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P27708

- PYR1_HUMAN

UniProt

P27708 - PYR1_HUMAN

Protein

CAD protein

Gene

CAD

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 171 (01 Oct 2014)
      Sequence version 3 (19 Jul 2004)
      Previous versions | rss
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    Functioni

    This protein is a "fusion" protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase).1 Publication

    Catalytic activityi

    2 ATP + L-glutamine + HCO3- + H2O = 2 ADP + phosphate + L-glutamate + carbamoyl phosphate.1 Publication
    Carbamoyl phosphate + L-aspartate = phosphate + N-carbamoyl-L-aspartate.1 Publication
    (S)-dihydroorotate + H2O = N-carbamoyl-L-aspartate.1 Publication

    Cofactori

    Binds 3 zinc ions per subunit (for dihydroorotase activity).2 Publications

    Enzyme regulationi

    Allosterically regulated and controlled by phosphorylation. 5-phosphoribose 1-diphosphate (PRPP) is an activator while UMP and UTP are inhibitors of the CPSase reaction.1 Publication

    Kineticsi

    1. KM=28 µM for dihydroorotate1 Publication
    2. KM=241 µM for N-carbamoyl-L-aspartate1 Publication

    Pathwayi

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Active sitei252 – 2521For GATase activityBy similarity
    Active sitei336 – 3361For GATase activityBy similarity
    Active sitei338 – 3381For GATase activityBy similarity
    Metal bindingi1471 – 14711Zinc 1; via tele nitrogen1 Publication
    Metal bindingi1471 – 14711Zinc 2; via pros nitrogen1 Publication
    Metal bindingi1473 – 14731Zinc 1; via tele nitrogen1 Publication
    Binding sitei1475 – 14751N-carbamoyl-L-aspartate
    Binding sitei1505 – 15051N-carbamoyl-L-aspartate
    Metal bindingi1556 – 15561Zinc 1; via carbamate group1 Publication
    Metal bindingi1556 – 15561Zinc 3; via carbamate group1 Publication
    Metal bindingi1590 – 15901Zinc 3; via pros nitrogen1 Publication
    Metal bindingi1613 – 16131Zinc 21 Publication
    Metal bindingi1614 – 16141Zinc 3; via tele nitrogen1 Publication
    Metal bindingi1637 – 16371Zinc 21 Publication
    Binding sitei1661 – 16611N-carbamoyl-L-aspartate; via amide nitrogen and carbonyl oxygen
    Metal bindingi1686 – 16861Zinc 11 Publication
    Binding sitei1686 – 16861N-carbamoyl-L-aspartate
    Binding sitei1690 – 16901N-carbamoyl-L-aspartate

    GO - Molecular functioni

    1. aspartate binding Source: BHF-UCL
    2. aspartate carbamoyltransferase activity Source: BHF-UCL
    3. ATP binding Source: BHF-UCL
    4. carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity Source: BHF-UCL
    5. dihydroorotase activity Source: UniProtKB
    6. enzyme binding Source: UniProtKB
    7. identical protein binding Source: BHF-UCL
    8. protein kinase activity Source: BHF-UCL
    9. zinc ion binding Source: UniProtKB

    GO - Biological processi

    1. 'de novo' pyrimidine nucleobase biosynthetic process Source: UniProtKB
    2. 'de novo' UMP biosynthetic process Source: UniProtKB-UniPathway
    3. carbamoyl phosphate biosynthetic process Source: InterPro
    4. cellular response to drug Source: Ensembl
    5. cellular response to epidermal growth factor stimulus Source: Ensembl
    6. drug metabolic process Source: BHF-UCL
    7. embryo development Source: Ensembl
    8. female pregnancy Source: Ensembl
    9. glutamine catabolic process Source: InterPro
    10. glutamine metabolic process Source: BHF-UCL
    11. lactation Source: Ensembl
    12. nucleobase-containing small molecule metabolic process Source: Reactome
    13. organ regeneration Source: Ensembl
    14. peptidyl-threonine phosphorylation Source: BHF-UCL
    15. protein autophosphorylation Source: BHF-UCL
    16. pyrimidine nucleobase metabolic process Source: Reactome
    17. pyrimidine nucleoside biosynthetic process Source: Reactome
    18. response to amine Source: Ensembl
    19. response to caffeine Source: Ensembl
    20. response to cortisol Source: Ensembl
    21. response to testosterone Source: Ensembl
    22. small molecule metabolic process Source: Reactome
    23. UTP biosynthetic process Source: Ensembl

