Regulation of pyrimidine biosynthesis via MAPK signalling

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Description

The activation of de novo pyrimidine biosynthesis is a requirement for cell proliferation in tumor tissues. Carbamoyl phosphate synthetase (CPSase) catalyses the rate-limiting step of the synthetic pathway. CPSase refers to one catalytic activity of the multifunctional protein CAD that catalyses the first three steps of the pathway. ERK1/2 phosphorylates CAD, which removes its feedback inhibition by UTP and makes it more sensitive to activation by PRPP.

References

  1. Del Caño-Ochoa F, Ramón-Maiques S. Deciphering CAD: Structure and function of a mega-enzymatic pyrimidine factory in health and disease. Protein Sci. 2021 Oct;30(10):1995-2008. doi: 10.1002/pro.4158. PMID: 34288185.
  2. Graves LM, Guy HI, Kozlowski P, Huang M, Lazarowski E, Pope RM, Collins MA, Dahlstrand EN, Earp HS 3rd, Evans DR. Regulation of carbamoyl phosphate synthetase by MAP kinase. Nature. 2000 Jan 20;403(6767):328-32. doi: 10.1038/35002111. PMID: 10659854.
  3. Roskoski R Jr. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012 Aug;66(2):105-43. doi: 10.1016/j.phrs.2012.04.005. PMID: 22569528.
  4. Sigoillot FD, Evans DR, Guy HI. Growth-dependent regulation of mammalian pyrimidine biosynthesis by the protein kinase A and MAPK signaling cascades. J Biol Chem. 2002 May 3;277(18):15745-51. doi: 10.1074/jbc.M201112200. PMID: 11872754.
  5. Sigoillot FD, Kotsis DH, Serre V, Sigoillot SM, Evans DR, Guy HI. Nuclear localization and mitogen-activated protein kinase phosphorylation of the multifunctional protein CAD. J Biol Chem. 2005 Jul 8;280(27):25611-20. doi: 10.1074/jbc.M504581200. PMID: 15890648.
  6. Sigoillot FD, Sigoillot SM, Guy HI. Breakdown of the regulatory control of pyrimidine biosynthesis in human breast cancer cells. Int J Cancer. 2004 Apr 20;109(4):491-8. doi: 10.1002/ijc.11717. PMID: 14991569.

Contributors

Hanna Borlinghaus1, Falk Schreiber1,2, John Albanese3

Affiliations
  1. 1University of Konstanz, Konstanz, Germany
  2. 2Faculty of Information Technology, Monash University, Clayton, Australia
  3. 3University of Connecticut School of Medicine, Farmington, USA