Europe PMC Scholia
  7. Horwich AL, Fenton WA, Williams KR, Kalousek F, Kraus JP, Doolittle RF, Konigsberg W, Rosenberg LE.; ''Structure and expression of a complementary DNA for the nuclear coded precursor of human mitochondrial ornithine transcarbamylase.''; PubMed Europe PMC Scholia
  8. Camacho JA, Rioseco-Camacho N, Andrade D, Porter J, Kong J.; ''Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder.''; PubMed Europe PMC Scholia
  9. Di Costanzo L, Sabio G, Mora A, Rodriguez PC, Ochoa AC, Centeno F, Christianson DW.; ''Crystal structure of human arginase I at 1.29-A resolution and exploration of inhibition in the immune response.''; PubMed Europe PMC Scholia
  10. Turner MA, Simpson A, McInnes RR, Howell PL.; ''Human argininosuccinate lyase: a structural basis for intragenic complementation.''; PubMed Europe PMC Scholia
  11. Uchino T, Snyderman SE, Lambert M, Qureshi IA, Shapira SK, Sansaricq C, Smit LM, Jakobs C, Matsuda I.; ''Molecular basis of phenotypic variation in patients with argininemia.''; PubMed Europe PMC Scholia
  12. Zheng X, Dai X, Zhao Y, Chen Q, Lu F, Yao D, Yu Q, Liu X, Zhang C, Gu X, Luo M.; ''Restructuring of the dinucleotide-binding fold in an NADP(H) sensor protein.''; PubMed Europe PMC Scholia
  13. Shi D, Morizono H, Yu X, Tong L, Allewell NM, Tuchman M.; ''Human ornithine transcarbamylase: crystallographic insights into substrate recognition and conformational changes.''; PubMed Europe PMC Scholia
  14. Morizono H, Caldovic L, Shi D, Tuchman M.; ''Mammalian N-acetylglutamate synthase.''; PubMed Europe PMC Scholia
  15. Camacho JA, Obie C, Biery B, Goodman BK, Hu CA, Almashanu S, Steel G, Casey R, Lambert M, Mitchell GA, Valle D.; ''Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter.''; PubMed Europe PMC Scholia
  16. Pierson DL, Brien JM.; ''Human carbamylphosphate synthetase I. Stabilization, purification, and partial characterization of the enzyme from human liver.''; PubMed Europe PMC Scholia
  17. Zhao Y, Zhang J, Li H, Li Y, Ren J, Luo M, Zheng X.; ''An NADPH sensor protein (HSCARG) down-regulates nitric oxide synthesis by association with argininosuccinate synthetase and is essential for epithelial cell viability.''; PubMed Europe PMC Scholia
  18. Fiermonte G, Dolce V, David L, Santorelli FM, Dionisi-Vici C, Palmieri F, Walker JE.; ''The mitochondrial ornithine transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms.''; PubMed Europe PMC Scholia
  19. Kanyo ZF, Scolnick LR, Ash DE, Christianson DW.; ''Structure of a unique binuclear manganese cluster in arginase.''; PubMed Europe PMC Scholia
  20. Karlberg T, Collins R, van den Berg S, Flores A, Hammarström M, Högbom M, Holmberg Schiavone L, Uppenberg J.; ''Structure of human argininosuccinate synthetase.''; PubMed Europe PMC Scholia
  21. O'Brien WE.; ''Isolation and characterization of argininosuccinate synthetase from human liver.''; PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
114676view16:14, 25 January 2021ReactomeTeamReactome version 75
113123view11:18, 2 November 2020ReactomeTeamReactome version 74
112786view17:43, 9 October 2020DeSlOntology Term : 'urea cycle pathway' added !
112739view16:14, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
AMPMetaboliteCHEBI:16027 (ChEBI)
ARG1 ProteinP05089 (Uniprot-TrEMBL)
ARG1 trimerComplexR-HSA-70567 (Reactome)
ARG2 ProteinP78540 (Uniprot-TrEMBL)
ARG2 trimerComplexR-HSA-452013 (Reactome)
ARSUAMetaboliteCHEBI:15682 (ChEBI)
ASL ProteinP04424 (Uniprot-TrEMBL)
ASL tetramerComplexR-HSA-70571 (Reactome)
ASS1 ProteinP00966 (Uniprot-TrEMBL)
ASS1 tetramer:NMRAL1 dimer:NADPHComplexR-HSA-6810875 (Reactome)
ATPMetaboliteCHEBI:30616 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
CAPMetaboliteCHEBI:17672 (ChEBI)
CPS1ProteinP31327 (Uniprot-TrEMBL)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
FUMAMetaboliteCHEBI:37154 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCO3-MetaboliteCHEBI:17544 (ChEBI)
L-ArgMetaboliteCHEBI:32682 (ChEBI)
L-AspMetaboliteCHEBI:29991 (ChEBI)
L-CitMetaboliteCHEBI:16349 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
L-OrnMetaboliteCHEBI:15729 (ChEBI)
Mitochondrial

