Full text data of CAD
CAD
[Confidence: low (only semi-automatic identification from reviews)]
CAD protein; Glutamine-dependent carbamoyl-phosphate synthase; 6.3.5.5; Aspartate carbamoyltransferase; 2.1.3.2; Dihydroorotase; 3.5.2.3
Note: presumably soluble (membrane word is not in UniProt keywords or features)
CAD protein; Glutamine-dependent carbamoyl-phosphate synthase; 6.3.5.5; Aspartate carbamoyltransferase; 2.1.3.2; Dihydroorotase; 3.5.2.3
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P27708
ID PYR1_HUMAN Reviewed; 2225 AA.
AC P27708; D6W552; Q6P0Q0; Q96CK3;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
read moreDT 19-JUL-2004, sequence version 3.
DT 22-JAN-2014, entry version 163.
DE RecName: Full=CAD protein;
DE Includes:
DE RecName: Full=Glutamine-dependent carbamoyl-phosphate synthase;
DE EC=6.3.5.5;
DE Includes:
DE RecName: Full=Aspartate carbamoyltransferase;
DE EC=2.1.3.2;
DE Includes:
DE RecName: Full=Dihydroorotase;
DE EC=3.5.2.3;
GN Name=CAD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fetal lung fibroblast;
RX PubMed=8619816; DOI=10.1006/bbrc.1996.0213;
RA Iwahana H., Fujimura M., Ii S., Kondo M., Moritani M., Takahashi Y.,
RA Yamaoka T., Yoshimoto K., Itakura M.;
RT "Molecular cloning of a human cDNA encoding a trifunctional enzyme of
RT carbamoyl-phosphate synthetase-aspartate transcarbamoylase-
RT dihydroorotase in de Novo pyrimidine synthesis.";
RL Biochem. Biophys. Res. Commun. 219:249-255(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PROTEIN SEQUENCE OF 2-13; 157-165; 169-177; 359-371; 501-516; 548-555;
RP 599-606; 697-719; 761-778; 843-854; 932-944; 1034-1048; 1067-1075;
RP 1110-1127; 1229-1240; 1263-1270; 1313-1323; 1326-1333; 1658-1667;
RP 1723-1731; 1840-1848; 1976-1986; 2025-2036; 2103-2110; 2179-2187 AND
RP 2215-2225, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND
RP MASS SPECTROMETRY.
RC TISSUE=Colon adenocarcinoma, and Hepatoma;
RA Bienvenut W.V., Dhillon A.S., Matallanas D., Murray L., Brunton V.G.,
RA Cooper W.N., Boldt K., von Kriegsheim A.F., Kolch W., Frame M.C.;
RL Submitted (FEB-2008) to UniProtKB.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1752-2225.
RX PubMed=1979741; DOI=10.1089/dna.1990.9.667;
RA Davidson J.N., Rao G.N., Niswander L., Andreano C., Tamer C.,
RA Chen K.C.;
RT "Organization and nucleotide sequence of the 3' end of the human CAD
RT gene.";
RL DNA Cell Biol. 9:667-676(1990).
RN [6]
RP MUTAGENESIS OF HIS-1471; HIS-1473; ASP-1512; HIS-1590; HIS-1642 AND
RP HIS-1690, COFACTOR, AND ZINC-BINDING SITES.
RX PubMed=7766613; DOI=10.1021/bi00021a015;
RA Zimmermann B.H., Kemling N.M., Evans D.R.;
RT "Function of conserved histidine residues in mammalian
RT dihydroorotase.";
RL Biochemistry 34:7038-7046(1995).
RN [7]
RP ENZYME REGULATION.
RX PubMed=11872754; DOI=10.1074/jbc.M201112200;
RA Sigoillot F.D., Evans D.R., Guy H.I.;
RT "Growth-dependent regulation of mammalian pyrimidine biosynthesis by
RT the protein kinase A and MAPK signaling cascades.";
RL J. Biol. Chem. 277:15745-15751(2002).
RN [8]
RP SUBCELLULAR LOCATION.
RX PubMed=15890648; DOI=10.1074/jbc.M504581200;
RA Sigoillot F.D., Kotsis D.H., Serre V., Sigoillot S.M., Evans D.R.,
RA Guy H.I.;
RT "Nuclear localization and mitogen-activated protein kinase
RT phosphorylation of the multifunctional protein CAD.";
RL J. Biol. Chem. 280:25611-25620(2005).
RN [9]
RP INDUCTION.
RX PubMed=16155188; DOI=10.1093/nar/gki839;
RA Chen K.F., Lai Y.Y., Sun H.S., Tsai S.J.;
RT "Transcriptional repression of human cad gene by hypoxia inducible
RT factor-1alpha.";
RL Nucleic Acids Res. 33:5190-5198(2005).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [12]
RP PHOSPHORYLATION AT THR-456; SER-1406; SER-1859 AND SER-1873, AND
RP MUTAGENESIS OF SER-1873.
RX PubMed=17485345; DOI=10.2741/2358;
RA Sigoillot F.D., Kotsis D.H., Masko E.M., Bame M., Evans D.R.,
RA Evans H.I.;
RT "Protein kinase C modulates the up-regulation of the pyrimidine
RT biosynthetic complex, CAD, by MAP kinase.";
RL Front. Biosci. 12:3892-3898(2007).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859 AND THR-1884, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1884, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-747 AND LYS-1411, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859; SER-1900 AND
RP THR-1906, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1406 AND SER-1859, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [21]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [22]
RP PHOSPHORYLATION AT SER-1859.
RX PubMed=23429704; DOI=10.1126/science.1228771;
RA Robitaille A.M., Christen S., Shimobayashi M., Cornu M., Fava L.L.,
RA Moes S., Prescianotto-Baschong C., Sauer U., Jenoe P., Hall M.N.;
RT "Quantitative phosphoproteomics reveal mTORC1 activates de novo
RT pyrimidine synthesis.";
RL Science 339:1320-1323(2013).
RN [23]
RP PHOSPHORYLATION AT SER-1859 AND SER-1900.
RX PubMed=23429703; DOI=10.1126/science.1228792;
RA Ben-Sahra I., Howell J.J., Asara J.M., Manning B.D.;
RT "Stimulation of de novo pyrimidine synthesis by growth signaling
RT through mTOR and S6K1.";
RL Science 339:1323-1328(2013).
RN [24]
RP VARIANTS [LARGE SCALE ANALYSIS] GLN-177 AND CYS-735.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: This protein is a "fusion" protein encoding four
CC enzymatic activities of the pyrimidine pathway (GATase, CPSase,
CC ATCase and DHOase).
CC -!- CATALYTIC ACTIVITY: 2 ATP + L-glutamine + HCO(3)(-) + H(2)O = 2
CC ADP + phosphate + L-glutamate + carbamoyl phosphate.
CC -!- CATALYTIC ACTIVITY: Carbamoyl phosphate + L-aspartate = phosphate
CC + N-carbamoyl-L-aspartate.
CC -!- CATALYTIC ACTIVITY: (S)-dihydroorotate + H(2)O = N-carbamoyl-L-
CC aspartate.
CC -!- COFACTOR: Binds 1 zinc ion per subunit (for dihydroorotase
CC activity).
CC -!- ENZYME REGULATION: Allosterically regulated and controlled by
CC phosphorylation. 5-phosphoribose 1-diphosphate (PRPP) is an
CC activator while UMP and UTP are inhibitors of the CPSase reaction.
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo
CC pathway; (S)-dihydroorotate from bicarbonate: step 1/3.
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo
CC pathway; (S)-dihydroorotate from bicarbonate: step 2/3.
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo
CC pathway; (S)-dihydroorotate from bicarbonate: step 3/3.
