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Details on Person UniProt:P27708 CAD
| Class:Id | ReferenceGeneProduct:62543 |
|---|---|
| _chainChangeLog | initiator methionine:1 added on Sat February 7 2015;chain:2-2225 added on Sat February 7 2015;initiator methionine:1 for 62543 removed on Fri Nov 03 2023;initiator methionine: for 62543 added on Fri Nov 03 2023;initiator methionine: for 62543 removed on Fri Aug 15 2025;initiator methionine:1 for 62543 added on Fri Aug 15 2025 |
| _displayName | UniProt:P27708 CAD |
| _timestamp | 2025-08-15 21:56:04 |
| chain | initiator methionine:1 chain:2-2225 |
| checksum | 2AB8E8413E825A8F |
| comment | FUNCTION Multifunctional protein that encodes the first 3 enzymatic activities of the de novo pyrimidine pathway: carbamoylphosphate synthetase (CPSase; EC 6.3.5.5), aspartate transcarbamylase (ATCase; EC 2.1.3.2) and dihydroorotase (DHOase; EC 3.5.2.3). The CPSase-function is accomplished in 2 steps, by a glutamine-dependent amidotransferase activity (GATase) that binds and cleaves glutamine to produce ammonia, followed by an ammonium-dependent carbamoyl phosphate synthetase, which reacts with the ammonia, hydrogencarbonate and ATP to form carbamoyl phosphate. The endogenously produced carbamoyl phosphate is sequestered and channeled to the ATCase active site. ATCase then catalyzes the formation of carbamoyl-L-aspartate from L-aspartate and carbamoyl phosphate. In the last step, DHOase catalyzes the cyclization of carbamoyl aspartate to dihydroorotate.CATALYTIC ACTIVITY hydrogencarbonate + L-glutamine + 2 ATP + H2O = carbamoyl phosphate + L-glutamate + 2 ADP + phosphate + 2 H(+)CATALYTIC ACTIVITY L-glutamine + H2O = L-glutamate + NH4(+)CATALYTIC ACTIVITY hydrogencarbonate + NH4(+) + 2 ATP = carbamoyl phosphate + 2 ADP + phosphate + 2 H(+)CATALYTIC ACTIVITY carbamoyl phosphate + L-aspartate = N-carbamoyl-L-aspartate + phosphate + H(+)CATALYTIC ACTIVITY (S)-dihydroorotate + H2O = N-carbamoyl-L-aspartate + H(+)COFACTOR Binds 3 Zn(2+) ions per subunit (for dihydroorotase activity).COFACTOR Binds 4 magnesium or manganese ions per subunit.ACTIVITY REGULATION Allosterically regulated and controlled by phosphorylation. 5-phosphoribose 1-diphosphate (PRPP) is an activator while UMP and UTP are inhibitors of the CPSase reaction.BIOPHYSICOCHEMICAL PROPERTIES Pyrimidine metabolism; UMP biosynthesis via de novo pathway; (S)-dihydroorotate from bicarbonate: step 1/3.PATHWAY Pyrimidine metabolism; UMP biosynthesis via de novo pathway; (S)-dihydroorotate from bicarbonate: step 2/3.PATHWAY Pyrimidine metabolism; UMP biosynthesis via de novo pathway; (S)-dihydroorotate from bicarbonate: step 3/3.SUBUNIT Homohexamer (PubMed:24332717). Interacts with CIPC (PubMed:26657846).INTERACTION Cytosolic and unphosphorylated in resting cells, translocates to the nucleus in response to EGF stimulation, nuclear import promotes optimal cell growth.INDUCTION Transcriptionally repressed following hypoxia by HIF1A.PTM Activated by MAP kinase (Erk1/2) phosphorylation just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. Phosphorylation at Ser-1859 by RPS6KB1 downstream of MTOR promotes oligomerization and stimulates dihydroorotase activity. Phosphorylation at Ser-1406 reduces sensitivity to feedback inhibition by UTP.DISEASE The disease is caused by variants affecting the gene represented in this entry.MISCELLANEOUS GATase (glutamine amidotransferase) and CPSase (carbamoyl phosphate synthase) form together the glutamine-dependent CPSase (GD-CPSase) (EC 6.3.5.5).SIMILARITY In the N-terminal section; belongs to the CarA family.SIMILARITY In the 2nd section; belongs to the CarB family.SIMILARITY In the 3rd section; belongs to the metallo-dependent hydrolases superfamily. DHOase family. CAD subfamily.SIMILARITY In the C-terminal section; belongs to the aspartate/ornithine carbamoyltransferase superfamily. ATCase family.ONLINE INFORMATION Aspartate carbamoyltransferase entry |
| description | recommendedName: fullName evidence="24"Multifunctional protein CAD alternativeName: Carbamoyl phosphate synthetase 2-aspartate transcarbamylase-dihydroorotase domain recommendedName: Glutamine-dependent carbamoyl phosphate synthase ecNumber evidence="18"6.3.5.5 /domain domain recommendedName: Glutamine amidotransferase shortName: GATase shortName: GLNase ecNumber evidence="3"3.5.1.2 /domain domain recommendedName: Ammonium-dependent carbamoyl phosphate synthase shortName: CPS shortName: CPSase ecNumber evidence="3"6.3.4.16 /domain domain recommendedName: Aspartate carbamoyltransferase ecNumber evidence="18"2.1.3.2 /domain domain recommendedName: Dihydroorotase ecNumber evidence="18"3.5.2.3 /domain |
| geneName | CAD |
| identifier | P27708 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Allosteric enzyme ATP-binding Congenital disorder of glycosylation Cytoplasm Direct protein sequencing Disease variant Epilepsy Hydrolase Ligase Magnesium Manganese Metal-binding Multifunctional enzyme Nucleotide-binding Nucleus Phosphoprotein Proteomics identification Pyrimidine biosynthesis Reference proteome Repeat Transferase Zinc |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 |
| name | CAD |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8990348] ENSEMBL:ENSG00000084774 CAD [Homo sapiens] |
| secondaryIdentifier | PYR1_HUMAN D6W552 Q6P0Q0 Q96CK3 |
| sequenceLength | 2225 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:73452] CAD [cytosol] [Homo sapiens] |
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No pathways have been reviewed or authored by UniProt:P27708 CAD (62543)
