PYR1_HUMAN
ID PYR1_HUMAN Reviewed; 2225 AA.
AC P27708; D6W552; Q6P0Q0; Q96CK3;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 3.
DT 03-AUG-2022, entry version 239.
DE RecName: Full=CAD protein;
DE Includes:
DE RecName: Full=Glutamine-dependent carbamoyl-phosphate synthase;
DE EC=6.3.5.5 {ECO:0000269|PubMed:24332717};
DE Includes:
DE RecName: Full=Aspartate carbamoyltransferase;
DE EC=2.1.3.2 {ECO:0000269|PubMed:24332717};
DE Includes:
DE RecName: Full=Dihydroorotase;
DE EC=3.5.2.3 {ECO:0000269|PubMed:24332717};
GN Name=CAD {ECO:0000312|HGNC:HGNC:1424};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC 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-dihydroorotase
RT 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., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., 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 project:
RT 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 IDENTIFICATION BY 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., 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 dihydroorotase.";
RL Biochemistry 34:7038-7046(1995).
RN [7]
RP ACTIVITY 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 the
RT 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 phosphorylation
RT 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 factor-
RT 1alpha.";
RL Nucleic Acids Res. 33:5190-5198(2005).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 phosphorylation
RT 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., 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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1884, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT 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
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA 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 AND SER-1900, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT 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., Buerckstuemmer T.,
RA 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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [21]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
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., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1038; SER-1406; SER-1859;
RP SER-1900 AND SER-1938, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [24]
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 pyrimidine
RT synthesis.";
RL Science 339:1320-1323(2013).
RN [25]
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 through
RT mTOR and S6K1.";
RL Science 339:1323-1328(2013).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [27]
RP INTERACTION WITH CIPC.
RX PubMed=26657846; DOI=10.1016/j.bbrc.2015.11.117;
RA Matsunaga R., Nishino T., Yokoyama A., Nakashima A., Kikkawa U.,
RA Konishi H.;
RT "Versatile function of the circadian protein CIPC as a regulator of Erk
RT activation.";
RL Biochem. Biophys. Res. Commun. 469:377-383(2016).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) OF 1456-1846 IN COMPLEX WITH
RP DIHYDROOROTATE; N-CARBAMOYL-L-ASPARTIC ACID AND ZINC, COFACTOR, CATALYTIC
RP ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF HIS-1471;
RP THR-1562; PHE-1563; HIS-1590; CYS-1613; HIS-1614; GLU-1637 AND ASP-1686,
RP AND CARBOXYLATION AT LYS-1556.
RX PubMed=24332717; DOI=10.1016/j.str.2013.10.016;
RA Grande-Garcia A., Lallous N., Diaz-Tejada C., Ramon-Maiques S.;
RT "Structure, functional characterization, and evolution of the
RT dihydroorotase domain of human CAD.";
RL Structure 22:185-198(2014).
RN [29]
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., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [30]
RP INVOLVEMENT IN DEE50, AND VARIANT DEE50 GLN-2024.
RX PubMed=25678555; DOI=10.1093/hmg/ddv057;
RA Ng B.G., Wolfe L.A., Ichikawa M., Markello T., He M., Tifft C.J.,
RA Gahl W.A., Freeze H.H.;
RT "Biallelic mutations in CAD, impair de novo pyrimidine biosynthesis and
RT decrease glycosylation precursors.";
RL Hum. Mol. Genet. 24:3050-3057(2015).
RN [31]
RP VARIANTS DEE50 ARG-33 AND 1789-ARG--PHE-2225 DEL.
RX PubMed=28087732; DOI=10.1093/hmg/ddx018;
RA Lohmann K., Masuho I., Patil D.N., Baumann H., Hebert E., Steinruecke S.,
RA Trujillano D., Skamangas N.K., Dobricic V., Huening I.,
RA Gillessen-Kaesbach G., Westenberger A., Savic-Pavicevic D., Muenchau A.,
RA Oprea G., Klein C., Rolfs A., Martemyanov K.A.;
RT "Novel GNB1 mutations disrupt assembly and function of G protein
RT heterotrimers and cause global developmental delay in humans.";
RL Hum. Mol. Genet. 26:1078-1086(2017).