CC -!- SUBUNIT: Homohexamer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Cytosolic and
CC unphosphorylated in resting cells, translocates to the nucleus in
CC response to EGF stimulation, nuclear import promotes optimal cell
CC growth.
CC -!- INDUCTION: Transcriptionally repressed following hypoxia by HIF1A.
CC -!- PTM: Activated by MAP kinase (Erk1/2) phosphorylation just prior
CC to the S phase of the cell cycle, when the demand for pyrimidine
CC nucleotides is greatest, and down-regulated as the cells emerge
CC from S phase by protein kinase A (PKA) phosphorylation.
CC Phosphorylation at Ser-1859 by RPS6KB1 downstream of MTOR promotes
CC oligomerization and stimulates dihydroorotase activity.
CC Phosphorylation at Ser-1406 reduces sensitivy to feedback
CC inhibition by UTP.
CC -!- MISCELLANEOUS: GATase (glutamine amidotransferase) and CPSase
CC (carbamoyl phosphate synthase) form together the glutamine-
CC dependent CPSase (GD-CPSase) (EC 6.3.5.5).
CC -!- SIMILARITY: In the central section; belongs to the DHOase family.
CC -!- SIMILARITY: Contains 2 ATP-grasp domains.
CC -!- SIMILARITY: Contains 1 glutamine amidotransferase type-1 domain.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Aspartate carbamoyltransferase
CC entry;
CC URL="http://en.wikipedia.org/wiki/Aspartate_carbamoyltransferase";
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DR EMBL; D78586; BAA11423.1; -; mRNA.
DR EMBL; CH471053; EAX00612.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00613.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00614.1; -; Genomic_DNA.
DR EMBL; BC014178; AAH14178.2; -; mRNA.
DR EMBL; BC065510; AAH65510.1; -; mRNA.
DR EMBL; M38561; AAA51907.1; -; Genomic_DNA.
DR PIR; A36240; A36240.
DR RefSeq; NP_004332.2; NM_004341.3.
DR UniGene; Hs.377010; -.
DR ProteinModelPortal; P27708; -.
DR SMR; P27708; 2-359, 394-1440, 1464-1843, 1923-2223.
DR DIP; DIP-39484N; -.
DR IntAct; P27708; 22.
DR MINT; MINT-5000537; -.
DR STRING; 9606.ENSP00000264705; -.
DR BindingDB; P27708; -.
DR ChEMBL; CHEMBL3093; -.
DR DrugBank; DB00128; L-Aspartic Acid.
DR DrugBank; DB00130; L-Glutamine.
DR MEROPS; C26.952; -.
DR PhosphoSite; P27708; -.
DR DMDM; 50403731; -.
DR PaxDb; P27708; -.
DR PeptideAtlas; P27708; -.
DR PRIDE; P27708; -.
DR Ensembl; ENST00000264705; ENSP00000264705; ENSG00000084774.
DR GeneID; 790; -.
DR KEGG; hsa:790; -.
DR UCSC; uc002rji.3; human.
DR CTD; 790; -.
DR GeneCards; GC02P027440; -.
DR HGNC; HGNC:1424; CAD.
DR HPA; CAB007781; -.
DR MIM; 114010; gene.
DR neXtProt; NX_P27708; -.
DR PharmGKB; PA26023; -.
DR eggNOG; COG0458; -.
DR HOGENOM; HOG000234584; -.
DR HOVERGEN; HBG000279; -.
DR InParanoid; P27708; -.
DR KO; K11540; -.
DR OrthoDB; EOG7M6D6F; -.
DR PhylomeDB; P27708; -.
DR BioCyc; MetaCyc:ENSG00000084774-MONOMER; -.
DR BRENDA; 3.5.2.3; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00070; UER00115.
DR UniPathway; UPA00070; UER00116.
DR UniPathway; UPA00070; UER00117.
DR ChiTaRS; cad; human.
DR GenomeRNAi; 790; -.
DR NextBio; 3214; -.
DR PMAP-CutDB; P27708; -.
DR PRO; PR:P27708; -.
DR ArrayExpress; P27708; -.
DR Bgee; P27708; -.
DR CleanEx; HS_CAD; -.
DR Genevestigator; P27708; -.
DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0016363; C:nuclear matrix; IDA:BHF-UCL.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl.
DR GO; GO:0016597; F:amino acid binding; IEA:InterPro.
DR GO; GO:0070335; F:aspartate binding; ISS:BHF-UCL.
DR GO; GO:0004070; F:aspartate carbamoyltransferase activity; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; ISS:BHF-UCL.
DR GO; GO:0004088; F:carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity; IEA:Ensembl.
DR GO; GO:0004151; F:dihydroorotase activity; IEA:Ensembl.
DR GO; GO:0042802; F:identical protein binding; ISS:BHF-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; ISS:BHF-UCL.
DR GO; GO:0006207; P:'de novo' pyrimidine nucleobase biosynthetic process; IEA:Ensembl.
DR GO; GO:0044205; P:'de novo' UMP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0070409; P:carbamoyl phosphate biosynthetic process; IEA:InterPro.
DR GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IEA:Ensembl.
DR GO; GO:0017144; P:drug metabolic process; IEA:Ensembl.
DR GO; GO:0009790; P:embryo development; IEA:Ensembl.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:0006543; P:glutamine catabolic process; IEA:InterPro.
DR GO; GO:0006541; P:glutamine metabolic process; IEA:Ensembl.
DR GO; GO:0007595; P:lactation; IEA:Ensembl.
DR GO; GO:0031100; P:organ regeneration; IEA:Ensembl.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISS:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:BHF-UCL.
DR GO; GO:0046134; P:pyrimidine nucleoside biosynthetic process; TAS:Reactome.
DR GO; GO:0014075; P:response to amine stimulus; IEA:Ensembl.
DR GO; GO:0031000; P:response to caffeine; IEA:Ensembl.
DR GO; GO:0051414; P:response to cortisol stimulus; IEA:Ensembl.
DR GO; GO:0033574; P:response to testosterone stimulus; IEA:Ensembl.
DR GO; GO:0006228; P:UTP biosynthetic process; IEA:Ensembl.
DR Gene3D; 1.10.1030.10; -; 1.
DR Gene3D; 3.30.1490.20; -; 1.
DR Gene3D; 3.30.470.20; -; 2.
DR Gene3D; 3.40.50.1370; -; 2.
DR Gene3D; 3.40.50.1380; -; 1.
DR Gene3D; 3.40.50.20; -; 2.
DR Gene3D; 3.50.30.20; -; 1.
DR InterPro; IPR006132; Asp/Orn_carbamoyltranf_P-bd.
DR InterPro; IPR006130; Asp/Orn_carbamoylTrfase.
DR InterPro; IPR002082; Asp_carbamoyltransf.
DR InterPro; IPR006131; Asp_carbamoyltransf_Asp/Orn-bd.
DR InterPro; IPR011761; ATP-grasp.
DR InterPro; IPR013815; ATP_grasp_subdomain_1.
DR InterPro; IPR013816; ATP_grasp_subdomain_2.
DR InterPro; IPR006275; CarbamoylP_synth_lsu.
DR InterPro; IPR005481; CarbamoylP_synth_lsu_N.
DR InterPro; IPR005480; CarbamoylP_synth_lsu_oligo.
DR InterPro; IPR006274; CarbamoylP_synth_ssu.
DR InterPro; IPR002474; CarbamoylP_synth_ssu_N.
DR InterPro; IPR005479; CbamoylP_synth_lsu-like_ATP-bd.
DR InterPro; IPR005483; CbamoylP_synth_lsu_CPSase_dom.
DR InterPro; IPR002195; Dihydroorotase_CS.
DR InterPro; IPR017926; GATASE.
