Urea cycle and associated pathways (Homo sapiens)

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UrineSuprahepatic Blood4297153611Portal BloodInteractions mostly occurs in intestineIn hepatocytesAGC1/2ChemicalMitochondrionInsufficient supply of NADN-acetylglutamate synthase deficiencyUnknown aethiologyFumarate1-Pyrroline-5-carboxylateCarbamoyl-phosphateMalateCitrullineALTP5CRP5CSAlanineCitrin(SLC25A13)GDHPyrimidine metabolismand diseasesFUMARG1OrnithineAspartateNH4+Aspartate metabolismArgininosuccinatea-KetoglutarateSLC25A12OATLDHAST2PyruvateGlutamateUreaMDH2L-Glutamatey-semialdehydeAcetyl-CoAGLS2ASS1ProlineLactateNAGSASLHCO3-OTCN-acetylglutamateMDHOxalacetateGlutamine88CPS1AspartateArginineOrnithineCarbamoyl-phosphate synthetase I deficiencyArginase deficiencyArginino-succinic aciduria Citrullinemia type I Ornithine transcarbamylase deficiencyOrnithine translocase deficiencyCitrullinemia Type II,Neonatal-onsetORNT1CitrullineOxalacetateGlutamatea-KetoglutarateASTPyrimidine metabolismand diseasesOrotateOMPUridineUMPUracilOrotidinePyrroline-5-carboxylate synthase deficiencyGlutamine synthetase deficiencyCytosolCarbamoyl-phosphateNH4+Nitric oxideiNOSUrea CycleMalateOxalacetateDiseaseCatalysisPathwayStimulationProteinMetaboliteConversionConnection to diseaseLegendCitrullinemia Type II,Adult-onset10GlutamateProtein with specficlocalisation informationnNOSIn nervous tissue,skeletal muscle Type IIeNOSIn endotheliumTHAN


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. There are several pathways associated with the urea cycle and with the associated disorders, parts of these pathways are also pictured here.

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 was inspired by Chapter 4 of the book of Blau (ISBN 3642403360 (978-3642403361)).

For the Urea cycle without additional pathways see: WP4571

Quality Tags

Ontology Terms



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  1. 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
  2. Takeyori Saheki, Yuan-Zong Song; ''Citrin Deficiency''; GeneReviews® [Internet], 2005 PubMed Europe PMC Scholia
  3. 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
  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. 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
  6. Shane C Quinonez, Jess G Thoene; ''Citrullinemia Type I''; GeneReviews® [Internet], 2004 PubMed Europe PMC Scholia
  7. Merrill MJ, Yeh GC, Phang JM; ''Purified human erythrocyte pyrroline-5-carboxylate reductase. Preferential oxidation of NADPH.''; J Biol Chem, 1989 PubMed Europe PMC Scholia
  8. Amoedo ND, Punzi G, Obre E, Lacombe D, De Grassi A, Pierri CL, Rossignol R; ''AGC1/2, the mitochondrial aspartate-glutamate carriers.''; Biochim Biophys Acta, 2016 PubMed Europe PMC Scholia
  9. 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
  10. Hayasaka K, Numakura C; ''Adult-onset type II citrullinemia: Current insights and therapy.''; Appl Clin Genet, 2018 PubMed Europe PMC Scholia
  11. Derek Wong, Stephen Cederbaum, Eric A Crombez; ''Arginase deficiency''; GeneReview® [Internet], 2004 PubMed Europe PMC Scholia