CC -!- FUNCTION: This protein is a 'fusion' protein encoding four enzymatic
CC activities of the pyrimidine pathway (GATase, CPSase, ATCase and
CC DHOase). {ECO:0000269|PubMed:24332717}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 ATP + H2O + hydrogencarbonate + L-glutamine = 2 ADP +
CC carbamoyl phosphate + 2 H(+) + L-glutamate + phosphate;
CC Xref=Rhea:RHEA:18633, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17544, ChEBI:CHEBI:29985, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58228, ChEBI:CHEBI:58359,
CC ChEBI:CHEBI:456216; EC=6.3.5.5;
CC Evidence={ECO:0000269|PubMed:24332717};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=carbamoyl phosphate + L-aspartate = H(+) + N-carbamoyl-L-
CC aspartate + phosphate; Xref=Rhea:RHEA:20013, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29991, ChEBI:CHEBI:32814, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:58228; EC=2.1.3.2;
CC Evidence={ECO:0000269|PubMed:24332717};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-dihydroorotate + H2O = H(+) + N-carbamoyl-L-aspartate;
CC Xref=Rhea:RHEA:24296, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30864, ChEBI:CHEBI:32814; EC=3.5.2.3;
CC Evidence={ECO:0000269|PubMed:24332717};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:24332717, ECO:0000269|PubMed:7766613};
CC Note=Binds 3 Zn(2+) ions per subunit (for dihydroorotase activity).
CC {ECO:0000269|PubMed:24332717, ECO:0000269|PubMed:7766613};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00409};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00409};
CC Note=Binds 4 magnesium or manganese ions per subunit.
CC {ECO:0000255|PROSITE-ProRule:PRU00409};
CC -!- ACTIVITY REGULATION: Allosterically regulated and controlled by
CC phosphorylation. 5-phosphoribose 1-diphosphate (PRPP) is an activator
CC while UMP and UTP are inhibitors of the CPSase reaction.
CC {ECO:0000269|PubMed:11872754}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=28 uM for dihydroorotate {ECO:0000269|PubMed:24332717};
CC KM=241 uM for N-carbamoyl-L-aspartate {ECO:0000269|PubMed:24332717};
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo pathway;
CC (S)-dihydroorotate from bicarbonate: step 1/3.
CC {ECO:0000269|PubMed:24332717}.
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo pathway;
CC (S)-dihydroorotate from bicarbonate: step 2/3.
CC {ECO:0000269|PubMed:24332717}.
CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo pathway;
CC (S)-dihydroorotate from bicarbonate: step 3/3.
CC {ECO:0000269|PubMed:24332717}.
CC -!- SUBUNIT: Homohexamer (PubMed:24332717). Interacts with CIPC
CC (PubMed:26657846). {ECO:0000269|PubMed:24332717,
CC ECO:0000269|PubMed:26657846}.
CC -!- INTERACTION:
CC P27708; P27708: CAD; NbExp=3; IntAct=EBI-355504, EBI-355504;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15890648}. Nucleus
CC {ECO:0000269|PubMed:15890648}. Note=Cytosolic and unphosphorylated in
CC resting cells, translocates to the nucleus in response to EGF
CC stimulation, nuclear import promotes optimal cell growth.
CC -!- INDUCTION: Transcriptionally repressed following hypoxia by HIF1A.
CC {ECO:0000269|PubMed:16155188}.
CC -!- PTM: Activated by MAP kinase (Erk1/2) phosphorylation just prior to the
CC S phase of the cell cycle, when the demand for pyrimidine nucleotides
CC is greatest, and down-regulated as the cells emerge from S phase by
CC protein kinase A (PKA) phosphorylation. Phosphorylation at Ser-1859 by
CC RPS6KB1 downstream of MTOR promotes oligomerization and stimulates
CC dihydroorotase activity. Phosphorylation at Ser-1406 reduces
CC sensitivity to feedback inhibition by UTP.
CC {ECO:0000269|PubMed:17485345, ECO:0000269|PubMed:23429703,
CC ECO:0000269|PubMed:23429704}.