DR InterPro; IPR011059; Metal-dep_hydrolase_composite.
DR InterPro; IPR011607; MGS-like_dom.
DR InterPro; IPR016185; PreATP-grasp_dom.
DR Pfam; PF00289; CPSase_L_chain; 2.
DR Pfam; PF02786; CPSase_L_D2; 2.
DR Pfam; PF02787; CPSase_L_D3; 1.
DR Pfam; PF00988; CPSase_sm_chain; 1.
DR Pfam; PF00117; GATase; 1.
DR Pfam; PF02142; MGS; 1.
DR Pfam; PF00185; OTCace; 1.
DR Pfam; PF02729; OTCace_N; 1.
DR PRINTS; PR00100; AOTCASE.
DR PRINTS; PR00101; ATCASE.
DR PRINTS; PR00098; CPSASE.
DR SMART; SM01096; CPSase_L_D3; 1.
DR SMART; SM01097; CPSase_sm_chain; 1.
DR SMART; SM00851; MGS; 1.
DR SUPFAM; SSF48108; SSF48108; 1.
DR SUPFAM; SSF51338; SSF51338; 1.
DR SUPFAM; SSF52021; SSF52021; 1.
DR SUPFAM; SSF52335; SSF52335; 1.
DR SUPFAM; SSF52440; SSF52440; 2.
DR SUPFAM; SSF53671; SSF53671; 1.
DR TIGRFAMs; TIGR00670; asp_carb_tr; 1.
DR TIGRFAMs; TIGR01369; CPSaseII_lrg; 1.
DR TIGRFAMs; TIGR01368; CPSaseIIsmall; 1.
DR PROSITE; PS50975; ATP_GRASP; 2.
DR PROSITE; PS00097; CARBAMOYLTRANSFERASE; 1.
DR PROSITE; PS00866; CPSASE_1; 2.
DR PROSITE; PS00867; CPSASE_2; 2.
DR PROSITE; PS00482; DIHYDROOROTASE_1; 1.
DR PROSITE; PS00483; DIHYDROOROTASE_2; 1.
DR PROSITE; PS51273; GATASE_TYPE_1; 1.
PE 1: Evidence at protein level;
KW Acetylation; Allosteric enzyme; ATP-binding; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Hydrolase; Ligase;
KW Metal-binding; Multifunctional enzyme; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Polymorphism; Pyrimidine biosynthesis;
KW Reference proteome; Repeat; Transferase; Zinc.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 2225 CAD protein.
FT /FTId=PRO_0000199506.
FT DOMAIN 177 363 Glutamine amidotransferase type-1.
FT DOMAIN 519 711 ATP-grasp 1.
FT DOMAIN 1052 1243 ATP-grasp 2.
FT REGION 2 365 GATase (Glutamine amidotransferase).
FT REGION 366 394 Linker.
FT REGION 395 1455 CPSase (Carbamoyl-phosphate synthase).
FT REGION 395 933 CPSase A.
FT REGION 934 1455 CPSase B.
FT REGION 1456 1788 DHOase (dihydroorotase).
FT REGION 1789 1917 Linker.
FT REGION 1918 2225 ATCase (Aspartate transcarbamylase).
FT ACT_SITE 252 252 For GATase activity (By similarity).
FT ACT_SITE 336 336 For GATase activity (By similarity).
FT ACT_SITE 338 338 For GATase activity (By similarity).
FT METAL 1471 1471 Zinc.
FT METAL 1473 1473 Zinc.
FT METAL 1590 1590 Zinc (Probable).
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 456 456 Phosphothreonine; by MAPK1.
FT MOD_RES 747 747 N6-acetyllysine.
FT MOD_RES 1406 1406 Phosphoserine; by PKA.
FT MOD_RES 1411 1411 N6-acetyllysine.
FT MOD_RES 1859 1859 Phosphoserine; by RPS6KB1 and PKA.
FT MOD_RES 1873 1873 Phosphoserine; by PKC; in vitro.
FT MOD_RES 1884 1884 Phosphothreonine.
FT MOD_RES 1900 1900 Phosphoserine.
FT MOD_RES 1906 1906 Phosphothreonine.
FT VARIANT 177 177 R -> Q (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035897.
FT VARIANT 735 735 Y -> C (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035898.
FT MUTAGEN 1471 1471 H->A: No zinc-binding and no catalytic
FT activity.
FT MUTAGEN 1473 1473 H->A: No zinc-binding and no catalytic
FT activity.
FT MUTAGEN 1512 1512 D->N: No change in catalytic activity.
FT MUTAGEN 1590 1590 H->N: No catalytic activity.
FT MUTAGEN 1642 1642 H->N: 11.5% of wild-type catalytic
FT activity.
FT MUTAGEN 1690 1690 H->N: 3% of wild-type catalytic activity.
FT MUTAGEN 1873 1873 S->A: Abolishes PMA-induced Thr-456
FT phosphorylation.
FT CONFLICT 505 505 P -> T (in Ref. 1; BAA11423).
FT CONFLICT 535 535 A -> G (in Ref. 1; BAA11423).
FT CONFLICT 560 560 L -> V (in Ref. 1; BAA11423).
FT CONFLICT 1103 1103 T -> A (in Ref. 1; BAA11423).
FT CONFLICT 1513 1513 A -> G (in Ref. 1; BAA11423).
FT CONFLICT 1676 1676 N -> D (in Ref. 1; BAA11423).
SQ SEQUENCE 2225 AA; 242984 MW; 2AB8E8413E825A8F CRC64;
MAALVLEDGS VLRGQPFGAA VSTAGEVVFQ TGMVGYPEAL TDPSYKAQIL VLTYPLIGNY
GIPPDEMDEF GLCKWFESSG IHVAALVVGE CCPTPSHWSA TRTLHEWLQQ HGIPGLQGVD
TRELTKKLRE QGSLLGKLVQ NGTEPSSLPF LDPNARPLVP EVSIKTPRVF NTGGAPRILA
LDCGLKYNQI RCLCQRGAEV TVVPWDHALD SQEYEGLFLS NGPGDPASYP SVVSTLSRVL
SEPNPRPVFG ICLGHQLLAL AIGAKTYKMR YGNRGHNQPC LLVGSGRCFL TSQNHGFAVE
TDSLPADWAP LFTNANDGSN EGIVHNSLPF FSVQFHPEHQ AGPSDMELLF DIFLETVKEA
TAGNPGGQTV RERLTERLCP PGIPTPGSGL PPPRKVLILG SGGLSIGQAG EFDYSGSQAI
KALKEENIQT LLINPNIATV QTSQGLADKV YFLPITPHYV TQVIRNERPD GVLLTFGGQT
ALNCGVELTK AGVLARYGVR VLGTPVETIE LTEDRRAFAA RMAEIGEHVA PSEAANSLEQ
AQAAAERLGY PVLVRAAFAL GGLGSGFASN REELSALVAP AFAHTSQVLV DKSLKGWKEI
EYEVVRDAYG NCVTVCNMEN LDPLGIHTGE SIVVAPSQTL NDREYQLLRQ TAIKVTQHLG
IVGECNVQYA LNPESEQYYI IEVNARLSRS SALASKATGY PLAYVAAKLA LGIPLPELRN
SVTGGTAAFE PSVDYCVVKI PRWDLSKFLR VSTKIGSCMK SVGEVMGIGR SFEEAFQKAL
RMVDENCVGF DHTVKPVSDM ELETPTDKRI FVVAAALWAG YSVDRLYELT RIDRWFLHRM
KRIIAHAQLL EQHRGQPLPP DLLQQAKCLG FSDKQIALAV LSTELAVRKL RQELGICPAV