    Keywords - Molecular functioni

    Hydrolase, Ligase, Transferase

    Keywords - Biological processi

    Pyrimidine biosynthesis

    Keywords - Ligandi

    ATP-binding, Metal-binding, Nucleotide-binding, Zinc

    Enzyme and pathway databases

    BioCyciMetaCyc:ENSG00000084774-MONOMER.
    BRENDAi3.5.2.3. 2681.
    ReactomeiREACT_21376. Pyrimidine biosynthesis.
    UniPathwayiUPA00070; UER00115.
    UPA00070; UER00116.
    UPA00070; UER00117.

    Protein family/group databases

    MEROPSiC26.952.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    CAD protein
    Including the following 3 domains:
    Glutamine-dependent carbamoyl-phosphate synthase (EC:6.3.5.5)
    Aspartate carbamoyltransferase (EC:2.1.3.2)
    Dihydroorotase (EC:3.5.2.3)
    Gene namesi
    Name:CAD
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 2

    Organism-specific databases

    HGNCiHGNC:1424. CAD.

    Subcellular locationi

    Cytoplasm 1 Publication. Nucleus 1 Publication
    Note: Cytosolic and unphosphorylated in resting cells, translocates to the nucleus in response to EGF stimulation, nuclear import promotes optimal cell growth.

    GO - Cellular componenti

    1. cell projection Source: BHF-UCL
    2. cytosol Source: BHF-UCL
    3. extracellular vesicular exosome Source: UniProt
    4. membrane Source: UniProtKB
    5. neuronal cell body Source: BHF-UCL
    6. nuclear matrix Source: BHF-UCL
    7. nucleus Source: BHF-UCL
    8. protein complex Source: Ensembl
    9. terminal bouton Source: BHF-UCL

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi1471 – 14711H → A: No zinc-binding and no catalytic activity. 2 Publications
    Mutagenesisi1471 – 14711H → N: Abolishes dihydroorotase activity. 2 Publications
    Mutagenesisi1473 – 14731H → A: No zinc-binding and no catalytic activity. 1 Publication
    Mutagenesisi1512 – 15121D → N: No change in catalytic activity. 1 Publication
    Mutagenesisi1562 – 15621T → A: Abolishes dihydroorotase activity. 1 Publication
    Mutagenesisi1563 – 15631F → A: Abolishes dihydroorotase activity. 1 Publication
    Mutagenesisi1590 – 15901H → A: Abolishes dihydroorotase activity. 2 Publications
    Mutagenesisi1590 – 15901H → N: No catalytic activity. 2 Publications
    Mutagenesisi1613 – 16131C → S: Reduces dihydroorotase activity. 1 Publication
    Mutagenesisi1614 – 16141H → A: Abolishes dihydroorotase activity. 1 Publication
    Mutagenesisi1637 – 16371E → T: Abolishes dihydroorotase activity. 1 Publication
    Mutagenesisi1642 – 16421H → N: 11.5% of wild-type catalytic activity. 1 Publication
    Mutagenesisi1686 – 16861D → N: Abolishes dihydroorotase activity. 1 Publication
    Mutagenesisi1690 – 16901H → N: 3% of wild-type catalytic activity. 1 Publication
    Mutagenesisi1873 – 18731S → A: Abolishes PMA-induced Thr-456 phosphorylation. 1 Publication

    Organism-specific databases

    PharmGKBiPA26023.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11Removed4 Publications
    Chaini2 – 22252224CAD proteinPRO_0000199506Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylalanine4 Publications
    Modified residuei456 – 4561Phosphothreonine; by MAPK11 Publication
    Modified residuei747 – 7471N6-acetyllysine1 Publication
    Modified residuei1406 – 14061Phosphoserine; by PKA2 Publications
    Modified residuei1411 – 14111N6-acetyllysine1 Publication
    Modified residuei1556 – 15561N6-carboxylysine1 Publication
    Modified residuei1859 – 18591Phosphoserine; by RPS6KB1 and PKA8 Publications
    Modified residuei1873 – 18731Phosphoserine; by PKC; in vitro1 Publication
    Modified residuei1884 – 18841Phosphothreonine2 Publications
    Modified residuei1900 – 19001Phosphoserine2 Publications
    Modified residuei1906 – 19061Phosphothreonine1 Publication