CC -!- DISEASE: Developmental and epileptic encephalopathy 50 (DEE50)
CC [MIM:616457]: A form of epileptic encephalopathy, a heterogeneous group
CC of severe early-onset epilepsies characterized by refractory seizures,
CC neurodevelopmental impairment, and poor prognosis. Development is
CC normal prior to seizure onset, after which cognitive and motor delays
CC become apparent. DEE50 is an autosomal recessive, progressive disease
CC with onset in infancy and favorable response to treatment with oral
CC uridine. {ECO:0000269|PubMed:25678555, ECO:0000269|PubMed:28087732}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- MISCELLANEOUS: GATase (glutamine amidotransferase) and CPSase
CC (carbamoyl phosphate synthase) form together the glutamine-dependent
CC CPSase (GD-CPSase) (EC 6.3.5.5). {ECO:0000305}.
CC -!- SIMILARITY: In the central section; belongs to the metallo-dependent
CC hydrolases superfamily. DHOase family. CAD subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Aspartate carbamoyltransferase
CC entry;
CC URL="https://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 CCDS; CCDS1742.1; -.
DR PIR; A36240; A36240.
DR RefSeq; NP_001293008.1; NM_001306079.1.
DR RefSeq; NP_004332.2; NM_004341.4.
DR PDB; 4BY3; X-ray; 1.73 A; A=1456-1846.
DR PDB; 4C6B; X-ray; 1.66 A; A=1456-1846.
DR PDB; 4C6C; X-ray; 1.45 A; A=1456-1846.
DR PDB; 4C6D; X-ray; 1.30 A; A=1456-1846.
DR PDB; 4C6E; X-ray; 1.26 A; A=1456-1846.
DR PDB; 4C6F; X-ray; 1.26 A; A=1456-1846.
DR PDB; 4C6I; X-ray; 1.35 A; A=1456-1846.
DR PDB; 4C6J; X-ray; 1.30 A; A=1456-1846.
DR PDB; 4C6K; X-ray; 1.48 A; A=1456-1846.
DR PDB; 4C6L; X-ray; 1.55 A; A=1456-1846.
DR PDB; 4C6M; X-ray; 1.62 A; A=1456-1846.
DR PDB; 4C6N; X-ray; 1.90 A; A=1456-1846.
DR PDB; 4C6O; X-ray; 1.65 A; A=1456-1846.
DR PDB; 4C6P; X-ray; 1.52 A; A=1456-1846.
DR PDB; 4C6Q; X-ray; 1.66 A; A=1456-1846.
DR PDB; 5G1N; X-ray; 2.10 A; A/B/C/D/E/F=1915-2225.
DR PDB; 5G1O; X-ray; 2.10 A; A/B/C/D/E/F=1915-2225.
DR PDB; 5G1P; X-ray; 3.19 A; A/B/C/D/E/F=1915-2225.
DR PDB; 5YNZ; X-ray; 2.77 A; A=1456-1846.
DR PDB; 6HFD; X-ray; 1.87 A; A=1456-1846.
DR PDB; 6HFE; X-ray; 1.48 A; A=1456-1846.
DR PDB; 6HFF; X-ray; 1.51 A; A=1456-1846.
DR PDB; 6HFH; X-ray; 1.45 A; A=1456-1846.
DR PDB; 6HFI; X-ray; 1.46 A; A=1456-1846.
DR PDB; 6HFJ; X-ray; 1.20 A; A=1456-1846.
DR PDB; 6HFK; X-ray; 1.46 A; A=1456-1846.
DR PDB; 6HFL; X-ray; 1.35 A; A=1456-1846.
DR PDB; 6HFN; X-ray; 1.45 A; A=1456-1846.
DR PDB; 6HFP; X-ray; 1.20 A; A=1456-1846.
DR PDB; 6HFQ; X-ray; 1.15 A; A=1456-1846.
DR PDB; 6HFR; X-ray; 1.30 A; A=1456-1846.
DR PDB; 6HFS; X-ray; 1.35 A; A=1456-1846.
DR PDB; 6HFU; X-ray; 1.40 A; A=1456-1846.
DR PDB; 6HG1; X-ray; 2.12 A; A=1460-1559, A=1571-1826.
DR PDBsum; 4BY3; -.
DR PDBsum; 4C6B; -.
DR PDBsum; 4C6C; -.
DR PDBsum; 4C6D; -.
DR PDBsum; 4C6E; -.
