CAD protein (CAD)
The protein contains 2225 amino acids for an estimated molecular weight of 242984 Da.
This protein is a 'fusion' protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase). (updated: Oct. 16, 2019)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
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.
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| Variant | Description |
|---|---|
| DEE50 | |
| a colorectal cancer sample | |
| a colorectal cancer sample; somatic mutation | |
| DEE50 |
Biological Process
'de novo' pyrimidine nucleobase biosynthetic process
'de novo' UMP biosynthetic process
Animal organ regeneration
Cellular response to drug
Cellular response to epidermal growth factor stimulus
Citrulline biosynthetic process
Drug metabolic process
Female pregnancy
Glutamine metabolic process
Heart development
Lactation
Liver development
Nitrogen compound metabolic process
Peptidyl-threonine phosphorylation
Protein autophosphorylation
Pyrimidine nucleoside biosynthetic process
Response to amine
Response to caffeine
Response to cortisol
Response to insulin
Response to starvation
Response to testosterone
UTP biosynthetic process
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 ... More on the omim web site
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).