    Post-translational modificationi

    Activated by MAP kinase (Erk1/2) phosphorylation just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. Phosphorylation at Ser-1859 by RPS6KB1 downstream of MTOR promotes oligomerization and stimulates dihydroorotase activity. Phosphorylation at Ser-1406 reduces sensitivy to feedback inhibition by UTP.9 Publications

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiP27708.
    PaxDbiP27708.
    PeptideAtlasiP27708.
    PRIDEiP27708.

    PTM databases

    PhosphoSiteiP27708.

    Miscellaneous databases

    PMAP-CutDBP27708.

    Expressioni

    Inductioni

    Transcriptionally repressed following hypoxia by HIF1A.1 Publication

    Gene expression databases

    ArrayExpressiP27708.
    BgeeiP27708.
    CleanExiHS_CAD.
    GenevestigatoriP27708.

    Organism-specific databases

    HPAiCAB007781.

    Interactioni

    Subunit structurei

    Homohexamer.1 Publication

    Protein-protein interaction databases

    BioGridi107243. 41 interactions.
    DIPiDIP-39484N.
    IntActiP27708. 23 interactions.
    MINTiMINT-5000537.
    STRINGi9606.ENSP00000264705.

    Structurei

    Secondary structure

    1
    2225
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi1462 – 14654
    Beta strandi1467 – 14726
    Turni1476 – 14783
    Turni1480 – 14823
    Helixi1485 – 149410
    Beta strandi1497 – 15026
    Beta strandi1506 – 15083
    Helixi1513 – 152614
    Beta strandi1528 – 15336
    Turni1546 – 15483
    Helixi1549 – 15513
    Beta strandi1555 – 15584
    Beta strandi1560 – 15634
    Turni1564 – 15663
    Helixi1571 – 158010
    Beta strandi1587 – 15904
    Helixi1594 – 160512
    Beta strandi1610 – 16123
    Helixi1618 – 162912
    Beta strandi1634 – 16385
    Helixi1640 – 16445
    Helixi1647 – 16493
    Helixi1650 – 16578
    Helixi1667 – 16759
    Helixi1677 – 16793
    Helixi1692 – 16954
    Beta strandi1697 – 16993
    Helixi1707 – 171913
    Helixi1725 – 17328
    Helixi1734 – 17407
    Beta strandi1749 – 175911
    Turni1773 – 17764
    Beta strandi1778 – 178811
    Beta strandi1791 – 17955
    Helixi1809 – 18113
    Helixi1813 – 18153

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    4BY3X-ray1.73A1456-1846[»]
    4C6BX-ray1.66A1456-1846[»]
    4C6CX-ray1.45A1456-1846[»]
    4C6DX-ray1.30A1456-1846[»]
    4C6EX-ray1.26A1456-1846[»]
    4C6FX-ray1.26A1456-1846[»]
    4C6IX-ray1.35A1456-1846[»]
    4C6JX-ray1.30A1456-1846[»]
    4C6KX-ray1.48A1456-1846[»]
    4C6LX-ray1.55A1456-1846[»]
    4C6MX-ray1.62A1456-1846[»]
    4C6NX-ray1.90A1456-1846[»]
    4C6OX-ray1.65A1456-1846[»]
    4C6PX-ray1.52A1456-1846[»]
    4C6QX-ray1.66A1456-1846[»]
    ProteinModelPortaliP27708.
    SMRiP27708. Positions 2-359, 394-1823, 1923-2223.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini177 – 363187Glutamine amidotransferase type-1Add
    BLAST
    Domaini519 – 711193ATP-grasp 1Add
    BLAST
    Domaini1052 – 1243192ATP-grasp 2Add
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni2 – 365364GATase (Glutamine amidotransferase)Add
    BLAST
    Regioni366 – 39429LinkerAdd
    BLAST
    Regioni395 – 14551061CPSase (Carbamoyl-phosphate synthase)Add
    BLAST
    Regioni395 – 933539CPSase AAdd
    BLAST
    Regioni934 – 1455522CPSase BAdd
    BLAST
    Regioni1456 – 1788333DHOase (dihydroorotase)Add
    BLAST
    Regioni1789 – 1917129LinkerAdd
    BLAST
    Regioni1918 – 2225308ATCase (Aspartate transcarbamylase)Add
    BLAST

