ID PYR1_SQUAC Reviewed; 2242 AA. AC Q91437; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 13-SEP-2023, entry version 145. 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 Squalus acanthias (Spiny dogfish). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Chondrichthyes; OC Elasmobranchii; Squalomorphii; Squaliformes; Squalidae; Squalus. OX NCBI_TaxID=7797; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RC TISSUE=Spleen, and Testis; RX PubMed=7775474; DOI=10.1074/jbc.270.23.14130; RA Hong J., Salo W.L., Anderson P.M.; RT "Nucleotide sequence and tissue-specific expression of the multifunctional RT protein carbamoyl-phosphate synthetase-aspartate transcarbamoylase- RT dihydroorotase (CAD) mRNA in Squalus acanthias."; RL J. Biol. Chem. 270:14130-14139(1995). CC -!- FUNCTION: This protein is a 'fusion' protein encoding four enzymatic CC activities of the pyrimidine pathway (GATase, CPSase, ATCase and CC DHOase). 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 -!- 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 -!- 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 -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250}; CC Note=Binds 3 Zn(2+) ions per subunit (for dihydroorotase activity). CC {ECO:0000250}; CC -!- ACTIVITY REGULATION: Allosterically regulated and controlled by CC phosphorylation. 5-phosphoribose 1-diphosphate is an activator while CC UMP is an inhibitor of the CPSase reaction (By similarity). CC {ECO:0000250}. CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo pathway; CC (S)-dihydroorotate from bicarbonate: step 1/3. CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo pathway; CC (S)-dihydroorotate from bicarbonate: step 2/3. CC -!- PATHWAY: Pyrimidine metabolism; UMP biosynthesis via de novo pathway; CC (S)-dihydroorotate from bicarbonate: step 3/3. CC -!- SUBUNIT: Homohexamer. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Present in the testis but not in the liver. CC {ECO:0000269|PubMed:7775474}. 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). CC -!- SIMILARITY: In the central section; belongs to the metallo-dependent CC hydrolases superfamily. DHOase family. CAD subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U18868; AAA74569.1; -; mRNA. DR PIR; A57541; A57541. DR AlphaFoldDB; Q91437; -. DR SMR; Q91437; -. DR UniPathway; UPA00070; UER00115. DR UniPathway; UPA00070; UER00116. DR UniPathway; UPA00070; UER00117. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0016597; F:amino acid binding; IEA:InterPro. DR GO; GO:0004070; F:aspartate carbamoyltransferase activity; IEA:UniProtKB-EC. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004088; F:carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity; IEA:UniProtKB-EC. DR GO; GO:0004151; F:dihydroorotase activity; ISS:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB. DR GO; GO:0006207; P:'de novo' pyrimidine nucleobase biosynthetic process; ISS:UniProtKB. DR GO; GO:0044205; P:'de novo' UMP biosynthetic process; IEA:UniProtKB-UniPathway. DR GO; GO:0006541; P:glutamine metabolic process; IEA:InterPro. DR CDD; cd01316; CAD_DHOase; 1. DR CDD; cd01744; GATase1_CPSase; 1. DR CDD; cd01423; MGS_CPS_I_III; 1. DR Gene3D; 3.40.50.20; -; 2. DR Gene3D; 3.40.50.880; -; 1. DR Gene3D; 3.40.50.1370; Aspartate/ornithine carbamoyltransferase; 2. DR Gene3D; 3.30.1490.20; ATP-grasp fold, A domain; 1. DR Gene3D; 3.30.470.20; ATP-grasp fold, B