DR PDBsum; 4C6F; -.
DR PDBsum; 4C6I; -.
DR PDBsum; 4C6J; -.
DR PDBsum; 4C6K; -.
DR PDBsum; 4C6L; -.
DR PDBsum; 4C6M; -.
DR PDBsum; 4C6N; -.
DR PDBsum; 4C6O; -.
DR PDBsum; 4C6P; -.
DR PDBsum; 4C6Q; -.
DR PDBsum; 5G1N; -.
DR PDBsum; 5G1O; -.
DR PDBsum; 5G1P; -.
DR PDBsum; 5YNZ; -.
DR PDBsum; 6HFD; -.
DR PDBsum; 6HFE; -.
DR PDBsum; 6HFF; -.
DR PDBsum; 6HFH; -.
DR PDBsum; 6HFI; -.
DR PDBsum; 6HFJ; -.
DR PDBsum; 6HFK; -.
DR PDBsum; 6HFL; -.
DR PDBsum; 6HFN; -.
DR PDBsum; 6HFP; -.
DR PDBsum; 6HFQ; -.
DR PDBsum; 6HFR; -.
DR PDBsum; 6HFS; -.
DR PDBsum; 6HFU; -.
DR PDBsum; 6HG1; -.
DR AlphaFoldDB; P27708; -.
DR SMR; P27708; -.
DR BioGRID; 107243; 299.
DR DIP; DIP-39484N; -.
DR IntAct; P27708; 115.
DR MINT; P27708; -.
DR STRING; 9606.ENSP00000264705; -.
DR BindingDB; P27708; -.
DR ChEMBL; CHEMBL3093; -.
DR DrugBank; DB00128; Aspartic acid.
DR DrugBank; DB00130; L-Glutamine.
DR DrugBank; DB03459; Sparfosic acid.
DR MEROPS; C26.952; -.
DR MEROPS; M38.972; -.
DR GlyGen; P27708; 3 sites, 1 O-linked glycan (3 sites).
DR iPTMnet; P27708; -.
DR MetOSite; P27708; -.
DR PhosphoSitePlus; P27708; -.
DR SwissPalm; P27708; -.
DR BioMuta; CAD; -.
DR DMDM; 50403731; -.
DR CPTAC; CPTAC-466; -.
DR CPTAC; CPTAC-467; -.
DR EPD; P27708; -.
DR jPOST; P27708; -.
DR MassIVE; P27708; -.
DR MaxQB; P27708; -.
DR PaxDb; P27708; -.
DR PeptideAtlas; P27708; -.
DR PRIDE; P27708; -.
DR ProteomicsDB; 54409; -.
DR Antibodypedia; 28293; 329 antibodies from 35 providers.
DR DNASU; 790; -.
DR Ensembl; ENST00000264705.9; ENSP00000264705.3; ENSG00000084774.14.
DR GeneID; 790; -.
DR KEGG; hsa:790; -.
DR MANE-Select; ENST00000264705.9; ENSP00000264705.3; NM_004341.5; NP_004332.2.
DR UCSC; uc002rji.4; human.
DR CTD; 790; -.
DR DisGeNET; 790; -.
DR GeneCards; CAD; -.
DR HGNC; HGNC:1424; CAD.
DR HPA; ENSG00000084774; Low tissue specificity.
DR MalaCards; CAD; -.
DR MIM; 114010; gene.
DR MIM; 616457; phenotype.
DR neXtProt; NX_P27708; -.
DR OpenTargets; ENSG00000084774; -.
DR Orphanet; 448010; CAD-CDG.
DR PharmGKB; PA26023; -.
DR VEuPathDB; HostDB:ENSG00000084774; -.
DR eggNOG; KOG0370; Eukaryota.
DR GeneTree; ENSGT00940000157241; -.
DR HOGENOM; CLU_000513_2_1_1; -.
DR InParanoid; P27708; -.
DR OMA; IPCTSML; -.
DR OrthoDB; 273358at2759; -.
DR PhylomeDB; P27708; -.
DR TreeFam; TF105604; -.
DR BioCyc; MetaCyc:ENSG00000084774-MON; -.
DR BRENDA; 2.1.3.2; 2681.
DR BRENDA; 3.5.2.3; 2681.
DR BRENDA; 6.3.5.5; 2681.
DR PathwayCommons; P27708; -.
DR Reactome; R-HSA-500753; Pyrimidine biosynthesis.
DR SABIO-RK; P27708; -.
DR SignaLink; P27708; -.
DR SIGNOR; P27708; -.
DR UniPathway; UPA00070; UER00115.
DR UniPathway; UPA00070; UER00116.
DR UniPathway; UPA00070; UER00117.
DR BioGRID-ORCS; 790; 280 hits in 1096 CRISPR screens.
DR ChiTaRS; CAD; human.
DR GenomeRNAi; 790; -.
DR Pharos; P27708; Tchem.
DR PRO; PR:P27708; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P27708; protein.
DR Bgee; ENSG00000084774; Expressed in body of uterus and 139 other tissues.
DR ExpressionAtlas; P27708; baseline and differential.
DR Genevisible; P27708; HS.
DR GO; GO:0042995; C:cell projection; ISS:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; ISS:BHF-UCL.
DR GO; GO:0016363; C:nuclear matrix; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0043195; C:terminal bouton; ISS:BHF-UCL.
DR GO; GO:0070335; F:aspartate binding; ISS:BHF-UCL.
DR GO; GO:0004070; F:aspartate carbamoyltransferase activity; ISS:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; ISS:BHF-UCL.
DR GO; GO:0004088; F:carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity; ISS:BHF-UCL.
DR GO; GO:0004151; F:dihydroorotase activity; IDA:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0004672; F:protein kinase activity; ISS:BHF-UCL.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0006207; P:'de novo' pyrimidine nucleobase biosynthetic process; IDA:UniProtKB.
DR GO; GO:0044205; P:'de novo' UMP biosynthetic process; IDA:MGI.
DR GO; GO:0019240; P:citrulline biosynthetic process; IBA:GO_Central.
DR GO; GO:0006541; P:glutamine metabolic process; ISS:BHF-UCL.
DR GO; GO:0006807; P:nitrogen compound metabolic process; IBA:GO_Central.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISS:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:BHF-UCL.
DR GO; GO:0006225; P:UDP biosynthetic process; IDA:MGI.
DR GO; GO:0006228; P:UTP biosynthetic process; IBA:GO_Central.
DR CDD; cd01744; GATase1_CPSase; 1.
DR DisProt; DP01024; -.
DR Gene3D; 1.10.1030.10; -; 1.
DR Gene3D; 3.30.1490.20; -; 1.
DR Gene3D; 3.40.50.1370; -; 2.
DR Gene3D; 3.40.50.1380; -; 1.
DR Gene3D; 3.40.50.880; -; 1.
DR Gene3D; 3.50.30.20; -; 1.
DR HAMAP; MF_00001; Asp_carb_tr; 1.
DR HAMAP; MF_01209; CPSase_S_chain; 1.
DR InterPro; IPR006680; Amidohydro-rel.
DR InterPro; IPR006132; Asp/Orn_carbamoyltranf_P-bd.
DR InterPro; IPR006130; Asp/Orn_carbamoylTrfase.
DR InterPro; IPR036901; Asp/Orn_carbamoylTrfase_sf.
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; IPR006275; CarbamoylP_synth_lsu.
DR InterPro; IPR005480; CarbamoylP_synth_lsu_oligo.
DR InterPro; IPR036897; CarbamoylP_synth_lsu_oligo_sf.
DR InterPro; IPR006274; CarbamoylP_synth_ssu.
DR InterPro; IPR002474; CarbamoylP_synth_ssu_N.
DR InterPro; IPR036480; CarbP_synth_ssu_N_sf.
DR InterPro; IPR005479; CbamoylP_synth_lsu-like_ATP-bd.
DR InterPro; IPR005483; CbamoylP_synth_lsu_CPSase_dom.
DR InterPro; IPR029062; Class_I_gatase-like.
DR InterPro; IPR035686; CPSase_GATase1.
DR InterPro; IPR002195; Dihydroorotase_CS.
DR InterPro; IPR017926; GATASE.
DR InterPro; IPR011059; Metal-dep_hydrolase_composite.
DR InterPro; IPR032466; Metal_Hydrolase.
DR InterPro; IPR011607; MGS-like_dom.