KQIDTVAAEW PAQTNYLYLT YWGTTHDLTF RTPHVLVLGS GVYRIGSSVE FDWCAVGCIQ
QLRKMGYKTI MVNYNPETVS TDYDMCDRLY FDEISFEVVM DIYELENPEG VILSMGGQLP
NNMAMALHRQ QCRVLGTSPE AIDSAENRFK FSRLLDTIGI SQPQWRELSD LESARQFCQT
VGYPCVVRPS YVLSGAAMNV AYTDGDLERF LSSAAAVSKE HPVVISKFIQ EAKEIDVDAV
ASDGVVAAIA ISEHVENAGV HSGDATLVTP PQDITAKTLE RIKAIVHAVG QELQVTGPFN
LQLIAKDDQL KVIECNVRVS RSFPFVSKTL GVDLVALATR VIMGEEVEPV GLMTGSGVVG
VKVPQFSFSR LAGADVVLGV EMTSTGEVAG FGESRCEAYL KAMLSTGFKI PKKNILLTIG
SYKNKSELLP TVRLLESLGY SLYASLGTAD FYTEHGVKVT AVDWHFEEAV DGECPPQRSI
LEQLAEKNFE LVINLSMRGA GGRRLSSFVT KGYRTRRLAA DFSVPLIIDI KCTKLFVEAL
GQIGPAPPLK VHVDCMTSQK LVRLPGLIDV HVHLREPGGT HKEDFASGTA AALAGGITMV
CAMPNTRPPI IDAPALALAQ KLAEAGARCD FALFLGASSE NAGTLGTVAG SAAGLKLYLN
ETFSELRLDS VVQWMEHFET WPSHLPIVAH AEQQTVAAVL MVAQLTQRSV HICHVARKEE
ILLIKAAKAR GLPVTCEVAP HHLFLSHDDL ERLGPGKGEV RPELGSRQDV EALWENMAVI
DCFASDHAPH TLEEKCGSRP PPGFPGLETM LPLLLTAVSE GRLSLDDLLQ RLHHNPRRIF
HLPPQEDTYV EVDLEHEWTI PSHMPFSKAH WTPFEGQKVK GTVRRVVLRG EVAYIDGQVL
VPPGYGQDVR KWPQGAVPQL PPSAPATSEM TTTPERPRRG IPGLPDGRFH LPPRIHRASD
PGLPAEEPKE KSSRKVAEPE LMGTPDGTCY PPPPVPRQAS PQNLGTPGLL HPQTSPLLHS
LVGQHILSVQ QFTKDQMSHL FNVAHTLRMM VQKERSLDIL KGKVMASMFY EVSTRTSSSF
AAAMARLGGA VLSFSEATSS VQKGESLADS VQTMSCYADV VVLRHPQPGA VELAAKHCRR
PVINAGDGVG EHPTQALLDI FTIREELGTV NGMTITMVGD LKHGRTVHSL ACLLTQYRVS
LRYVAPPSLR MPPTVRAFVA SRGTKQEEFE SIEEALPDTD VLYMTRIQKE RFGSTQEYEA
CFGQFILTPH IMTRAKKKMV VMHPMPRVNE ISVEVDSDPR AAYFRQAENG MYIRMALLAT
VLGRF
//
ID PYR1_HUMAN Reviewed; 2225 AA.
AC P27708; D6W552; Q6P0Q0; Q96CK3;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
read moreDT 19-JUL-2004, sequence version 3.
DT 22-JAN-2014, entry version 163.
DE RecName: Full=CAD protein;
DE Includes:
DE RecName: Full=Glutamine-dependent carbamoyl-phosphate synthase;
DE EC=6.3.5.5;
DE Includes:
DE RecName: Full=Aspartate carbamoyltransferase;
DE EC=2.1.3.2;
DE Includes:
DE RecName: Full=Dihydroorotase;
DE EC=3.5.2.3;
GN Name=CAD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fetal lung fibroblast;
RX PubMed=8619816; DOI=10.1006/bbrc.1996.0213;
RA Iwahana H., Fujimura M., Ii S., Kondo M., Moritani M., Takahashi Y.,
RA Yamaoka T., Yoshimoto K., Itakura M.;
RT "Molecular cloning of a human cDNA encoding a trifunctional enzyme of
RT carbamoyl-phosphate synthetase-aspartate transcarbamoylase-
RT dihydroorotase in de Novo pyrimidine synthesis.";
RL Biochem. Biophys. Res. Commun. 219:249-255(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PROTEIN SEQUENCE OF 2-13; 157-165; 169-177; 359-371; 501-516; 548-555;
RP 599-606; 697-719; 761-778; 843-854; 932-944; 1034-1048; 1067-1075;
RP 1110-1127; 1229-1240; 1263-1270; 1313-1323; 1326-1333; 1658-1667;
RP 1723-1731; 1840-1848; 1976-1986; 2025-2036; 2103-2110; 2179-2187 AND
RP 2215-2225, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND
RP MASS SPECTROMETRY.
RC TISSUE=Colon adenocarcinoma, and Hepatoma;
RA Bienvenut W.V., Dhillon A.S., Matallanas D., Murray L., Brunton V.G.,
RA Cooper W.N., Boldt K., von Kriegsheim A.F., Kolch W., Frame M.C.;
RL Submitted (FEB-2008) to UniProtKB.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1752-2225.
RX PubMed=1979741; DOI=10.1089/dna.1990.9.667;
RA Davidson J.N., Rao G.N., Niswander L., Andreano C., Tamer C.,
RA Chen K.C.;
RT "Organization and nucleotide sequence of the 3' end of the human CAD
RT gene.";
RL DNA Cell Biol. 9:667-676(1990).
RN [6]
RP MUTAGENESIS OF HIS-1471; HIS-1473; ASP-1512; HIS-1590; HIS-1642 AND
RP HIS-1690, COFACTOR, AND ZINC-BINDING SITES.
RX PubMed=7766613; DOI=10.1021/bi00021a015;
RA Zimmermann B.H., Kemling N.M., Evans D.R.;
RT "Function of conserved histidine residues in mammalian
RT dihydroorotase.";
RL Biochemistry 34:7038-7046(1995).
RN [7]
RP ENZYME REGULATION.
RX PubMed=11872754; DOI=10.1074/jbc.M201112200;
RA Sigoillot F.D., Evans D.R., Guy H.I.;
RT "Growth-dependent regulation of mammalian pyrimidine biosynthesis by
RT the protein kinase A and MAPK signaling cascades.";
RL J. Biol. Chem. 277:15745-15751(2002).
RN [8]
RP SUBCELLULAR LOCATION.
RX PubMed=15890648; DOI=10.1074/jbc.M504581200;
RA Sigoillot F.D., Kotsis D.H., Serre V., Sigoillot S.M., Evans D.R.,
RA Guy H.I.;
RT "Nuclear localization and mitogen-activated protein kinase
RT phosphorylation of the multifunctional protein CAD.";
RL J. Biol. Chem. 280:25611-25620(2005).
RN [9]
RP INDUCTION.
RX PubMed=16155188; DOI=10.1093/nar/gki839;
RA Chen K.F., Lai Y.Y., Sun H.S., Tsai S.J.;
RT "Transcriptional repression of human cad gene by hypoxia inducible
RT factor-1alpha.";
RL Nucleic Acids Res. 33:5190-5198(2005).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [12]
RP PHOSPHORYLATION AT THR-456; SER-1406; SER-1859 AND SER-1873, AND
RP MUTAGENESIS OF SER-1873.