domain; 2. DR Gene3D; 3.50.30.20; Carbamoyl-phosphate synthase small subunit, N-terminal domain; 1. DR Gene3D; 1.10.1030.10; Carbamoyl-phosphate synthetase, large subunit oligomerisation domain; 1. DR Gene3D; 3.20.20.140; Metal-dependent hydrolases; 1. DR Gene3D; 3.40.50.1380; Methylglyoxal synthase-like domain; 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 NCBIfam; TIGR00670; asp_carb_tr; 1. DR NCBIfam; TIGR01369; CPSaseII_lrg; 1. DR NCBIfam; TIGR01368; CPSaseIIsmall; 1. DR PANTHER; PTHR11405:SF5; CAD PROTEIN; 1. DR PANTHER; PTHR11405; CARBAMOYLTRANSFERASE FAMILY MEMBER; 1. 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; PR00101; ATCASE. DR PRINTS; PR00098; CPSASE. DR PRINTS; PR00099; CPSGATASE. DR SMART; SM01096; CPSase_L_D3; 1. DR SMART; SM01097; CPSase_sm_chain; 1. DR SMART; SM00851; MGS; 1. DR SUPFAM; SSF53671; Aspartate/ornithine carbamoyltransferase; 1. DR SUPFAM; SSF48108; Carbamoyl phosphate synthetase, large subunit connection domain; 1. DR SUPFAM; SSF52021; Carbamoyl phosphate synthetase, small subunit N-terminal domain; 1. DR SUPFAM; SSF52317; Class I glutamine amidotransferase-like; 1. DR SUPFAM; SSF51338; Composite domain of metallo-dependent hydrolases; 1. DR SUPFAM; SSF56059; Glutathione synthetase ATP-binding domain-like; 2. DR SUPFAM; SSF51556; Metallo-dependent hydrolases; 1. DR SUPFAM; SSF52335; Methylglyoxal synthase-like; 1. DR SUPFAM; SSF52440; PreATP-grasp domain; 2. 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 2: Evidence at transcript level; KW Allosteric enzyme; ATP-binding; Cytoplasm; Hydrolase; Ligase; KW Metal-binding; Multifunctional enzyme; Nucleotide-binding; Nucleus; KW Phosphoprotein; Pyrimidine biosynthesis; Repeat; Transferase; Zinc. FT CHAIN 1..2242 FT /note="CAD protein" FT /id="PRO_0000199508" FT DOMAIN 177..363 FT /note="Glutamine amidotransferase type-1" FT DOMAIN 522..714 FT /note="ATP-grasp 1" FT DOMAIN 1057..1248 FT /note="ATP-grasp 2" FT DOMAIN 1313..1469 FT /note="MGS-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01202" FT REGION 1..365 FT /note="GATase (Glutamine amidotransferase)" FT REGION 366..397 FT /note="Linker" FT REGION 398..1462 FT /note="CPSase (Carbamoyl-phosphate synthase)" FT REGION 398..937 FT /note="CPSase A" FT REGION 938..1462 FT /note="CPSase B" FT REGION 1463..1796 FT /note="DHOase (dihydroorotase)" FT REGION 1797..1934 FT /note="Linker" FT REGION 1829..1862 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1935..2242 FT /note="ATCase (Aspartate transcarbamylase)" FT COMPBIAS 1835..1855 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 252 FT /note="For GATase activity" FT /evidence="ECO:0000250" FT ACT_SITE 336 FT /note="For GATase activity" FT /evidence="ECO:0000250" FT ACT_SITE 338 FT /note="For GATase activity" FT /evidence="ECO:0000250" FT BINDING 1478 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250" FT BINDING 1478 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250" FT BINDING 1480 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250" FT BINDING 1482 FT /ligand="N-carbamoyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:32814" FT /evidence="ECO:0000250" FT BINDING 1512 FT /ligand="N-carbamoyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:32814" FT /evidence="ECO:0000250" FT BINDING 1563 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /note="via carbamate group" FT /evidence="ECO:0000250" FT BINDING 1563 