DR InterPro; IPR036914; MGS-like_dom_sf.
DR InterPro; IPR016185; PreATP-grasp_dom_sf.
DR Pfam; PF01979; Amidohydro_1; 1.
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; 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; SSF51556; SSF51556; 1.
DR SUPFAM; SSF52021; SSF52021; 1.
DR SUPFAM; SSF52317; SSF52317; 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.
DR PROSITE; PS51855; MGS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Allosteric enzyme; ATP-binding;
KW Congenital disorder of glycosylation; Cytoplasm; Direct protein sequencing;
KW Disease variant; Epilepsy; Hydrolase; Ligase; Magnesium; Manganese;
KW Metal-binding; Multifunctional enzyme; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Pyrimidine biosynthesis; Reference proteome; Repeat;
KW Transferase; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|Ref.4, ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378"
FT CHAIN 2..2225
FT /note="CAD protein"
FT /id="PRO_0000199506"
FT DOMAIN 177..363
FT /note="Glutamine amidotransferase type-1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00605"
FT DOMAIN 519..711
FT /note="ATP-grasp 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT DOMAIN 1052..1243
FT /note="ATP-grasp 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT DOMAIN 1308..1462
FT /note="MGS-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01202"
FT REGION 2..365
FT /note="GATase (Glutamine amidotransferase)"
FT /evidence="ECO:0000250|UniProtKB:P08955"
FT REGION 366..394
FT /note="Linker"
FT /evidence="ECO:0000250|UniProtKB:P08955"
FT REGION 395..1455
FT /note="CPSase (Carbamoyl-phosphate synthase)"
FT /evidence="ECO:0000250|UniProtKB:P08955"
FT REGION 395..933
FT /note="CPSase A"
FT /evidence="ECO:0000250|UniProtKB:P08955"
FT REGION 934..1455
FT /note="CPSase B"
FT /evidence="ECO:0000250|UniProtKB:P08955"
FT REGION 1456..1788
FT /note="DHOase (dihydroorotase)"
FT /evidence="ECO:0000250|UniProtKB:P08955"
FT REGION 1789..1917
FT /note="Linker"
FT /evidence="ECO:0000250|UniProtKB:P08955"
FT REGION 1811..1899
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1918..2225
FT /note="ATCase (Aspartate transcarbamylase)"
FT /evidence="ECO:0000250|UniProtKB:P08955"
FT COMPBIAS 1850..1877
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 252
FT /note="Nucleophile; for GATase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00605"
FT ACT_SITE 336
FT /note="For GATase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00605"
FT ACT_SITE 338
FT /note="For GATase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00605"
FT BINDING 545..600
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT BINDING 668
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT BINDING 682
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT BINDING 682
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT BINDING 684
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT BINDING 1078..1135
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT BINDING 1202
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT BINDING 1214
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT BINDING 1214
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT BINDING 1216
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00409"
FT BINDING 1471
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0007744|PDB:4C6D"
FT BINDING 1471
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0007744|PDB:4C6D"
FT BINDING 1473
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0007744|PDB:4C6D"
FT BINDING 1475
FT /ligand="N-carbamoyl-L-aspartate"
FT /ligand_id="ChEBI:CHEBI:32814"
FT /evidence="ECO:0000269|PubMed:24332717"
FT BINDING 1505
FT /ligand="N-carbamoyl-L-aspartate"
FT /ligand_id="ChEBI:CHEBI:32814"
FT /evidence="ECO:0000269|PubMed:24332717"
FT BINDING 1556
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /note="via carbamate group"
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0007744|PDB:4C6D"
FT BINDING 1556
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /note="via carbamate group"
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0007744|PDB:4C6D"
FT BINDING 1590
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0007744|PDB:4C6D"
FT BINDING 1613
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0007744|PDB:4C6D"
FT BINDING 1614
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0007744|PDB:4C6D"
FT BINDING 1637
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0007744|PDB:4C6D"
FT BINDING 1661
FT /ligand="N-carbamoyl-L-aspartate"
FT /ligand_id="ChEBI:CHEBI:32814"
FT /evidence="ECO:0000269|PubMed:24332717"
FT BINDING 1686
FT /ligand="N-carbamoyl-L-aspartate"
FT /ligand_id="ChEBI:CHEBI:32814"
FT /evidence="ECO:0000269|PubMed:24332717"
FT BINDING 1686
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0007744|PDB:4C6D"
FT BINDING 1690
FT /ligand="N-carbamoyl-L-aspartate"
FT /ligand_id="ChEBI:CHEBI:32814"
FT /evidence="ECO:0000269|PubMed:24332717"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000269|Ref.4, ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378"
FT MOD_RES 456
FT /note="Phosphothreonine; by MAPK1"
FT /evidence="ECO:0000269|PubMed:17485345"
FT MOD_RES 747
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 1038
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1406
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:17485345,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 1411
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 1556
FT /note="N6-carboxylysine"
FT /evidence="ECO:0000269|PubMed:24332717"
FT MOD_RES 1859
FT /note="Phosphoserine; by RPS6KB1 and PKA"
FT /evidence="ECO:0000269|PubMed:17485345,
FT ECO:0000269|PubMed:23429703, ECO:0000269|PubMed:23429704,
FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 1873
FT /note="Phosphoserine; by PKC; in vitro"
FT /evidence="ECO:0000269|PubMed:17485345"
FT MOD_RES 1884
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976"
FT MOD_RES 1900
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23429703,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT MOD_RES 1938
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VARIANT 33
FT /note="M -> R (in DEE50; unknown pathological significance;
FT dbSNP:rs751610198)"
FT /evidence="ECO:0000269|PubMed:28087732"
FT /id="VAR_078289"
FT VARIANT 177
FT /note="R -> Q (in a colorectal cancer sample; somatic
FT mutation; dbSNP:rs374122292)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035897"
FT VARIANT 735
FT /note="Y -> C (in a colorectal cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035898"
FT VARIANT 1789..2225
FT /note="Missing (in DEE50; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:28087732"
FT /id="VAR_078290"
FT VARIANT 2024
FT /note="R -> Q (in DEE50; dbSNP:rs763410987)"
FT /evidence="ECO:0000269|PubMed:25678555"
FT /id="VAR_073955"
FT MUTAGEN 1471
FT /note="H->A: No zinc-binding and no catalytic activity."
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0000269|PubMed:7766613"
FT MUTAGEN 1471
FT /note="H->N: Abolishes dihydroorotase activity."
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0000269|PubMed:7766613"
FT MUTAGEN 1473
FT /note="H->A: No zinc-binding and no catalytic activity."
FT /evidence="ECO:0000269|PubMed:7766613"
FT MUTAGEN 1512
FT /note="D->N: No change in catalytic activity."
FT /evidence="ECO:0000269|PubMed:7766613"
FT MUTAGEN 1562
FT /note="T->A: Abolishes dihydroorotase activity."
FT /evidence="ECO:0000269|PubMed:24332717"
FT MUTAGEN 1563
FT /note="F->A: Abolishes dihydroorotase activity."
FT /evidence="ECO:0000269|PubMed:24332717"
FT MUTAGEN 1590
FT /note="H->A: Abolishes dihydroorotase activity."
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0000269|PubMed:7766613"
FT MUTAGEN 1590
FT /note="H->N: No catalytic activity."
FT /evidence="ECO:0000269|PubMed:24332717,
FT ECO:0000269|PubMed:7766613"
FT MUTAGEN 1613
FT /note="C->S: Reduces dihydroorotase activity."
FT /evidence="ECO:0000269|PubMed:24332717"
FT MUTAGEN 1614
FT /note="H->A: Abolishes dihydroorotase activity."
FT /evidence="ECO:0000269|PubMed:24332717"
FT MUTAGEN 1637
FT /note="E->T: Abolishes dihydroorotase activity."
FT /evidence="ECO:0000269|PubMed:24332717"
FT MUTAGEN 1642
FT /note="H->N: 11.5% of wild-type catalytic activity."
FT /evidence="ECO:0000269|PubMed:7766613"
FT MUTAGEN 1686
FT /note="D->N: Abolishes dihydroorotase activity."
FT /evidence="ECO:0000269|PubMed:24332717"
FT MUTAGEN 1690
FT /note="H->N: 3% of wild-type catalytic activity."