    Sequence similaritiesi

    In the central section; belongs to the DHOase family.Curated
    Contains 2 ATP-grasp domains.Curated

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiCOG0458.
    HOGENOMiHOG000234584.
    HOVERGENiHBG000279.
    InParanoidiP27708.
    KOiK11540.
    OMAiACLQCWI.
    OrthoDBiEOG7M6D6F.
    PhylomeDBiP27708.
    TreeFamiTF105604.

    Family and domain databases

    Gene3Di1.10.1030.10. 1 hit.
    3.30.1490.20. 1 hit.
    3.30.470.20. 2 hits.
    3.40.50.1370. 2 hits.
    3.40.50.1380. 1 hit.
    3.40.50.20. 2 hits.
    3.40.50.880. 1 hit.
    3.50.30.20. 1 hit.
    HAMAPiMF_00001. Asp_carb_tr.
    MF_01209. CPSase_S_chain.
    InterProiIPR006132. Asp/Orn_carbamoyltranf_P-bd.
    IPR006130. Asp/Orn_carbamoylTrfase.
    IPR002082. Asp_carbamoyltransf.
    IPR006131. Asp_carbamoyltransf_Asp/Orn-bd.
    IPR011761. ATP-grasp.
    IPR013815. ATP_grasp_subdomain_1.
    IPR013816. ATP_grasp_subdomain_2.
    IPR006275. CarbamoylP_synth_lsu.
    IPR005481. CarbamoylP_synth_lsu_N.
    IPR005480. CarbamoylP_synth_lsu_oligo.
    IPR006274. CarbamoylP_synth_ssu.
    IPR002474. CarbamoylP_synth_ssu_N.
    IPR005479. CbamoylP_synth_lsu-like_ATP-bd.
    IPR005483. CbamoylP_synth_lsu_CPSase_dom.
    IPR029062. Class_I_gatase-like.
    IPR002195. Dihydroorotase_CS.
    IPR017926. GATASE.
    IPR011059. Metal-dep_hydrolase_composite.
    IPR011607. MGS-like_dom.
    IPR016185. PreATP-grasp_dom.
    [Graphical view]
    PfamiPF00289. CPSase_L_chain. 2 hits.
    PF02786. CPSase_L_D2. 2 hits.
    PF02787. CPSase_L_D3. 1 hit.
    PF00988. CPSase_sm_chain. 1 hit.
    PF00117. GATase. 1 hit.
    PF02142. MGS. 1 hit.
    PF00185. OTCace. 1 hit.
    PF02729. OTCace_N. 1 hit.
    [Graphical view]
    PRINTSiPR00100. AOTCASE.
    PR00101. ATCASE.
    PR00098. CPSASE.
    SMARTiSM01096. CPSase_L_D3. 1 hit.
    SM01097. CPSase_sm_chain. 1 hit.
    SM00851. MGS. 1 hit.
    [Graphical view]
    SUPFAMiSSF48108. SSF48108. 1 hit.
    SSF51338. SSF51338. 1 hit.
    SSF52021. SSF52021. 1 hit.
    SSF52317. SSF52317. 1 hit.
    SSF52335. SSF52335. 1 hit.
    SSF52440. SSF52440. 2 hits.
    SSF53671. SSF53671. 1 hit.
    TIGRFAMsiTIGR00670. asp_carb_tr. 1 hit.
    TIGR01369. CPSaseII_lrg. 1 hit.
    TIGR01368. CPSaseIIsmall. 1 hit.
    PROSITEiPS50975. ATP_GRASP. 2 hits.
    PS00097. CARBAMOYLTRANSFERASE. 1 hit.
    PS00866. CPSASE_1. 2 hits.
    PS00867. CPSASE_2. 2 hits.
    PS00482. DIHYDROOROTASE_1. 1 hit.
    PS00483. DIHYDROOROTASE_2. 1 hit.
    PS51273. GATASE_TYPE_1. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P27708-1 [UniParc]FASTAAdd to Basket

