Urea cycle and associated pathways (WP4595)

Homo sapiens

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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

Authors

Irene Hemel , Denise Slenter , Friederike Ehrhart , Egon Willighagen , and Eric Weitz

Activity

last edited

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Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Disease Ontology

ornithine carbamoyltransferase deficiency hyperargininemia carbamoyl phosphate synthetase I deficiency disease urea cycle disorder argininosuccinic aciduria citrullinemia

Cell Type Ontology

hepatocyte

Pathway Ontology

urea cycle pathway inborn error of urea cycle pathway disease pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
a-Ketoglutarate Metabolite chebi:16810 aka 2-oxoglutarate
Citrulline Metabolite chebi:57743 Zwitterion needed for conversion to take place
1-Pyrroline-5-carboxylate Metabolite chebi:17388
Aspartate Metabolite chebi:29991 (1-) charge needed for conversion to take place
Acetyl-CoA Metabolite chebi:57288 (4-) charge needed for conversion to take place
L-Glutamatey-semialdehyde Metabolite chebi:58066
Oxalacetate Metabolite chebi:16452
Argininosuccinate Metabolite chebi:57472 (1-) charge needed for conversion to take place
Ornithine Metabolite chebi:46911 (1) charge needed for conversion to take place
Urea Metabolite chebi:16199
Proline Metabolite chebi:60039
Glutamate Metabolite chebi:29985 (1-) charge needed for conversion to take place
Carbamoyl-phosphate Metabolite chebi:58228 (2-) charge needed for conversion to take place
Fumarate Metabolite chebi:29806 (2-) charge needed for conversion to take place
NH4+ Metabolite chebi:28938
N-acetylglutamate Metabolite chebi:44337 (2-) charge needed for conversion to take place
Pyruvate Metabolite chebi:15361
Lactate Metabolite chebi:16651
Glutamine Metabolite chebi:58359 Zwitterion needed for conversion to take place
Alanine Metabolite chebi:57972
Malate Metabolite chebi:15589
HCO3- Metabolite chebi:17544
Aspartate Metabolite chebi:29991 (1-) charge needed for conversion to take place
Arginine Metabolite chebi:32682 (1) charge needed for conversion to take place
Ornithine Metabolite chebi:46911 (1) charge needed for conversion to take place
Citrulline Metabolite chebi:57743 Zwitterion needed for conversion to take place
Oxalacetate Metabolite chebi:16452
Glutamate Metabolite chebi:29985 (1-) charge needed for conversion to take place
a-Ketoglutarate Metabolite chebi:16810 aka 2-oxoglutarate
Orotate Metabolite chebi:30839
OMP Metabolite chebi:57538 Orotidylic acid
(3-) charge needed for conversion to take place
Uridine Metabolite chebi:16704
UMP Metabolite chebi:57865 (2-) charge needed for conversion to take place
Uracil Metabolite chebi:17568
Orotidine Metabolite chebi:25722
Carbamoyl-phosphate Metabolite chebi:58228 (2-) charge needed for conversion to take place
NH4+ Metabolite chebi:28938
Nitric oxide Metabolite chebi:16480 (1) charge needed for conversion to take place
Malate Metabolite chebi:15589
Oxalacetate Metabolite chebi:16452
Glutamate Metabolite chebi:29985 (1-) charge needed for conversion to take place
ARG1 Protein uniprot:P05089
GLS2 Protein uniprot:Q9UI32
P5CS Protein uniprot:P30038
Citrin(SLC25A13) Protein uniprot:Q9UJS0 AKA CTLN2, SLC25A13, AGC2
ASS1 Protein uniprot:P00966
ASL Protein uniprot:P04424
GDH Protein uniprot:P00367
LDH Protein uniprot:P07195
ALT Protein uniprot:P24298
NAGS Protein uniprot:Q8N159
MDH Protein uniprot:P40925
MDH2 Protein uniprot:P40926
OTC Protein uniprot:P00480
OAT Protein uniprot:P04181
SLC25A12 Protein uniprot:O75746 AKA AGC1
AST2 Protein uniprot:P00505
FUM Protein uniprot:P07954
P5CR Protein uniprot:P32322
CPS1 Protein uniprot:P31327
ORNT1 Protein uniprot:Q9Y619 Exchanges ornithine for citruline
AST Protein uniprot:P17174
iNOS Protein uniprot:P35228 'Nitric oxide synthases (EC 1.14.13.39) (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
nNOS Protein uniprot:P29475 'Nitric oxide synthases (EC 1.14.13.39) (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
eNOS Protein uniprot:P29474 'Nitric oxide synthases (EC 1.14.13.39) (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

References

  1. Purified human erythrocyte pyrroline-5-carboxylate reductase. Preferential oxidation of NADPH. Merrill MJ, Yeh GC, Phang JM. J Biol Chem. 1989 Jun 5;264(16):9352–8. PubMed Europe PMC Scholia
  2. Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Camacho JA, Mardach R, Rioseco-Camacho N, Ruiz-Pesini E, Derbeneva O, Andrade D, et al. Pediatr Res. 2006 Oct;60(4):423–9. PubMed Europe PMC Scholia
  3. Arginase Deficiency. Sun A, Crombez EA, Wong D. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2004. PubMed Europe PMC Scholia
  4. Citrin Deficiency. Saheki T, Song YZ. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2005. PubMed Europe PMC Scholia
  5. Citrullinemia Type I. Quinonez SC, Lee KN. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2004. PubMed Europe PMC Scholia
  6. AGC1/2, the mitochondrial aspartate-glutamate carriers. Amoedo ND, Punzi G, Obre E, Lacombe D, De Grassi A, Pierri CL, et al. Biochim Biophys Acta. 2016 Oct;1863(10):2394–412. PubMed Europe PMC Scholia
  7. Hyperammonemia crisis following parturition in a female patient with ornithine transcarbamylase deficiency. Kido J, Kawasaki T, Mitsubuchi H, Kamohara H, Ohba T, Matsumoto S, et al. World J Hepatol. 2017 Feb 28;9(6):343–8. PubMed Europe PMC Scholia
  8. Neonatal-onset carbamoyl phosphate synthetase I deficiency: A case report. Yang X, Shi J, Lei H, Xia B, Mu D. Medicine (Baltimore). 2017 Jun;96(26):e7365. PubMed Europe PMC Scholia
  9. Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer. Baruteau J, Perocheau DP, Hanley J, Lorvellec M, Rocha-Ferreira E, Karda R, et al. Nat Commun. 2018 Aug 29;9(1):3505. PubMed Europe PMC Scholia
  10. N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region. Williams M, Burlina A, Rubert L, Polo G, Ruijter GJG, van den Born M, et al. Sci Rep. 2018 Oct 18;8(1):15436. PubMed Europe PMC Scholia
  11. Adult-onset type II citrullinemia: Current insights and therapy. Hayasaka K, Numakura C. Appl Clin Genet. 2018 Dec 12;11:163–70. PubMed Europe PMC Scholia