RX PubMed=17485345; DOI=10.2741/2358;
RA Sigoillot F.D., Kotsis D.H., Masko E.M., Bame M., Evans D.R.,
RA Evans H.I.;
RT "Protein kinase C modulates the up-regulation of the pyrimidine
RT biosynthetic complex, CAD, by MAP kinase.";
RL Front. Biosci. 12:3892-3898(2007).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859 AND THR-1884, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1884, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-747 AND LYS-1411, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859; SER-1900 AND
RP THR-1906, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1406 AND SER-1859, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [21]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [22]
RP PHOSPHORYLATION AT SER-1859.
RX PubMed=23429704; DOI=10.1126/science.1228771;
RA Robitaille A.M., Christen S., Shimobayashi M., Cornu M., Fava L.L.,
RA Moes S., Prescianotto-Baschong C., Sauer U., Jenoe P., Hall M.N.;
RT "Quantitative phosphoproteomics reveal mTORC1 activates de novo
RT pyrimidine synthesis.";
RL Science 339:1320-1323(2013).
RN [23]
RP PHOSPHORYLATION AT SER-1859 AND SER-1900.
RX PubMed=23429703; DOI=10.1126/science.1228792;
RA Ben-Sahra I., Howell J.J., Asara J.M., Manning B.D.;
RT "Stimulation of de novo pyrimidine synthesis by growth signaling
RT through mTOR and S6K1.";
RL Science 339:1323-1328(2013).
RN [24]
RP VARIANTS [LARGE SCALE ANALYSIS] GLN-177 AND CYS-735.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: This protein is a "fusion" protein encoding four
CC enzymatic activities of the pyrimidine pathway (GATase, CPSase,
CC ATCase and DHOase).
CC -!- CATALYTIC ACTIVITY: 2 ATP + L-glutamine + HCO(3)(-) + H(2)O = 2
CC ADP + phosphate + L-glutamate + carbamoyl phosphate.
CC -!- CATALYTIC ACTIVITY: Carbamoyl phosphate + L-aspartate = phosphate
CC + N-carbamoyl-L-aspartate.
CC -!- CATALYTIC ACTIVITY: (S)-dihydroorotate + H(2)O = N-carbamoyl-L-
CC aspartate.
CC -!- COFACTOR: Binds 1 zinc ion per subunit (for dihydroorotase
CC activity).
CC -!- ENZYME REGULATION: Allosterically regulated and controlled by
CC phosphorylation. 5-phosphoribose 1-diphosphate (PRPP) is an
CC activator while UMP and UTP are inhibitors of the CPSase reaction.
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo
CC pathway; (S)-dihydroorotate from bicarbonate: step 1/3.
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo
CC pathway; (S)-dihydroorotate from bicarbonate: step 2/3.
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo
CC pathway; (S)-dihydroorotate from bicarbonate: step 3/3.
CC -!- SUBUNIT: Homohexamer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Cytosolic and
CC unphosphorylated in resting cells, translocates to the nucleus in
CC response to EGF stimulation, nuclear import promotes optimal cell
CC growth.
CC -!- INDUCTION: Transcriptionally repressed following hypoxia by HIF1A.
CC -!- PTM: Activated by MAP kinase (Erk1/2) phosphorylation just prior
CC to the S phase of the cell cycle, when the demand for pyrimidine
CC nucleotides is greatest, and down-regulated as the cells emerge
CC from S phase by protein kinase A (PKA) phosphorylation.
CC Phosphorylation at Ser-1859 by RPS6KB1 downstream of MTOR promotes
CC oligomerization and stimulates dihydroorotase activity.
CC Phosphorylation at Ser-1406 reduces sensitivy to feedback
CC inhibition by UTP.
CC -!- MISCELLANEOUS: GATase (glutamine amidotransferase) and CPSase
CC (carbamoyl phosphate synthase) form together the glutamine-
CC dependent CPSase (GD-CPSase) (EC 6.3.5.5).
CC -!- SIMILARITY: In the central section; belongs to the DHOase family.
CC -!- SIMILARITY: Contains 2 ATP-grasp domains.
CC -!- SIMILARITY: Contains 1 glutamine amidotransferase type-1 domain.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Aspartate carbamoyltransferase
CC entry;
CC URL="http://en.wikipedia.org/wiki/Aspartate_carbamoyltransferase";
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DR EMBL; D78586; BAA11423.1; -; mRNA.
DR EMBL; CH471053; EAX00612.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00613.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00614.1; -; Genomic_DNA.
DR EMBL; BC014178; AAH14178.2; -; mRNA.
DR EMBL; BC065510; AAH65510.1; -; mRNA.
DR EMBL; M38561; AAA51907.1; -; Genomic_DNA.
DR PIR; A36240; A36240.
DR RefSeq; NP_004332.2; NM_004341.3.
DR UniGene; Hs.377010; -.
DR ProteinModelPortal; P27708; -.
DR SMR; P27708; 2-359, 394-1440, 1464-1843, 1923-2223.
DR DIP; DIP-39484N; -.
DR IntAct; P27708; 22.
DR MINT; MINT-5000537; -.
DR STRING; 9606.ENSP00000264705; -.
DR BindingDB; P27708; -.
DR ChEMBL; CHEMBL3093; -.
DR DrugBank; DB00128; L-Aspartic Acid.
DR DrugBank; DB00130; L-Glutamine.
DR MEROPS; C26.952; -.
DR PhosphoSite; P27708; -.
DR DMDM; 50403731; -.
DR PaxDb; P27708; -.
DR PeptideAtlas; P27708; -.
DR PRIDE; P27708; -.
DR Ensembl; ENST00000264705; ENSP00000264705; ENSG00000084774.
DR GeneID; 790; -.
DR KEGG; hsa:790; -.
DR UCSC; uc002rji.3; human.
DR CTD; 790; -.
DR GeneCards; GC02P027440; -.
DR HGNC; HGNC:1424; CAD.
DR HPA; CAB007781; -.
DR MIM; 114010; gene.
DR neXtProt; NX_P27708; -.
DR PharmGKB; PA26023; -.
DR eggNOG; COG0458; -.
DR HOGENOM; HOG000234584; -.
DR HOVERGEN; HBG000279; -.
DR InParanoid; P27708; -.
DR KO; K11540; -.
DR OrthoDB; EOG7M6D6F; -.
DR PhylomeDB; P27708; -.
DR BioCyc; MetaCyc:ENSG00000084774-MONOMER; -.
DR BRENDA; 3.5.2.3; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00070; UER00115.
DR UniPathway; UPA00070; UER00116.
DR UniPathway; UPA00070; UER00117.
DR ChiTaRS; cad; human.
DR GenomeRNAi; 790; -.
DR NextBio; 3214; -.
DR PMAP-CutDB; P27708; -.
DR PRO; PR:P27708; -.
DR ArrayExpress; P27708; -.
DR Bgee; P27708; -.
DR CleanEx; HS_CAD; -.
DR Genevestigator; P27708; -.
DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0016363; C:nuclear matrix; IDA:BHF-UCL.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl.
DR GO; GO:0016597; F:amino acid binding; IEA:InterPro.
DR GO; GO:0070335; F:aspartate binding; ISS:BHF-UCL.
DR GO; GO:0004070; F:aspartate carbamoyltransferase activity; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; ISS:BHF-UCL.
DR GO; GO:0004088; F:carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity; IEA:Ensembl.
DR GO; GO:0004151; F:dihydroorotase activity; IEA:Ensembl.
DR GO; GO:0042802; F:identical protein binding; ISS:BHF-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; ISS:BHF-UCL.
DR GO; GO:0006207; P:'de novo' pyrimidine nucleobase biosynthetic process; IEA:Ensembl.
DR GO; GO:0044205; P:'de novo' UMP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0070409; P:carbamoyl phosphate biosynthetic process; IEA:InterPro.
DR GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IEA:Ensembl.
DR GO; GO:0017144; P:drug metabolic process; IEA:Ensembl.
DR GO; GO:0009790; P:embryo development; IEA:Ensembl.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:0006543; P:glutamine catabolic process; IEA:InterPro.
DR GO; GO:0006541; P:glutamine metabolic process; IEA:Ensembl.
DR GO; GO:0007595; P:lactation; IEA:Ensembl.
DR GO; GO:0031100; P:organ regeneration; IEA:Ensembl.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISS:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:BHF-UCL.
DR GO; GO:0046134; P:pyrimidine nucleoside biosynthetic process; TAS:Reactome.
DR GO; GO:0014075; P:response to amine stimulus; IEA:Ensembl.
DR GO; GO:0031000; P:response to caffeine; IEA:Ensembl.
DR GO; GO:0051414; P:response to cortisol stimulus; IEA:Ensembl.
DR GO; GO:0033574; P:response to testosterone stimulus; IEA:Ensembl.
DR GO; GO:0006228; P:UTP biosynthetic process; IEA:Ensembl.
DR Gene3D; 1.10.1030.10; -; 1.
DR Gene3D; 3.30.1490.20; -; 1.
DR Gene3D; 3.30.470.20; -; 2.
DR Gene3D; 3.40.50.1370; -; 2.
DR Gene3D; 3.40.50.1380; -; 1.
DR Gene3D; 3.40.50.20; -; 2.
DR Gene3D; 3.50.30.20; -; 1.
DR InterPro; IPR006132; Asp/Orn_carbamoyltranf_P-bd.
DR InterPro; IPR006130; Asp/Orn_carbamoylTrfase.
DR InterPro; IPR002082; Asp_carbamoyltransf.
DR InterPro; IPR006131; Asp_carbamoyltransf_Asp/Orn-bd.
DR InterPro; IPR011761; ATP-grasp.
DR InterPro; IPR013815; ATP_grasp_subdomain_1.
DR InterPro; IPR013816; ATP_grasp_subdomain_2.
DR InterPro; IPR006275; CarbamoylP_synth_lsu.
DR InterPro; IPR005481; CarbamoylP_synth_lsu_N.
DR InterPro; IPR005480; CarbamoylP_synth_lsu_oligo.
DR InterPro; IPR006274; CarbamoylP_synth_ssu.
DR InterPro; IPR002474; CarbamoylP_synth_ssu_N.
DR InterPro; IPR005479; CbamoylP_synth_lsu-like_ATP-bd.
DR InterPro; IPR005483; CbamoylP_synth_lsu_CPSase_dom.
DR InterPro; IPR002195; Dihydroorotase_CS.
DR InterPro; IPR017926; GATASE.
DR InterPro; IPR011059; Metal-dep_hydrolase_composite.
DR InterPro; IPR011607; MGS-like_dom.
DR InterPro; IPR016185; PreATP-grasp_dom.
DR Pfam; PF00289; CPSase_L_chain; 2.
DR Pfam; PF02786; CPSase_L_D2; 2.
DR Pfam; PF02787; CPSase_L_D3; 1.
DR Pfam; PF00988; CPSase_sm_chain; 1.
DR Pfam; PF00117; GATase; 1.
DR Pfam; PF02142; MGS; 1.
DR Pfam; PF00185; OTCace; 1.
DR Pfam; PF02729; OTCace_N; 1.
DR PRINTS; PR00100; AOTCASE.
DR PRINTS; PR00101; ATCASE.
DR PRINTS; PR00098; CPSASE.
DR SMART; SM01096; CPSase_L_D3; 1.
DR SMART; SM01097; CPSase_sm_chain; 1.
DR SMART; SM00851; MGS; 1.
DR SUPFAM; SSF48108; SSF48108; 1.
DR SUPFAM; SSF51338; SSF51338; 1.
DR SUPFAM; SSF52021; SSF52021; 1.
DR SUPFAM; SSF52335; SSF52335; 1.
DR SUPFAM; SSF52440; SSF52440; 2.
DR SUPFAM; SSF53671; SSF53671; 1.
DR TIGRFAMs; TIGR00670; asp_carb_tr; 1.
DR TIGRFAMs; TIGR01369; CPSaseII_lrg; 1.
DR TIGRFAMs; TIGR01368; CPSaseIIsmall; 1.
DR PROSITE; PS50975; ATP_GRASP; 2.
DR PROSITE; PS00097; CARBAMOYLTRANSFERASE; 1.
DR PROSITE; PS00866; CPSASE_1; 2.
DR PROSITE; PS00867; CPSASE_2; 2.
DR PROSITE; PS00482; DIHYDROOROTASE_1; 1.
DR PROSITE; PS00483; DIHYDROOROTASE_2; 1.
DR PROSITE; PS51273; GATASE_TYPE_1; 1.
PE 1: Evidence at protein level;
KW Acetylation; Allosteric enzyme; ATP-binding; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Hydrolase; Ligase;
KW Metal-binding; Multifunctional enzyme; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Polymorphism; Pyrimidine biosynthesis;
KW Reference proteome; Repeat; Transferase; Zinc.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 2225 CAD protein.
FT /FTId=PRO_0000199506.
FT DOMAIN 177 363 Glutamine amidotransferase type-1.
FT DOMAIN 519 711 ATP-grasp 1.
FT DOMAIN 1052 1243 ATP-grasp 2.
FT REGION 2 365 GATase (Glutamine amidotransferase).
FT REGION 366 394 Linker.
FT REGION 395 1455 CPSase (Carbamoyl-phosphate synthase).
FT REGION 395 933 CPSase A.
FT REGION 934 1455 CPSase B.
FT REGION 1456 1788 DHOase (dihydroorotase).
FT REGION 1789 1917 Linker.
FT REGION 1918 2225 ATCase (Aspartate transcarbamylase).
FT ACT_SITE 252 252 For GATase activity (By similarity).
FT ACT_SITE 336 336 For GATase activity (By similarity).
FT ACT_SITE 338 338 For GATase activity (By similarity).
FT METAL 1471 1471 Zinc.
FT METAL 1473 1473 Zinc.
FT METAL 1590 1590 Zinc (Probable).
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 456 456 Phosphothreonine; by MAPK1.
FT MOD_RES 747 747 N6-acetyllysine.
FT MOD_RES 1406 1406 Phosphoserine; by PKA.
FT MOD_RES 1411 1411 N6-acetyllysine.
FT MOD_RES 1859 1859 Phosphoserine; by RPS6KB1 and PKA.
FT MOD_RES 1873 1873 Phosphoserine; by PKC; in vitro.
FT MOD_RES 1884 1884 Phosphothreonine.
FT MOD_RES 1900 1900 Phosphoserine.
FT MOD_RES 1906 1906 Phosphothreonine.
FT VARIANT 177 177 R -> Q (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035897.
FT VARIANT 735 735 Y -> C (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035898.
FT MUTAGEN 1471 1471 H->A: No zinc-binding and no catalytic
FT activity.
FT MUTAGEN 1473 1473 H->A: No zinc-binding and no catalytic
FT activity.
FT MUTAGEN 1512 1512 D->N: No change in catalytic activity.
FT MUTAGEN 1590 1590 H->N: No catalytic activity.
FT MUTAGEN 1642 1642 H->N: 11.5% of wild-type catalytic
FT activity.
FT MUTAGEN 1690 1690 H->N: 3% of wild-type catalytic activity.
FT MUTAGEN 1873 1873 S->A: Abolishes PMA-induced Thr-456
FT phosphorylation.
FT CONFLICT 505 505 P -> T (in Ref. 1; BAA11423).
FT CONFLICT 535 535 A -> G (in Ref. 1; BAA11423).
FT CONFLICT 560 560 L -> V (in Ref. 1; BAA11423).
FT CONFLICT 1103 1103 T -> A (in Ref. 1; BAA11423).
FT CONFLICT 1513 1513 A -> G (in Ref. 1; BAA11423).
FT CONFLICT 1676 1676 N -> D (in Ref. 1; BAA11423).
SQ SEQUENCE 2225 AA; 242984 MW; 2AB8E8413E825A8F CRC64;
MAALVLEDGS VLRGQPFGAA VSTAGEVVFQ TGMVGYPEAL TDPSYKAQIL VLTYPLIGNY
GIPPDEMDEF GLCKWFESSG IHVAALVVGE CCPTPSHWSA TRTLHEWLQQ HGIPGLQGVD
TRELTKKLRE QGSLLGKLVQ NGTEPSSLPF LDPNARPLVP EVSIKTPRVF NTGGAPRILA
LDCGLKYNQI RCLCQRGAEV TVVPWDHALD SQEYEGLFLS NGPGDPASYP SVVSTLSRVL
SEPNPRPVFG ICLGHQLLAL AIGAKTYKMR YGNRGHNQPC LLVGSGRCFL TSQNHGFAVE
TDSLPADWAP LFTNANDGSN EGIVHNSLPF FSVQFHPEHQ AGPSDMELLF DIFLETVKEA
TAGNPGGQTV RERLTERLCP PGIPTPGSGL PPPRKVLILG SGGLSIGQAG EFDYSGSQAI
KALKEENIQT LLINPNIATV QTSQGLADKV YFLPITPHYV TQVIRNERPD GVLLTFGGQT
ALNCGVELTK AGVLARYGVR VLGTPVETIE LTEDRRAFAA RMAEIGEHVA PSEAANSLEQ
AQAAAERLGY PVLVRAAFAL GGLGSGFASN REELSALVAP AFAHTSQVLV DKSLKGWKEI
EYEVVRDAYG NCVTVCNMEN LDPLGIHTGE SIVVAPSQTL NDREYQLLRQ TAIKVTQHLG
IVGECNVQYA LNPESEQYYI IEVNARLSRS SALASKATGY PLAYVAAKLA LGIPLPELRN
SVTGGTAAFE PSVDYCVVKI PRWDLSKFLR VSTKIGSCMK SVGEVMGIGR SFEEAFQKAL
RMVDENCVGF DHTVKPVSDM ELETPTDKRI FVVAAALWAG YSVDRLYELT RIDRWFLHRM
KRIIAHAQLL EQHRGQPLPP DLLQQAKCLG FSDKQIALAV LSTELAVRKL RQELGICPAV
KQIDTVAAEW PAQTNYLYLT YWGTTHDLTF RTPHVLVLGS GVYRIGSSVE FDWCAVGCIQ
QLRKMGYKTI MVNYNPETVS TDYDMCDRLY FDEISFEVVM DIYELENPEG VILSMGGQLP
NNMAMALHRQ QCRVLGTSPE AIDSAENRFK FSRLLDTIGI SQPQWRELSD LESARQFCQT
VGYPCVVRPS YVLSGAAMNV AYTDGDLERF LSSAAAVSKE HPVVISKFIQ EAKEIDVDAV
ASDGVVAAIA ISEHVENAGV HSGDATLVTP PQDITAKTLE RIKAIVHAVG QELQVTGPFN
LQLIAKDDQL KVIECNVRVS RSFPFVSKTL GVDLVALATR VIMGEEVEPV GLMTGSGVVG
VKVPQFSFSR LAGADVVLGV EMTSTGEVAG FGESRCEAYL KAMLSTGFKI PKKNILLTIG
SYKNKSELLP TVRLLESLGY SLYASLGTAD FYTEHGVKVT AVDWHFEEAV DGECPPQRSI
LEQLAEKNFE LVINLSMRGA GGRRLSSFVT KGYRTRRLAA DFSVPLIIDI KCTKLFVEAL
GQIGPAPPLK VHVDCMTSQK LVRLPGLIDV HVHLREPGGT HKEDFASGTA AALAGGITMV
CAMPNTRPPI IDAPALALAQ KLAEAGARCD FALFLGASSE NAGTLGTVAG SAAGLKLYLN
ETFSELRLDS VVQWMEHFET WPSHLPIVAH AEQQTVAAVL MVAQLTQRSV HICHVARKEE
ILLIKAAKAR GLPVTCEVAP HHLFLSHDDL ERLGPGKGEV RPELGSRQDV EALWENMAVI
DCFASDHAPH TLEEKCGSRP PPGFPGLETM LPLLLTAVSE GRLSLDDLLQ RLHHNPRRIF
HLPPQEDTYV EVDLEHEWTI PSHMPFSKAH WTPFEGQKVK GTVRRVVLRG EVAYIDGQVL
VPPGYGQDVR KWPQGAVPQL PPSAPATSEM TTTPERPRRG IPGLPDGRFH LPPRIHRASD
PGLPAEEPKE KSSRKVAEPE LMGTPDGTCY PPPPVPRQAS PQNLGTPGLL HPQTSPLLHS
LVGQHILSVQ QFTKDQMSHL FNVAHTLRMM VQKERSLDIL KGKVMASMFY EVSTRTSSSF
AAAMARLGGA VLSFSEATSS VQKGESLADS VQTMSCYADV VVLRHPQPGA VELAAKHCRR
PVINAGDGVG EHPTQALLDI FTIREELGTV NGMTITMVGD LKHGRTVHSL ACLLTQYRVS
LRYVAPPSLR MPPTVRAFVA SRGTKQEEFE SIEEALPDTD VLYMTRIQKE RFGSTQEYEA
CFGQFILTPH IMTRAKKKMV VMHPMPRVNE ISVEVDSDPR AAYFRQAENG MYIRMALLAT
VLGRF
//
MIM
114010
*RECORD*
*FIELD* NO
114010
*FIELD* TI
*114010 CARBAMOYL PHOSPHATE SYNTHETASE/ASPARTATE TRANSCARBAMOYLASE/DIHYDROOROTASE;
read moreCAD
;;CAD TRIFUNCTIONAL PROTEIN;;
CPSase/ATCase/DHOase
*FIELD* TX
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. (1987, 1989) mapped the CAD gene to 2p22-p21 by in situ
hybridization, by Southern analysis of DNA from somatic cell hybrids,
and by nutritional complementation tests in hamster/human somatic cell
hybrids containing reduced numbers of human chromosomes.
By a study of cells from 2 patients with holoprosencephaly and a 2p
interstitial deletion, Muenke et al. (1989) excluded CAD from the
segment 2p23.3-p21.01.
Bertoni et al. (1993) used fluorescence in situ hybridization to
localize the Chinese hamster CAD gene to a region of chromosome 7 where
other genes homologous to genes on human chromosome 2p have been mapped.
EVOLUTION
Simmer et al. (1990) suggested that all dihydroorotases (DHOases) are
descendants of a common ancestor. In some organisms, the enzyme has
remained monofunctional. Simmer et al. (1990) suggested that in mammals
DHOase gene duplication and insertion into an ancestral bifunctional
locus occurred.
*FIELD* RF
1. Ben-Sahra, I.; Howell, J. J.; Asara, J. M.; Manning, B. D.: Stimulation
of de novo pyrimidine synthesis by growth signaling through mTOR and
S6K1. Science 339: 1323-1328, 2013.
2. Bertoni, L.; Attolini, C.; Simi, S.; Giulotto, E.: Localization
of the Chinese hamster CAD gene reveals homology between human chromosome
2p and Chinese hamster 7q. Genomics 16: 779-781, 1993.
3. Chen, K.-C.; Vannais, D. B.; Jones, C.; Patterson, D.; Davidson,
J. N.: Chromosomal localization of the human CAD gene to 2p21-22.
(Abstract) Am. J. Hum. Genet. 41: A161 only, 1987.