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114567view16:07, 21 January 2021DeSlAdded THAN disease
114566view15:56, 21 January 2021DeSlAdded NOS localisation info.
114565view15:49, 21 January 2021DeSlAdded cellular localisation info in visual manner as well
114564view15:43, 21 January 2021DeSlAdded more details on some interactions as comments.
114563view15:39, 21 January 2021DeSlReconnected Ornithine/citrulline translocation from ORNT1
114562view15:12, 21 January 2021DeSlUpdated layout to fit Citr. Type II disorder in figure.
114561view15:10, 21 January 2021DeSlAdded ref for SLC25A12/13 info
114560view15:09, 21 January 2021DeSlConnected SLC25A12 to translocation interaction
114559view14:19, 21 January 2021DeSlAdded SLC25A12
114557view14:10, 21 January 2021DeSlSmall visual updates, added alternative names for disorders in comments, added Citrullinemia Type II adult onset individual disease node.
108217view12:34, 29 November 2019FehrhartOntology Term : 'disease pathway' added !
104830view15:07, 19 June 2019IreneHemelCombined the two ORNT1 transporters
104807view07:48, 19 June 2019IreneHemelAdded legend
104400view14:34, 23 May 2019DeSlRemoved weird signs in lit. ref
104331view13:55, 17 May 2019IreneHemelModified description
104313view08:14, 16 May 2019IreneHemelChanged first letters of text in node to capitals
104304view14:24, 15 May 2019IreneHemelChanged ID for iNOS to a Uniprot ID
104303view14:22, 15 May 2019IreneHemelAdded alternative route for aspartate production as mentioned in Blau Ch4
104224view13:54, 10 May 2019IreneHemelAdded reaction catalyzed by OAT
104223view13:27, 10 May 2019DeSlLast layout changes for different PW parts.
104222view13:04, 10 May 2019DeSlSome more layouting
104221view13:00, 10 May 2019DeSlAdded line from lactate to suprahepatic blood.
104217view11:51, 10 May 2019IreneHemelChanged layout
104216view11:44, 10 May 2019IreneHemelAdded Suprahepatic Blood and Urine labels
104212view10:24, 10 May 2019DeSlLayout changes to the right and bottom.
104211view10:16, 10 May 2019DeSlMore layout changes (within mitochondria).
104210view10:11, 10 May 2019DeSlFirst layout changes.
104209view09:37, 10 May 2019IreneHemelChanged interactions to graphical lines for 2 diseases
104203view06:53, 10 May 2019IreneHemelModified description
104202view06:52, 10 May 2019IreneHemelNew pathway

External references


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NameTypeDatabase referenceComment
1-Pyrroline- 5-carboxylateMetaboliteCHEBI:17388 (ChEBI)
ALTProteinP24298 (Uniprot-TrEMBL)
ARG1ProteinP05089 (Uniprot-TrEMBL)
ASLProteinP04424 (Uniprot-TrEMBL)
ASS1ProteinP00966 (Uniprot-TrEMBL)
AST2ProteinP00505 (Uniprot-TrEMBL)
ASTProteinP17174 (Uniprot-TrEMBL)
Acetyl-CoAMetaboliteCHEBI:57288 (ChEBI) (4-) charge needed for conversion to take place
AlanineMetaboliteCHEBI:57972 (ChEBI)
ArginineMetaboliteCHEBI:32682 (ChEBI) (1) charge needed for conversion to take place
ArgininosuccinateMetaboliteCHEBI:57472 (ChEBI) (1-) charge needed for conversion to take place
Aspartate metabolismPathwayWP106 (WikiPathways)
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
Citrin (SLC25A13)ProteinQ9UJS0 (Uniprot-TrEMBL) AKA CTLN2, SLC25A13, AGC2
CitrullineMetaboliteCHEBI:57743 (ChEBI) Zwitterion needed for conversion to take place
FUMProteinP07954 (Uniprot-TrEMBL)
FumarateMetaboliteCHEBI:29806 (ChEBI) (2-) charge needed for conversion to take place
GDHProteinP00367 (Uniprot-TrEMBL)
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)
L-Glutamatey- semialdehydeMetaboliteCHEBI:58066 (ChEBI)
LDHProteinP07195 (Uniprot-TrEMBL)
LactateMetaboliteCHEBI:16651 (ChEBI)
MDH ProteinP40925 (Uniprot-TrEMBL)
MDH2ProteinP40926 (Uniprot-TrEMBL)
MalateMetaboliteCHEBI:15589 (ChEBI)
N-acetylglutamateMetaboliteCHEBI:44337 (ChEBI) (2-) charge needed for conversion to take place
NAGSProteinQ8N159 (Uniprot-TrEMBL)
NH4+MetaboliteCHEBI:28938 (ChEBI)
Nitric oxideMetaboliteCHEBI:16480 (ChEBI) (1) charge needed for conversion to take place
OATProteinP04181 (Uniprot-TrEMBL)
OMPMetaboliteCHEBI:57538 (ChEBI)
  • Orotidylic acid
  • (3-) charge needed for conversion to take place
ORNT1ProteinQ9Y619 (Uniprot-TrEMBL) Exchanges ornithine for citruline
OTCProteinP00480 (Uniprot-TrEMBL)
OrnithineMetaboliteCHEBI:46911 (ChEBI) (1) charge needed for conversion to take place
OrotateMetaboliteCHEBI:30839 (ChEBI)
OrotidineMetaboliteCHEBI:25722 (ChEBI)
OxalacetateMetaboliteCHEBI:16452 (ChEBI)
P5CRProteinP32322 (Uniprot-TrEMBL)
P5CSProteinP30038 (Uniprot-TrEMBL)
ProlineMetaboliteCHEBI:60039 (ChEBI)


