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: [https://www.wikipathways.org/index.php/Pathway:WP4571 WP4571] 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 e8b aka 2-oxoglutarate Zwitterion needed for conversion to take place AKA CTLN2, SLC25A13, AGC2 c42 (1-) charge needed for conversion to take place (4-) charge needed for conversion to take place (1-) charge needed for conversion to take place (1) charge needed for conversion to take place (1-) charge needed for conversion to take place (2-) charge needed for conversion to take place (2-) charge needed for conversion to take place (2-) charge needed for conversion to take place AKA AGC1 c42 Zwitterion needed for conversion to take place (1-) charge needed for conversion to take place (1) charge needed for conversion to take place (1) charge needed for conversion to take place Exchanges ornithine for citruline Zwitterion needed for conversion to take place (1-) charge needed for conversion to take place aka 2-oxoglutarate Orotidylic acid (3-) charge needed for conversion to take place (2-) charge needed for conversion to take place (2-) charge needed for conversion to take place (1) charge needed for conversion to take place (1-) charge needed for conversion to take place "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 "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 "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 Interaction mostly occurs in intestine, only important for ureagenesis during fasting. allosteric activation b2c Interaction mostly occurs in intestine, only important for ureagenesis during fasting. chemical conversion cf7 b08 a94 b59 dda f13 f42 b16 ba1 DISEASE Mitochondrial aspartate-glutamate carriers DISEASE aka Hyperargininemia, argininemia, arginase 1 deficiency DISEASE DISEASE aka Argininosuccinate Synthetase Deficiency DISEASE aka Ornithine Carbamoyltransferase Deficiency DISEASE aka Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome or HHH syndrome DISEASE aka Citrullinemia Type II DISEASE DISEASE aka Hypoprolinaemia DISEASE aka Citrullinemia Type II DISEASE aka transient hyperammonemia of the newborn/prematurity. DISEASE Unconfirmed aethiology, however "transient hyperammonemia is known to be caused by increased levels of ammonia in the blood stream, as well as a failure of the urea cycle to convert enough of the ammonia into urea." [https://en.wikipedia.org/wiki/Transient_hyperammonemia_of_the_newborn] ornithine carbamoyltransferase deficiency DOID:9271 Disease hyperargininemia DOID:9278 Disease 20301338 PubMed Arginase deficiency GeneReview® [Internet] 2004 20301338 PubMed Arginase deficiency GeneReviews® [Internet] 2004 20301338 PubMed Arginase deficiency GeneReviews® [Internet] 2004 Derek Wong Stephen Cederbaum Eric A Crombez 30337552 PubMed N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region Sci Rep 2018 Williams M Burlina A Rubert L Polo G Ruijter GJG et al. hepatocyte CL:0000182 Cell Type carbamoyl phosphate synthetase I deficiency disease DOID:9280 Disease urea cycle disorder DOID:9267 Disease urea cycle pathway PW:0000076 Pathway Ontology inborn error of urea cycle pathway PW:0002142 Pathway Ontology 20301631 PubMed Citrullinemia Type I GeneReviews® [Internet] 2004 20301631 PubMed Citrullinemia Type I GeneReviews® [Internet] 2004 20301631 PubMed Citrullinemia Type I GeneReviews® [Internet] 2004 Shane C Quinonez Jess G Thoene argininosuccinic aciduria DOID:14755 Disease 28658158 PubMed Neonatal-onset carbamoyl phosphate synthetase I deficiency: A case report. Medicine (Baltimore) 2017 Yang X Shi J Lei H Xia B Mu D 28293384 PubMed Hyperammonemia crisis following parturition in a female patient with ornithine transcarbamylase deficiency World J Hepatol 2017 Kido J Kawasaki T Mitsubuchi H Kamohara H Ohba T Matsumoto S Endo F Nakamura K disease pathway PW:0000013 Pathway Ontology 30158522 PubMed Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer Nat Commun 2018 Baruteau J Perocheau DP Hanley J Lorvellec M Rocha-Ferreira E et al. 30588060 PubMed Adult-onset type II citrullinemia: Current insights and therapy. Appl Clin Genet 2018 Hayasaka K Numakura C PubMed Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases Springer-Verlag Berlin Heidelberg, ed.4 2014 Blau, Nenad Duran, Marinus, Gibson K. Michael Dionisi-Vici, Carlo citrullinemia DOID:9273 Disease 27132995 PubMed AGC1/2, the mitochondrial aspartate-glutamate carriers. Biochim Biophys Acta 2016 Amoedo ND Punzi G Obre E Lacombe D De Grassi A Pierri CL Rossignol R 20301360 PubMed Citrin Deficiency GeneReviews® [Internet] 2005 20301360 PubMed Citrin Deficiency GeneReviews® [Internet] 2005 20301360 PubMed Citrin Deficiency GeneReviews® [Internet] 2005 Takeyori Saheki Yuan-Zong Song 16940241 PubMed Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome Pediatr Res 2006 Camacho JA Mardach R Rioseco-Camacho N Ruiz-Pesini E Derbeneva O Andrade D Zaldivar F Qu Y Cederbaum SD 2722838 PubMed Purified human erythrocyte pyrroline-5-carboxylate reductase. Preferential oxidation of NADPH. J Biol Chem 1989 Merrill MJ Yeh GC Phang JM