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /note="via carbamate group" FT /evidence="ECO:0000250" FT BINDING 1597 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000250" FT BINDING 1620 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250" FT BINDING 1621 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000250" FT BINDING 1644 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250" FT BINDING 1668 FT /ligand="N-carbamoyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:32814" FT /evidence="ECO:0000250" FT BINDING 1693 FT /ligand="N-carbamoyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:32814" FT /evidence="ECO:0000250" FT BINDING 1693 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250" FT BINDING 1697 FT /ligand="N-carbamoyl-L-aspartate" FT /ligand_id="ChEBI:CHEBI:32814" FT /evidence="ECO:0000250" FT MOD_RES 1563 FT /note="N6-carboxylysine" FT /evidence="ECO:0000250" SQ SEQUENCE 2242 AA; 249393 MW; 99F1986BA41244EA CRC64; MATLFLDDGS SFKGRLFGAS STVSGEVVFQ TGMVGYPEAL TDPSYLSQIL VLTYPLIGNY GIPKDEEDEH GLSKWFESAK IHAAALVIGE NSQNPSHWSS VRSLDQRLKE HGIPALEGID TRSLTKKIRE KGTLLGKLVI DGTDENSLPY DDPNKRHLVK EVSIKEPKVY HPSGNVKIMA VDCGMKYNQI RSLCKRGAAV TVVPWDYLFD SNEFDGLFIS NGPGDPEYCQ QTINNVKKAI SEEKPKPLFG ICLGHQILSL AIGAKTYKMK YGNRGHNQPC IHEGTQRCFY TSQNHGFAVE PCSLPRDWSV LFTNANDQSN EGIIHNSKPL FSVQFHPEHK AGPTDLVDLF DIFLECARDV KLGVNLDKTV KGRVISHYSF KNGTENSKTP PGRIQPHKVL ILGSGGLSIG QAGEFDYSGS QAIKALKEEN VQSVLINPNI ATVQTSKGLA DKVYFLPITP EYVTQVIMNE RPDGILLTFG GQTALNCGVE LQKRGVLEKY HVRVLGTPVS SIEMTEDRKI FVEKMAEINE YVVPSEAAFT LEQAQGAAER LGYPVLVRAA FALGGLGSGF AQNKEELVTL VTQAFAHTSQ ILVDKSLKGW KEIEYEVVRD AYDNCITVCN MENVDPLGIH TGESIVVAPS QTLNDKEYNL LRTTAIKVIR HLGVVGECNI QYALSPESEQ YFIIEVNARL SRSSALASKA TGYPLAYVAA KLALGIPLPV LRNSVTNSTT ANYEPSLDYC VVKVPRWDLS KFLRLSTKIG SSMKSVGEVM AIGRNFEEAF QKALRMVDEN CVGFDHTLKP ASDEELETPT DKRIFVLAAA LRAGYEIDRL YELTKIDKWF LHKMKNIVEY SLKLSELYMK DEVPRHDLLK VKRLGFSDKQ IAMAIQSTEL AVRRLRQEWK ILPVVKQIDT VAAEWPAQTN YLYLTYNGEG HDLDFTKPHV MVIGSGVYRI GSSVEFDWCA VRCIQQLRKM GYKTRMVNYN PETVSTDYDM CDRLYFDEIS FEVVMDIYEL ENPEGIILSM GGQLPNNIAM DLHRQQCRIL GTSPESIDTA ENRFKFSRML DTIGISQPRW KELSDTESSK QFCTKVGYPC LIRPSYVLSG VAMNVAYSDN DLEKFLSSAV AVSKEHPVVI SKFIQEAKEI DVDAVACDGV VIAVAISEHV ENAGVHSGDA TLVTPPQDLN QKTTERIKAI VHAIGQELQA TGPFNLQLIA KDDQLKVIEC NVRVSRSFPF VSKTLGVDMI ALATKVIMGE EVEPVGLMTG TGVVGVKVPQ FSFSRLAGAD VVLGVEMTST GEVACFGENR YEAYLKAMLS TGFKIPKKNI LLSIGSYKNK SELLSTVQSL EQLGYNLYAS LGTADFYTEH GVKIKAVDWP FEDTDNGCPL KERHRNIMDY LEENHFDLVI NLSMRNSGGR RLSSFVTKGY RTRRLAVDYS VPLIIDIKCT KLFVEALRLV GDTPPVKTHI DSMSSHKLIR LPGLIDVHVH LREPGGTHKE DFASGTAAAL AGGVTMVCAM PNTNPAITDQ TSFALVQKLA TAGARCDFAL FLGASSDNAD VLPLISNSAA GLKMYLNDTF STLKMDNVSL WMEHFEKWPK HLPIVVHAER QTVAAILMVA QLYQRPVHIC HVARKEEIQI IRAAKQKGVQ VTCEVAPHHL FLNEEDLESI GHGKGQVRPM LSTKEDVNAL WENLDVIDCF ATDHAPHSVE EKNSDSPPPG YPGLETMLPL LLTAVSEGRL TIDDLVKRLY ENPRKIFSLP VQENTYVEVD LEQEWIIPSY MQFTKSKWTP FEGKKVKGRV RRVVLRGEVA YIDGQVLVPP GYGQDVRAWP LGVPLPPPPT TVKTPEHSKP TQTETVRTRT ASPRRLASSG PAVDARFHLP PRIHRCSDPG LPNAEGEYKE KPVKKFIEQD TVSQDGYIYP PPVSRLLSPQ NLAAQAVPHP YSLLLHPFVG QHILSVKRFT KDQLSHLFNV AHNLRLTVQK DRSLDILKGK VMASMFYEVS TRTSSSFRAA MHRLGGSVIH FSEATSSVQK GESLLDSVQT MSCYVDVVVL RHPEPGAVEL AAKHSRKPII NAGDGVGEHP TQALLDIFTI REELGTVNGM TITMVGDLKH GRTVHSLAYL LTLYRVNLRY VTPRNLRMPP NIIRFLASRG IKQEEFDSLE EALPDTDVLY MTRIQKERFA SEEEYEACFG QFILTPHIMT KGKKKMVVMH PLPRVNEVSV EVDSDPRAAY FRQAENGMYV RMALLATVLG KF //