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    MAALVLEDGS VLRGQPFGAA VSTAGEVVFQ TGMVGYPEAL TDPSYKAQIL     50
    VLTYPLIGNY GIPPDEMDEF GLCKWFESSG IHVAALVVGE CCPTPSHWSA 100
    TRTLHEWLQQ HGIPGLQGVD TRELTKKLRE QGSLLGKLVQ NGTEPSSLPF 150
    LDPNARPLVP EVSIKTPRVF NTGGAPRILA LDCGLKYNQI RCLCQRGAEV 200
    TVVPWDHALD SQEYEGLFLS NGPGDPASYP SVVSTLSRVL SEPNPRPVFG 250
    ICLGHQLLAL AIGAKTYKMR YGNRGHNQPC LLVGSGRCFL TSQNHGFAVE 300
    TDSLPADWAP LFTNANDGSN EGIVHNSLPF FSVQFHPEHQ AGPSDMELLF 350
    DIFLETVKEA TAGNPGGQTV RERLTERLCP PGIPTPGSGL PPPRKVLILG 400
    SGGLSIGQAG EFDYSGSQAI KALKEENIQT LLINPNIATV QTSQGLADKV 450
    YFLPITPHYV TQVIRNERPD GVLLTFGGQT ALNCGVELTK AGVLARYGVR 500
    VLGTPVETIE LTEDRRAFAA RMAEIGEHVA PSEAANSLEQ AQAAAERLGY 550
    PVLVRAAFAL GGLGSGFASN REELSALVAP AFAHTSQVLV DKSLKGWKEI 600
    EYEVVRDAYG NCVTVCNMEN LDPLGIHTGE SIVVAPSQTL NDREYQLLRQ 650
    TAIKVTQHLG IVGECNVQYA LNPESEQYYI IEVNARLSRS SALASKATGY 700
    PLAYVAAKLA LGIPLPELRN SVTGGTAAFE PSVDYCVVKI PRWDLSKFLR 750
    VSTKIGSCMK SVGEVMGIGR SFEEAFQKAL RMVDENCVGF DHTVKPVSDM 800
    ELETPTDKRI FVVAAALWAG YSVDRLYELT RIDRWFLHRM KRIIAHAQLL 850
    EQHRGQPLPP DLLQQAKCLG FSDKQIALAV LSTELAVRKL RQELGICPAV 900
    KQIDTVAAEW PAQTNYLYLT YWGTTHDLTF RTPHVLVLGS GVYRIGSSVE 950
    FDWCAVGCIQ QLRKMGYKTI MVNYNPETVS TDYDMCDRLY FDEISFEVVM 1000
    DIYELENPEG VILSMGGQLP NNMAMALHRQ QCRVLGTSPE AIDSAENRFK 1050
    FSRLLDTIGI SQPQWRELSD LESARQFCQT VGYPCVVRPS YVLSGAAMNV 1100
    AYTDGDLERF LSSAAAVSKE HPVVISKFIQ EAKEIDVDAV ASDGVVAAIA 1150
    ISEHVENAGV HSGDATLVTP PQDITAKTLE RIKAIVHAVG QELQVTGPFN 1200
    LQLIAKDDQL KVIECNVRVS RSFPFVSKTL GVDLVALATR VIMGEEVEPV 1250
    GLMTGSGVVG VKVPQFSFSR LAGADVVLGV EMTSTGEVAG FGESRCEAYL 1300
    KAMLSTGFKI PKKNILLTIG SYKNKSELLP TVRLLESLGY SLYASLGTAD 1350
    FYTEHGVKVT AVDWHFEEAV DGECPPQRSI LEQLAEKNFE LVINLSMRGA 1400
    GGRRLSSFVT KGYRTRRLAA DFSVPLIIDI KCTKLFVEAL GQIGPAPPLK 1450
    VHVDCMTSQK LVRLPGLIDV HVHLREPGGT HKEDFASGTA AALAGGITMV 1500
    CAMPNTRPPI IDAPALALAQ KLAEAGARCD FALFLGASSE NAGTLGTVAG 1550
    SAAGLKLYLN ETFSELRLDS VVQWMEHFET WPSHLPIVAH AEQQTVAAVL 1600
    MVAQLTQRSV HICHVARKEE ILLIKAAKAR GLPVTCEVAP HHLFLSHDDL 1650
    ERLGPGKGEV RPELGSRQDV EALWENMAVI DCFASDHAPH TLEEKCGSRP 1700
    PPGFPGLETM LPLLLTAVSE GRLSLDDLLQ RLHHNPRRIF HLPPQEDTYV 1750
    EVDLEHEWTI PSHMPFSKAH WTPFEGQKVK GTVRRVVLRG EVAYIDGQVL 1800
