This protein is a 'fusion' protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase). (updated: Oct. 16, 2019)
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
No sequence conservation computed yet.
Total structural coverage: 0%
No model available.
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The reference OMIM entry for this protein is 114010
Carbamoyl phosphate synthetase/aspartate transcarbamoylase/dihydroorotase; cad
Cad trifunctional protein
Cpsase/atcase/dhoase
DESCRIPTION
The CAD gene encodes a trifunctional protein which is associated with the enzymatic activity of the first 3 enzymes in the 6-step pathway of pyrimidine biosynthesis: carbamoyl phosphate synthetase (EC 6.3.5.5), aspartate transcarbamoylase (EC 2.1.3.2), and dihydroorotase (EC 3.5.2.3) (summary by Simmer et al., 1990). The carbamoyl phosphate synthetase activity of the CAD trifunctional protein is designated CPS II (CPS2). CPS I is encoded by the CPS1 gene (
608307), which maps to 2q.
GENE FUNCTION
The de novo synthesis of pyrimidine nucleotides is required for mammalian cells to proliferate. The rate-limiting step in this pathway is catalyzed by carbamoyl phosphate synthetase (CPS II), part of the multifunctional enzyme CAD. Graves et al. (2000) described the regulation of CAD by the mitogen-activated protein kinase (MAPK) cascade (see
602425). When phosphorylated by MAPK1 (
176948) in vitro or activated by epidermal growth factor (
131530) in vivo, CAD lost its feedback inhibition, which is dependent on uridine triphosphate, and became more sensitive to activation, which depends upon phosphoribosyl pyrophosphate. Both these allosteric regulatory changes favor biosynthesis of pyrimidines for growth. They were accompanied by increased epidermal growth factor-dependent phosphorylation of CAD in vivo and were prevented by inhibition of MAPK1. Mutation of a consensus MAP kinase phosphorylation site abolished the changes in CAD allosteric regulation that were stimulated by growth factors. Finally, consistent with an effect of MAP kinase signaling on CPS II activity, epidermal growth factor increased cellular uridine triphosphate, and this increase was reversed by inhibition of MAPK1. Hence, Graves et al. (2000) concluded that their studies may indicate a direct link between activation of the MAP kinase cascade and de novo biosynthesis of pyrimidine nucleotides. Chen et al. (2001) found that the rate of CAD gene amplification is elevated 50- to 100-fold in human cell lines deficient in MLH1 (
120436) or MSH6 (
600678), as compared with mismatch repair-proficient control cells. Fluorescence in situ hybridization indicated that these amplification events are the probable consequence of unequal sister chromatid exchanges involving chromosome 2, as well as translocation events involving other chromosomes. These results implicated the products of the MLH1 and MSH6 genes in the suppression of gene amplification and suggested that defects in this genetic stabilization function may contribute to the cancer predisposition associated with mismatch repair deficiency. Robitaille et al. (2013) found that mTOR complex-1 (mTORC1; see
601231) indirectly phosphorylated CAD residue S1859 through S6 kinase (S6K; see RPSKB1,
608938). CAD-S1859 phosphorylation promoted CAD oligomerization and thereby stimulated de novo synthesis of pyrimidines and progression through S phase of the cell cycle in mammalian cells. Ben-Sahra et al. (2013) independently showed that activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target S6K1, which directly phosphorylates S1859 on CAD. Growth signaling through mTORC1 thus stimulates the production of new nucleotides to accommodate an increase in RNA and DNA synthesis needed for ribosome biogenesis and anabolic growth.
MAPPING
Chen et al. (1 ...
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Subscribe to this protein entry history
Oct. 27, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
July 4, 2019: Protein entry updated
Automatic update: OMIM entry 114010 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).