Urea cycle and related diseases (Homo sapiens)

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986154723ProteinN-acetylglutamate synthase deficiencyConnection to diseaseDiseaseCatalysisConversionLegendMitochondrionPathwayMetaboliteHyperammonaemiaStimulationFumarateAcetyl-CoAASS1CitrullineAspartateNAGSORNT1OTCPyrimidine metabolismand diseasesOrnithineGLS2CitrinASLNH4+HCO3-GlutamateUreaN-acetylglutamateGlutamineCarbamoyl-phosphatePyrimidine metabolismand diseasesArgininosuccinateARG1CPS1AspartateArginineOrnithineCarbamoylphosphate synthetase I deficiencyArginase deficiencyArgininosuccinic aciduria Citrullinemia type I Ornithine transcarbamylase deficiencyOrnithine translocase deficiencyCitrin deficiencyCitrulline


The urea cycle converts toxic nitrogenous compounds to excretable urea in five biochemical reactions. It is also the source for endogenous arginine, ornithine and citrulline production. The process mainly takes place in the liver, partly in the mitochondria and partly in the cytoplasm of the hepatocytes.

Because there is no alternative way to convert toxic nitrogenous compounds, defects in the enzymes or transporters can lead to several diseases (diseases highlighted in pink). The diseases are characterised by hyperammonemia, respiratory alkalosis and encephalopathy and the severity of the disease depends on the severity of the defect and the place of the defect in the cycle. Severe forms usually have an onset in infancy, while mild forms can also present in adulthood.

This pathway is based on: Mew NA, et al. Urea cycle disorders overview (2003) [1]

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  1. Williams M, Burlina A, Rubert L, Polo G, Ruijter GJG, et al.; ''N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region''; Sci Rep, 2018 PubMed Europe PMC Scholia
  2. Yang X, Shi J, Lei H, Xia B, Mu D; ''Neonatal-onset carbamoyl phosphate synthetase I deficiency: A case report.''; Medicine (Baltimore), 2017 PubMed Europe PMC Scholia
  3. Baruteau J, Perocheau DP, Hanley J, Lorvellec M, Rocha-Ferreira E, et al.; ''Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer''; Nat Commun, 2018 PubMed Europe PMC Scholia
  4. Kido J, Kawasaki T, Mitsubuchi H, Kamohara H, Ohba T, Matsumoto S, Endo F, Nakamura K; ''Hyperammonemia crisis following parturition in a female patient with ornithine transcarbamylase deficiency''; World J Hepatol, 2017 PubMed Europe PMC Scholia
  5. Takeyori Saheki, Yuan-Zong Song; ''Citrin Deficiency''; GeneReviews® [Internet], 2005 PubMed Europe PMC Scholia
  6. Derek Wong, Stephen Cederbaum, Eric A Crombez; ''Arginase deficiency''; GeneReviews® [Internet], 2004 PubMed Europe PMC Scholia
  7. Shane C Quinonez, Jess G Thoene; ''Citrullinemia Type I''; GeneReviews® [Internet], 2004 PubMed Europe PMC Scholia
  8. Camacho JA, Mardach R, Rioseco-Camacho N, Ruiz-Pesini E, Derbeneva O, Andrade D, Zaldivar F, Qu Y, Cederbaum SD; ''Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome''; Pediatr Res, 2006 PubMed Europe PMC Scholia
  9. Nicholas Ah Mew, Kara L Simpson, Andrea L Gropman, Brendan C Lanpher, Kimberly A Chapman, Marshall L Summar; ''Urea Cycle Disorders Overview''; GeneReviews® [Internet], 2003 PubMed Europe PMC Scholia