and diseases
PathwayWP4225 (WikiPathways)
Pyrimidine metabolism and diseasesPathwayWP4225 (WikiPathways)
PyruvateMetaboliteCHEBI:15361 (ChEBI)
SLC25A12ProteinO75746 (Uniprot-TrEMBL) AKA AGC1
UMPMetaboliteCHEBI:57865 (ChEBI) (2-) charge needed for conversion to take place
UracilMetaboliteCHEBI:17568 (ChEBI)
Urea CyclePathwayWP4571 (WikiPathways)
UreaMetaboliteCHEBI:16199 (ChEBI)
UridineMetaboliteCHEBI:16704 (ChEBI)
a-KetoglutarateMetaboliteCHEBI:16810 (ChEBI) aka 2-oxoglutarate
eNOSProteinP29474 (Uniprot-TrEMBL)
  • "Nitric oxide synthases (EC (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule." [https://en.wikipedia.org/wiki/Nitric_oxide_synthase#iNOS].
  • eNOS (endotheiliall) is the protein active in endothelium
  • AKA NOS3, cNOS
iNOSProteinP35228 (Uniprot-TrEMBL)
  • "Nitric oxide synthases (EC (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule." [https://en.wikipedia.org/wiki/Nitric_oxide_synthase#iNOS].
  • iNOS (inducible) is the protein active in hepatocytes, immune and cardiovascular system.
  • aka NOS2
nNOSProteinP29475 (Uniprot-TrEMBL)
  • "Nitric oxide synthases (EC (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule." [https://en.wikipedia.org/wiki/Nitric_oxide_synthase#iNOS].
  • nNOS (neuronal) is the protein active in nervous tissue and skeletal muscle type II.
  • AKA NOS1

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
1-Pyrroline- 5-carboxylateProlinemim-conversion26126 (Rhea)
Acetyl-CoAmim-conversion24293 (Rhea)
AlaninePyruvatemim-conversion19454 (Rhea)
ArginineCitrullinemim-conversion33944 (Rhea)
ArginineOrnithinemim-conversion20570 (Rhea)
ArgininosuccinateArgininemim-conversion24021 (Rhea)
Aspartatemim-conversion10933 (Rhea)
Aspartatemim-conversion21826 (Rhea)
Carbamoyl-phosphatemim-conversion19514 (Rhea)
CitrullineArgininosuccinatemim-conversion10933 (Rhea)
FumarateMalatemim-conversion12462 (Rhea)
Fumaratemim-conversion24021 (Rhea)
GlutamateN-acetylglutamatemim-conversion24293 (Rhea)
Glutamatemim-conversion15134 (Rhea)
Glutamatemim-conversion21826 (Rhea)
Glutamatemim-conversion30237 (Rhea) Interaction mostly occurs in intestine, only important for ureagenesis during fasting.
GlutamineGlutamatemim-conversion15890 (Rhea)
HCO3-mim-conversion18030 (Rhea)
L-Glutamatey- semialdehyde1-Pyrroline- 5-carboxylatemim-conversion28235 (Rhea) chemical conversion
L-Glutamatey- semialdehydeOrnithinemim-conversion13879 (Rhea) Interaction mostly occurs in intestine, only important for ureagenesis during fasting.
MalateOxalacetatemim-conversion21433 (Rhea)
NH4+Carbamoyl-phosphatemim-conversion18030 (Rhea)
NH4+mim-conversion15134 (Rhea)
NH4+mim-conversion15890 (Rhea)
OMPUMPmim-conversion11597 (Rhea)
OrnithineCitrullinemim-conversion19514 (Rhea)
OrotateOMPmim-conversion10382 (Rhea)
OxalacetateAspartatemim-conversion21826 (Rhea)
Oxalacetatemim-conversion21825 (Rhea)
Oxalacetatemim-conversion21826 (Rhea)
PyruvateLactateArrow23446 (Rhea)
UMPUridinemim-conversion29360 (Rhea)
Ureamim-conversion20570 (Rhea)
UridineUracilmim-conversion24389 (Rhea)
a-KetoglutarateGlutamatemim-conversion21825 (Rhea)
a-Ketoglutaratemim-conversion21826 (Rhea)
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