Regulation of the urea cycle via CPS1

GraphML   PNG   SVG   CellDesigner   SBML   SBGN-ML   Annotation   Newt   MINERVA  

Reactome-Recon connection

The connection was chosen from the Reactome-Recon lists: proteins of the Recon2 metabolic reconstruction that take part in Reactome signalling processes. CPS1 is in the lists through the Reactome processes SIRT5 desuccinylates CPS1 (R-HSA-9955518) and SIRT5 deglutarylates CPS1 (R-HSA-9955504).

Description

The urea cycle converts ammonia into urea in the liver. Its rate-limiting step, the synthesis of carbamoyl phosphate by carbamoyl phosphate synthetase 1 (CPS1) in mitochondria, needs N-acetylglutamate, made from acetyl-CoA and glutamate by N-acetylglutamate synthase (NAGS). Carbamoyl phosphate then enters the cycle through ornithine transcarbamylase. Succinyl and glutaryl groups on CPS1 lysines lower its activity. The mitochondrial sirtuin SIRT5 removes them and activates the enzyme, and mice lacking SIRT5 have higher blood ammonia.

References

  1. Caldovic L, Ah Mew N, Shi D, Morizono H, Yudkoff M, Tuchman M. N-acetylglutamate synthase: structure, function and defects. Mol Genet Metab. 2010;100 Suppl 1:S13-9. doi: 10.1016/j.ymgme.2010.02.018. PMID: 20303810.
  2. de Cima S, Polo LM, Díez-Fernández C, Martínez AI, Cervera J, Fita I, Rubio V. Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. Sci Rep. 2015 Nov 23;5:16950. doi: 10.1038/srep16950. PMID: 26592762.
  3. Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, Kim J, Woo J, Kim JH, Choi BH, He B, Chen W, Zhang S, Cerione RA, Auwerx J, Hao Q, Lin H. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science. 2011 Nov 11;334(6057):806-9. doi: 10.1126/science.1207861. PMID: 22076378.
  4. 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. J Biol Chem. 2003 Aug 29;278(35):32778-83. doi: 10.1074/jbc.M302317200. PMID: 12807890.
  5. Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012 May 29;7:32. doi: 10.1186/1750-1172-7-32. PMID: 22642880.
  6. Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell. 2009 May 1;137(3):560-70. doi: 10.1016/j.cell.2009.02.026. PMID: 19410549.
  7. Reactome: Urea cycle. Reactome:R-HSA-70635.
  8. Tan M, Peng C, Anderson KA, Chhoy P, Xie Z, Dai L, Park J, Chen Y, Huang H, Zhang Y, Ro J, Wagner GR, Green MF, Madsen AS, Schmiesing J, Peterson BS, Xu G, Ilkayeva OR, Muehlbauer MJ, Braulke T, Mühlhausen C, Backos DS, Olsen CA, McGuire PJ, Pletcher SD, Lombard DB, Hirschey MD, Zhao Y. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab. 2014 Apr 1;19(4):605-17. doi: 10.1016/j.cmet.2014.03.014. PMID: 24703693.

Contributors

Marcio Luis Acencio1

Affiliations
  1. 1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg