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Gene Review

CAD  -  carbamoyl-phosphate synthetase 2,...

Homo sapiens

Synonyms: CAD protein
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Disease relevance of CAD


High impact information on CAD

  • The trifunctional protein CAD, which contains the first three enzyme activities of pyrimidine nucleotide biosynthesis (carbamyl phosphate synthetase II, aspartate transcarbamylase and dihydro-orotase), is phosphorylated stoichiometrically by cyclic AMP-dependent protein kinase [5].
  • In vitro transcription and translation of this cDNA resulted in a functional CAD protein when the protein was synthesized in the presence of its inhibitor (inhibitor of CAD) [6].
  • At the enzymatic level, the activity of aspartate transcarbamylase, one of the three enzymes encoded by the CAD gene, decreased by about half within 24 h of induction, suggesting a CAD protein half-life of 24 h in differentiating HL-60 cells [7].
  • CAD codes for a trifunctional protein involved in the catalysis of the first three enzymatic activities in the de novo pyrimidine biosynthetic pathway, namely, carbamoyl-phosphate synthetase II (EC, aspartate transcarbamylase (EC, and dihydroorotase (EC [7].
  • We suspect that the inactivation of the CAD gene in induced HL-60 cells is a consequence of the differentiating cells leaving the cell cycle and becoming nonproliferating [7].

Biological context of CAD


Anatomical context of CAD


Associations of CAD with chemical compounds

  • CAD, a large multifunctional protein that carries carbamoyl phosphate synthetase (CPSase), aspartate transcarbamoylase, and dihydroorotase activities, catalyzes the first three steps of de novo pyrimidine biosynthesis in mammalian cells [8].
  • Both pTP and CAD were confirmed to colocalize with active sites of replication detected by bromodeoxyuridine incorporation [1].
  • In mammals, this enzyme along with carbamyl phosphate synthetase II and dihydroorotase (DHOase) is encoded by a single gene called CAD [12].
  • The potential advantages of IAD over CAD therapy are an improved QoL, a prolonged period of androgen dependence, a reduced incidence of the side-effects normally associated with AD therapy, and a decrease in the cost of care [4].

Other interactions of CAD

  • In contrast, NES-CAD was confined to the cytoplasm, and Thr-456 remained unphosphorylated [9].
  • Nuclear localization and mitogen-activated protein kinase phosphorylation of the multifunctional protein CAD [9].
  • Once activated, pyrimidine biosynthesis remained elevated until rephosphorylation of CAD by PKA and dephosphorylation of the CAD MAPK site late in S phase [10].
  • On day 1 after ischemia, however, CAD mRNA and protein were significantly increased in the CA1 sector, and then CAD protein immunohistochemically showed a translocation from the perikarya into the nucleus [13].

Analytical, diagnostic and therapeutic context of CAD


  1. Adenovirus preterminal protein binds to the CAD enzyme at active sites of viral DNA replication on the nuclear matrix. Angeletti, P.C., Engler, J.A. J. Virol. (1998) [Pubmed]
  2. Mapping of the gene encoding the multifunctional protein carrying out the first three steps of pyrimidine biosynthesis to human chromosome 2. Chen, K.C., Vannais, D.B., Jones, C., Patterson, D., Davidson, J.N. Hum. Genet. (1989) [Pubmed]
  3. Transcriptional repression of human cad gene by hypoxia inducible factor-1alpha. Chen, K.F., Lai, Y.Y., Sun, H.S., Tsai, S.J. Nucleic Acids Res. (2005) [Pubmed]
  4. The current status of intermittent androgen deprivation (IAD) therapy for prostate cancer: putting IAD under the spotlight. Tunn, U. BJU Int. (2007) [Pubmed]
  5. Phosphorylation and activation of hamster carbamyl phosphate synthetase II by cAMP-dependent protein kinase. A novel mechanism for regulation of pyrimidine nucleotide biosynthesis. Carrey, E.A., Campbell, D.G., Hardie, D.G. EMBO J. (1985) [Pubmed]
  6. Molecular cloning and characterization of human caspase-activated DNase. Mukae, N., Enari, M., Sakahira, H., Fukuda, Y., Inazawa, J., Toh, H., Nagata, S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  7. Transcriptional regulation of the human CAD gene during myeloid differentiation. Rao, G.N., Buford, E.S., Davidson, J.N. Mol. Cell. Biol. (1987) [Pubmed]
  8. Autophosphorylation of the mammalian multifunctional protein that initiates de novo pyrimidine biosynthesis. Sigoillot, F.D., Evans, D.R., Guy, H.I. J. Biol. Chem. (2002) [Pubmed]
  9. Nuclear localization and mitogen-activated protein kinase phosphorylation of the multifunctional protein CAD. Sigoillot, F.D., Kotsis, D.H., Serre, V., Sigoillot, S.M., Evans, D.R., Guy, H.I. J. Biol. Chem. (2005) [Pubmed]
  10. Cell cycle-dependent regulation of pyrimidine biosynthesis. Sigoillot, F.D., Berkowski, J.A., Sigoillot, S.M., Kotsis, D.H., Guy, H.I. J. Biol. Chem. (2003) [Pubmed]
  11. Caspase-dependent cleavage of carbamoyl phosphate synthetase II during apoptosis. Huang, M., Kozlowski, P., Collins, M., Wang, Y., Haystead, T.A., Graves, L.M. Mol. Pharmacol. (2002) [Pubmed]
  12. Organization and nucleotide sequence of the 3' end of the human CAD gene. Davidson, J.N., Rao, G.N., Niswander, L., Andreano, C., Tamer, C., Chen, K.C. DNA Cell Biol. (1990) [Pubmed]
  13. Implications of CAD and DNase II in ischemic neuronal necrosis specific for the primate hippocampus. Tsukada, T., Watanabe, M., Yamashima, T. J. Neurochem. (2001) [Pubmed]
  14. Molecular cloning of a human cDNA encoding a trifunctional enzyme of carbamoyl-phosphate synthetase-aspartate transcarbamoylase-dihydroorotase in de Novo pyrimidine synthesis. Iwahana, H., Fujimura, M., Ii, S., Kondo, M., Moritani, M., Takahashi, Y., Yamaoka, T., Yoshimoto, K., Itakura, M. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
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