4. Chen, K.-C.; Vannais, D. B.; Jones, C.; Patterson, D.; Davidson,
J. N.: Mapping of the gene encoding the multifunctional protein carrying
out the first three steps of pyrimidine biosynthesis to human chromosome
2. Hum. Genet. 82: 40-44, 1989.
5. Chen, S.; Bigner, S. H.; Modrich, P.: High rate of CAD gene amplification
in human cells deficient in MLH1 or MSH6. Proc. Nat. Acad. Sci. 98:
13802-13807, 2001.
6. Graves, L. M.; Guy, H. I.; Kozlowski, P.; Huang, M.; Lazarowski,
E.; Pope, R. M.; Collins, M. A.; Dahlstrand, E. N.; Earp, H. S., III;
Evans, D. R.: Regulation of carbamoyl phosphate synthetase by MAP
kinase. Nature 403: 328-332, 2000.
7. Muenke, M.; Sosnoski, D. M.; Wilson, W. G.; Wassman, E. R.; Davidson,
J. N.; Patterson, D.; Nussbaum, R. L.: Exclusion of the CAD locus
from 2p2101-p23.3 using 2p interstitial deletions from patients with
holoprosencephaly. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A84
only, 1989.
8. Robitaille, A. M.; Christen, S.; Shimobayashi, M.; Cornu, M.; Fava,
L. L.; Moes, S.; Prescianotto-Baschong, C.; Sauer, U.; Jenoe, P.;
Hall, M. N.: Quantitative phosphoproteomics reveal mTORC1 activates
de novo pyrimidine synthesis. Science 339: 1320-1323, 2013.
9. Simmer, J. P.; Kelly, R. E.; Rinker, A. G., Jr.; Zimmermann, B.
H.; Scully, J. L.; Kim, H.; Evans, D. R.: Mammalian dihydroorotase:
nucleotide sequence, peptide sequences, and evolution of the dihydroorotase
domain of the multifunctional protein CAD. Proc. Nat. Acad. Sci. 87:
174-178, 1990.
*FIELD* CN
Ada Hamosh - updated: 07/08/2013
Victor A. McKusick - updated: 1/7/2002
Ada Hamosh - updated: 1/19/2000
*FIELD* CD
Victor A. McKusick: 10/28/1987
*FIELD* ED
alopez: 07/08/2013
alopez: 3/2/2012
alopez: 10/19/2010
terry: 11/25/2009
carol: 12/4/2003
ckniffin: 12/4/2003
mcapotos: 1/10/2002
terry: 1/7/2002
alopez: 1/20/2000
terry: 1/19/2000
joanna: 6/19/1997
mark: 7/19/1995
carol: 6/24/1993
supermim: 3/16/1992
supermim: 4/25/1990
supermim: 3/20/1990
carol: 3/6/1990
*RECORD*
*FIELD* NO
114010
*FIELD* TI
*114010 CARBAMOYL PHOSPHATE SYNTHETASE/ASPARTATE TRANSCARBAMOYLASE/DIHYDROOROTASE;
read moreCAD
;;CAD TRIFUNCTIONAL PROTEIN;;
CPSase/ATCase/DHOase
*FIELD* TX
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. (1987, 1989) mapped the CAD gene to 2p22-p21 by in situ
hybridization, by Southern analysis of DNA from somatic cell hybrids,
and by nutritional complementation tests in hamster/human somatic cell
hybrids containing reduced numbers of human chromosomes.
By a study of cells from 2 patients with holoprosencephaly and a 2p
interstitial deletion, Muenke et al. (1989) excluded CAD from the
segment 2p23.3-p21.01.
Bertoni et al. (1993) used fluorescence in situ hybridization to
localize the Chinese hamster CAD gene to a region of chromosome 7 where
other genes homologous to genes on human chromosome 2p have been mapped.
EVOLUTION
Simmer et al. (1990) suggested that all dihydroorotases (DHOases) are
descendants of a common ancestor. In some organisms, the enzyme has
remained monofunctional. Simmer et al. (1990) suggested that in mammals
DHOase gene duplication and insertion into an ancestral bifunctional
locus occurred.
*FIELD* RF
1. Ben-Sahra, I.; Howell, J. J.; Asara, J. M.; Manning, B. D.: Stimulation
of de novo pyrimidine synthesis by growth signaling through mTOR and
S6K1. Science 339: 1323-1328, 2013.
2. Bertoni, L.; Attolini, C.; Simi, S.; Giulotto, E.: Localization
of the Chinese hamster CAD gene reveals homology between human chromosome
2p and Chinese hamster 7q. Genomics 16: 779-781, 1993.
3. Chen, K.-C.; Vannais, D. B.; Jones, C.; Patterson, D.; Davidson,
J. N.: Chromosomal localization of the human CAD gene to 2p21-22.
(Abstract) Am. J. Hum. Genet. 41: A161 only, 1987.
4. Chen, K.-C.; Vannais, D. B.; Jones, C.; Patterson, D.; Davidson,
J. N.: Mapping of the gene encoding the multifunctional protein carrying
out the first three steps of pyrimidine biosynthesis to human chromosome
2. Hum. Genet. 82: 40-44, 1989.
5. Chen, S.; Bigner, S. H.; Modrich, P.: High rate of CAD gene amplification
in human cells deficient in MLH1 or MSH6. Proc. Nat. Acad. Sci. 98:
13802-13807, 2001.
6. Graves, L. M.; Guy, H. I.; Kozlowski, P.; Huang, M.; Lazarowski,
E.; Pope, R. M.; Collins, M. A.; Dahlstrand, E. N.; Earp, H. S., III;
Evans, D. R.: Regulation of carbamoyl phosphate synthetase by MAP
kinase. Nature 403: 328-332, 2000.
7. Muenke, M.; Sosnoski, D. M.; Wilson, W. G.; Wassman, E. R.; Davidson,
J. N.; Patterson, D.; Nussbaum, R. L.: Exclusion of the CAD locus
from 2p2101-p23.3 using 2p interstitial deletions from patients with
holoprosencephaly. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A84
only, 1989.
8. Robitaille, A. M.; Christen, S.; Shimobayashi, M.; Cornu, M.; Fava,
L. L.; Moes, S.; Prescianotto-Baschong, C.; Sauer, U.; Jenoe, P.;
Hall, M. N.: Quantitative phosphoproteomics reveal mTORC1 activates
de novo pyrimidine synthesis. Science 339: 1320-1323, 2013.
9. Simmer, J. P.; Kelly, R. E.; Rinker, A. G., Jr.; Zimmermann, B.
H.; Scully, J. L.; Kim, H.; Evans, D. R.: Mammalian dihydroorotase:
nucleotide sequence, peptide sequences, and evolution of the dihydroorotase
domain of the multifunctional protein CAD. Proc. Nat. Acad. Sci. 87:
174-178, 1990.
*FIELD* CN
Ada Hamosh - updated: 07/08/2013
Victor A. McKusick - updated: 1/7/2002
Ada Hamosh - updated: 1/19/2000
*FIELD* CD
Victor A. McKusick: 10/28/1987
*FIELD* ED
alopez: 07/08/2013
alopez: 3/2/2012
alopez: 10/19/2010
terry: 11/25/2009
carol: 12/4/2003
ckniffin: 12/4/2003
mcapotos: 1/10/2002
terry: 1/7/2002
alopez: 1/20/2000
terry: 1/19/2000
joanna: 6/19/1997
mark: 7/19/1995
carol: 6/24/1993
supermim: 3/16/1992
supermim: 4/25/1990
supermim: 3/20/1990
carol: 3/6/1990