FT /evidence="ECO:0000269|PubMed:7766613"
FT MUTAGEN 1873
FT /note="S->A: Abolishes PMA-induced Thr-456
FT phosphorylation."
FT /evidence="ECO:0000269|PubMed:17485345"
FT CONFLICT 505
FT /note="P -> T (in Ref. 1; BAA11423)"
FT /evidence="ECO:0000305"
FT CONFLICT 535
FT /note="A -> G (in Ref. 1; BAA11423)"
FT /evidence="ECO:0000305"
FT CONFLICT 560
FT /note="L -> V (in Ref. 1; BAA11423)"
FT /evidence="ECO:0000305"
FT CONFLICT 1103
FT /note="T -> A (in Ref. 1; BAA11423)"
FT /evidence="ECO:0000305"
FT CONFLICT 1513
FT /note="A -> G (in Ref. 1; BAA11423)"
FT /evidence="ECO:0000305"
FT CONFLICT 1676
FT /note="N -> D (in Ref. 1; BAA11423)"
FT /evidence="ECO:0000305"
FT STRAND 1462..1465
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1467..1472
FT /evidence="ECO:0007829|PDB:6HFQ"
FT TURN 1476..1478
FT /evidence="ECO:0007829|PDB:6HFQ"
FT TURN 1480..1482
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1485..1494
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1497..1502
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1506..1508
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1513..1526
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1528..1533
FT /evidence="ECO:0007829|PDB:6HFQ"
FT TURN 1542..1544
FT /evidence="ECO:0007829|PDB:6HG1"
FT TURN 1546..1548
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1549..1551
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1555..1558
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1560..1563
FT /evidence="ECO:0007829|PDB:4C6F"
FT TURN 1564..1566
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1571..1580
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1587..1590
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1594..1605
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1610..1612
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1618..1629
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1634..1638
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1641..1644
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1647..1649
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1650..1657
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1667..1675
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1677..1679
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1692..1695
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1697..1699
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1707..1719
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1721..1723
FT /evidence="ECO:0007829|PDB:5YNZ"
FT HELIX 1725..1732
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1734..1740
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1749..1759
FT /evidence="ECO:0007829|PDB:6HFQ"
FT TURN 1773..1776
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1778..1788
FT /evidence="ECO:0007829|PDB:6HFQ"
FT STRAND 1791..1795
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1809..1811
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1813..1815
FT /evidence="ECO:0007829|PDB:6HFQ"
FT HELIX 1929..1931
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 1934..1952
FT /evidence="ECO:0007829|PDB:5G1N"
FT TURN 1959..1962
FT /evidence="ECO:0007829|PDB:5G1N"
FT STRAND 1964..1971
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 1975..1986
FT /evidence="ECO:0007829|PDB:5G1N"
FT STRAND 1990..1995
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 1996..1998
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2000..2003
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2007..2014
FT /evidence="ECO:0007829|PDB:5G1N"
FT TURN 2015..2017
FT /evidence="ECO:0007829|PDB:5G1N"
FT STRAND 2019..2027
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2030..2035
FT /evidence="ECO:0007829|PDB:5G1N"
FT STRAND 2042..2047
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2053..2067
FT /evidence="ECO:0007829|PDB:5G1N"
FT STRAND 2074..2079
FT /evidence="ECO:0007829|PDB:5G1N"
FT TURN 2081..2083
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2085..2094
FT /evidence="ECO:0007829|PDB:5G1N"
FT STRAND 2100..2104
FT /evidence="ECO:0007829|PDB:5G1N"
FT STRAND 2107..2109
FT /evidence="ECO:0007829|PDB:5G1P"
FT HELIX 2113..2121
FT /evidence="ECO:0007829|PDB:5G1N"
FT STRAND 2126..2131
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2132..2135
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2136..2138
FT /evidence="ECO:0007829|PDB:5G1O"
FT STRAND 2140..2144
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2149..2151
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2155..2160
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2169..2172
FT /evidence="ECO:0007829|PDB:5G1N"
FT STRAND 2180..2182
FT /evidence="ECO:0007829|PDB:5G1N"
FT STRAND 2188..2191
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2193..2195
FT /evidence="ECO:0007829|PDB:5G1N"
FT HELIX 2203..2221
FT /evidence="ECO:0007829|PDB:5G1N"
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