ornithine

transporters		ComplexR-HSA-374018 (Reactome)
Mn2+ MetaboliteCHEBI:29035 (ChEBI)
NADPH MetaboliteCHEBI:16474 (ChEBI)
NAGS(19-534)ProteinQ8N159 (Uniprot-TrEMBL)
NAcGluMetaboliteCHEBI:17533 (ChEBI)
NH4+MetaboliteCHEBI:28938 (ChEBI)
NMRAL1 ProteinQ9HBL8 (Uniprot-TrEMBL)
OTC ProteinP00480 (Uniprot-TrEMBL)
OTC trimerComplexR-HSA-70558 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
PiMetaboliteCHEBI:43474 (ChEBI)
SLC25A15 ProteinQ9Y619 (Uniprot-TrEMBL)
SLC25A2 ProteinQ9BXI2 (Uniprot-TrEMBL)
UreaMetaboliteCHEBI:16199 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-70555 (Reactome)
AMPArrowR-HSA-70577 (Reactome)
ARG1 trimermim-catalysisR-HSA-70569 (Reactome)
ARG2 trimermim-catalysisR-HSA-452036 (Reactome)
ARSUAArrowR-HSA-70577 (Reactome)
ARSUAR-HSA-70573 (Reactome)
ASL tetramermim-catalysisR-HSA-70573 (Reactome)
ASS1 tetramer:NMRAL1 dimer:NADPHmim-catalysisR-HSA-70577 (Reactome)
ATPR-HSA-70555 (Reactome)
ATPR-HSA-70577 (Reactome)
Ac-CoAR-HSA-70542 (Reactome)
CAPArrowR-HSA-70555 (Reactome)
CAPR-HSA-70560 (Reactome)
CPS1mim-catalysisR-HSA-70555 (Reactome)
CoA-SHArrowR-HSA-70542 (Reactome)
FUMAArrowR-HSA-70573 (Reactome)
H2OR-HSA-452036 (Reactome)
H2OR-HSA-70569 (Reactome)
HCO3-R-HSA-70555 (Reactome)
L-ArgArrowR-HSA-70542 (Reactome)
L-ArgArrowR-HSA-70573 (Reactome)
L-ArgR-HSA-452036 (Reactome)
L-ArgR-HSA-70569 (Reactome)
L-AspR-HSA-70577 (Reactome)
L-CitArrowR-HSA-70560 (Reactome)
L-CitArrowR-HSA-70634 (Reactome)
L-CitR-HSA-70577 (Reactome)
L-CitR-HSA-70634 (Reactome)
L-GluR-HSA-70542 (Reactome)
L-OrnArrowR-HSA-452036 (Reactome)
L-OrnArrowR-HSA-70569 (Reactome)
L-OrnArrowR-HSA-70634 (Reactome)
L-OrnR-HSA-70560 (Reactome)
L-OrnR-HSA-70634 (Reactome)
Mitochondrial