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108392view14:27, 16 December 2019DeSlChanged ornithine+citruline arrows to translocationMIM.
108216view12:33, 29 November 2019FehrhartOntology Term : 'disease pathway' added !
104803view17:26, 18 June 2019IreneHemelAdded legend
104204view06:59, 10 May 2019IreneHemelRemoved second ORNT1 transporter, as is exchanges ornithine for citrulline
104172view13:29, 8 May 2019IreneHemelAdded transporter for citrulline
104171view11:17, 8 May 2019IreneHemelAdded second link to pyrimidine pathway
104156view07:22, 7 May 2019IreneHemelAdded information about metabolite charge to DataNode comments
104042view10:05, 26 April 2019IreneHemelCombined reactions from Glutamine to glutamate and NH4+
103965view08:35, 18 April 2019IreneHemelAdded pathway node to pyrimidine metabolism
103945view12:25, 17 April 2019DeSlRemoved characters in references
103944view12:03, 17 April 2019IreneHemelChanged sizes of DataNodes and disease nodes
103943view11:52, 17 April 2019IreneHemelChanged basic interaction to mim-conversion for 1 side metabolite
103925view08:49, 16 April 2019IreneHemelAdded alternative name for 1 disease
103924view08:44, 16 April 2019IreneHemelAdded OMIM links for diseases
103923view08:35, 16 April 2019IreneHemelRemoved symbols in names references
103922view08:19, 16 April 2019IreneHemelChanged basic interaction to mim-conversion for side metabolites
103921view08:11, 16 April 2019IreneHemelChanged lines for diseases to graphical line
103916view15:08, 15 April 2019IreneHemelModified description
103900view11:58, 15 April 2019IreneHemelAdded alternative disease names
103893view06:41, 15 April 2019IreneHemelModified description
103891view14:46, 12 April 2019DeSlOntology Term : 'urea cycle disorder' added !
103890view14:45, 12 April 2019DeSlOntology Term : 'inborn error of urea cycle pathway' added !
103889view14:45, 12 April 2019DeSlOntology Term : 'hepatocyte' added !
103888view14:33, 12 April 2019DeSlRemoved symbol in references before trademark logo.
103887view14:32, 12 April 2019DeSlModified description
103878view09:27, 12 April 2019IreneHemelOntology Term : 'ornithine carbamoyltransferase deficiency' added !
103877view09:27, 12 April 2019IreneHemelOntology Term : 'hyperargininemia' added !
103876view09:27, 12 April 2019IreneHemelOntology Term : 'citrullinemia' added !
103875view09:21, 12 April 2019IreneHemelOntology Term : 'argininosuccinic aciduria' added !
103874view09:16, 12 April 2019IreneHemelOntology Term : 'carbamoyl phosphate synthetase I deficiency disease' added !
103873view09:16, 12 April 2019IreneHemelOntology Term : 'urea cycle pathway' added !
103872view09:13, 12 April 2019IreneHemelNew pathway

External references


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NameTypeDatabase referenceComment
ARG1ProteinP05089 (Uniprot-TrEMBL)
ASLProteinP04424 (Uniprot-TrEMBL)
ASS1ProteinP00966 (Uniprot-TrEMBL)
Acetyl-CoAMetaboliteCHEBI:57288 (ChEBI) (4-) charge needed for conversion to take place
ArginineMetaboliteCHEBI:32682 (ChEBI) (1) charge needed for conversion to take place
ArgininosuccinateMetaboliteCHEBI:57472 (ChEBI) (1-) charge needed for conversion to take place
AspartateMetaboliteCHEBI:29991 (ChEBI) (1-) charge needed for conversion to take place
CPS1ProteinP31327 (Uniprot-TrEMBL)
Carbamoyl-phosphateMetaboliteCHEBI:58228 (ChEBI) (2-) charge needed for conversion to take place
CitrinProteinQ9UJS0 (Uniprot-TrEMBL)
CitrullineMetaboliteCHEBI:57743 (ChEBI) Zwitterion needed for conversion to take place
FumarateMetaboliteCHEBI:29806 (ChEBI) (2-) charge needed for conversion to take place
GLS2ProteinQ9UI32 (Uniprot-TrEMBL)
GlutamateMetaboliteCHEBI:29985 (ChEBI) (1-) charge needed for conversion to take place
GlutamineMetaboliteCHEBI:58359 (ChEBI) Zwitterion needed for conversion to take place
HCO3-MetaboliteCHEBI:17544 (ChEBI)
N-acetylglutamateMetaboliteCHEBI:44337 (ChEBI) (2-) charge needed for conversion to take place
NAGSProteinQ8N159 (Uniprot-TrEMBL)
NH4+MetaboliteCHEBI:28938 (ChEBI)
ORNT1ProteinQ9Y619 (Uniprot-TrEMBL)
OTCProteinP00480 (Uniprot-TrEMBL)
OrnithineMetaboliteCHEBI:46911 (ChEBI) (1) charge needed for conversion to take place
Pyrimidine metabolism and diseasesPathwayWP4225 (WikiPathways)
UreaMetaboliteCHEBI:16199 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
Acetyl-CoAmim-conversion24293 (Rhea)
ArginineOrnithinemim-conversion20570 (Rhea)
ArgininosuccinateArgininemim-conversion24021 (Rhea)
Aspartatemim-conversion10933 (Rhea)
Carbamoyl-phosphateCitrullinemim-conversion19514 (Rhea)
CitrullineArgininosuccinatemim-conversion10933 (Rhea)
Fumaratemim-conversion24021 (Rhea)
GlutamateN-acetylglutamatemim-conversion24293 (Rhea)
GlutamineGlutamatemim-conversion15890 (Rhea)
HCO3-mim-conversion18030 (Rhea)
NH4+Carbamoyl-phosphatemim-conversion18030 (Rhea)
NH4+mim-conversion15890 (Rhea)
Ornithinemim-conversion19514 (Rhea)
mim-conversion20570 (Rhea)
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