ornithine

transporters		mim-catalysisR-HSA-70634 (Reactome)
NAGS(19-534)mim-catalysisR-HSA-70542 (Reactome)
NAcGluArrowR-HSA-70542 (Reactome)
NAcGluArrowR-HSA-70555 (Reactome)
NH4+R-HSA-70555 (Reactome)
OTC trimermim-catalysisR-HSA-70560 (Reactome)
PPiArrowR-HSA-70577 (Reactome)
PiArrowR-HSA-70555 (Reactome)
PiArrowR-HSA-70560 (Reactome)
R-HSA-452036 (Reactome) Arginase 2 (ARG2) trimer catalyzes the hydrolysis of arginine to form urea and ornithine (Cama et al. 2003). ARG2 is localized to the mitochondrion (Gotoh ea 1996). The enzyme is expressed in many tissues in addition to liver and while its function appears to mitigate the effects of ARG1 deficiency on urea synthesis, its normal physiological roles have not been fully defined (Iyer et al. 1998).
R-HSA-70542 (Reactome) Mitochondrial N acetylglutamate synthetase (NAGS) catalyzes the reaction of glutamate and acetyl-CoA to form N-acetylglutamate and CoA. NAGS is activated by arginine and the N-acetylglutamate produced in the reaction in turn is required to activate carbamoyl synthetase I. Consistent with this regulatory role in urea synthesis, NAGS mutations in humans are associated with hyperammonemia (Caldovic et al. 2002; Morizono et al. 2004).
R-HSA-70555 (Reactome) At the beginning of this reaction, 1 molecule of 'NH4+', 1 molecule of 'HCO3-', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'Carbamoyl phosphate', 1 molecule of 'ADP', and 1 molecule of 'Orthophosphate' are present.

This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'carbamoyl-phosphate synthase (ammonia) activity' of 'carbamoyl-phosphate synthetase I dimer'.

R-HSA-70560 (Reactome) Mitochondrial ornithine transcarbamoylase (OTC) catalyzes the reaction of ornithine and carbamoyl phosphate to form citrulline (Horwich et al. 1984). The enzyme is a homotrimer (Shi et al. 2001).
R-HSA-70569 (Reactome) Cytosolic Arginase 1 (ARG1) trimer catalyzes the hydrolysis of arginine to yield ornithine and urea (DiCostanzo et al. 2005). Patients expressing mutated forms of the enzyme with diminished in vitro arginase activity can accumulate arginine to pathogenic levels in the blood (e.g., Uchino et al. 1995).
R-HSA-70573 (Reactome) Cytosolic argininosuccinate lyase (ASL) catalyzes the reversible reaction of argininosuccinate to form fumarate and arginine. The enzyme is a homotetramer (Turner et al. 1997). The function of the human enzyme in vivo is inferred from the defective argininosuccinate lyase enzyme activity observed in patients with mutant forms of the ASL gene (e.g., Walker et al. 1990).
R-HSA-70577 (Reactome) Cytosolic argininosuccinate synthase (ASS1 tetramer) catalyzes the reaction of aspartate (L-Asp), citrulline (L-Cit), and ATP to form argininosuccinate (ARSUA), AMP, and pyrophosphate (PPi). The function of the human enzyme in vivo is inferred from the hypercitrullinemia observed in patients with defective forms of the enzyme (e.g., Engel et al. 2009). The enzyme is active as a homotetramer (O'Brien 1980; Karlberg et al. 2008) and binds NmrA-like family domain-containing protein 1 (NMRAL1). NMRAL1 is a redox sensor protein that can undergo restructuring and subcellular redistribution in response to changes in intracellular NADPH/NADP+ levels. Under normal NADPH levels, it can form an asymmetrical dimer with one subunit occupied by one NADPH molecule, hiding the binding site for ASS1 thus impairing its activity and reducing the production of nitric oxide (Zheng et al. 2007, Zhao et al. 2008).
R-HSA-70634 (Reactome) The mitochondrial ornithine transporters SLC25A15 and SLC25A2 mediate the exchange of cytosolic ornithine for citrulline from the mitochondrial matrix. SLC25A15 was the first protein shown to have this function, identified because mutations in the protein are associated with elevated levels of ammonia, ornithine, and citrulline in affected individuals (Camacho et al. 1999). The second transporter, SLC25A2, identified later, is also expressed in normal cells and their apparently partly redundant function may explain the relatively mild symptoms associated with SLC25A15 deficiency compared to other defects of the urea cycle (Fiermonte et al. 2003).
UreaArrowR-HSA-452036 (Reactome)
UreaArrowR-HSA-70569 (Reactome)

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