    VPPGYGQDVR KWPQGAVPQL PPSAPATSEM TTTPERPRRG IPGLPDGRFH 1850
    LPPRIHRASD PGLPAEEPKE KSSRKVAEPE LMGTPDGTCY PPPPVPRQAS 1900
    PQNLGTPGLL HPQTSPLLHS LVGQHILSVQ QFTKDQMSHL FNVAHTLRMM 1950
    VQKERSLDIL KGKVMASMFY EVSTRTSSSF AAAMARLGGA VLSFSEATSS 2000
    VQKGESLADS VQTMSCYADV VVLRHPQPGA VELAAKHCRR PVINAGDGVG 2050
    EHPTQALLDI FTIREELGTV NGMTITMVGD LKHGRTVHSL ACLLTQYRVS 2100
    LRYVAPPSLR MPPTVRAFVA SRGTKQEEFE SIEEALPDTD VLYMTRIQKE 2150
    RFGSTQEYEA CFGQFILTPH IMTRAKKKMV VMHPMPRVNE ISVEVDSDPR 2200
    AAYFRQAENG MYIRMALLAT VLGRF 2225
    Length:2,225
    Mass (Da):242,984
    Last modified:July 19, 2004 - v3
    Checksum:i2AB8E8413E825A8F
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti505 – 5051P → T in BAA11423. (PubMed:8619816)Curated
    Sequence conflicti535 – 5351A → G in BAA11423. (PubMed:8619816)Curated
    Sequence conflicti560 – 5601L → V in BAA11423. (PubMed:8619816)Curated
    Sequence conflicti1103 – 11031T → A in BAA11423. (PubMed:8619816)Curated
    Sequence conflicti1513 – 15131A → G in BAA11423. (PubMed:8619816)Curated
    Sequence conflicti1676 – 16761N → D in BAA11423. (PubMed:8619816)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti177 – 1771R → Q in a colorectal cancer sample; somatic mutation. 1 Publication
    VAR_035897
    Natural varianti735 – 7351Y → C in a colorectal cancer sample; somatic mutation. 1 Publication
    VAR_035898

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D78586 mRNA. Translation: BAA11423.1.
    CH471053 Genomic DNA. Translation: EAX00612.1.
    CH471053 Genomic DNA. Translation: EAX00613.1.
    CH471053 Genomic DNA. Translation: EAX00614.1.
    BC014178 mRNA. Translation: AAH14178.2.
    BC065510 mRNA. Translation: AAH65510.1.
    M38561 Genomic DNA. Translation: AAA51907.1.
    CCDSiCCDS1742.1.
    PIRiA36240.
    RefSeqiNP_004332.2. NM_004341.3.
    UniGeneiHs.377010.

    Genome annotation databases

    EnsembliENST00000264705; ENSP00000264705; ENSG00000084774.
    GeneIDi790.
    KEGGihsa:790.
    UCSCiuc002rji.3. human.

    Polymorphism databases

    DMDMi50403731.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Web resourcesi

    Wikipedia

    Aspartate carbamoyltransferase entry

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D78586 mRNA. Translation: BAA11423.1 .
    CH471053 Genomic DNA. Translation: EAX00612.1 .
    CH471053 Genomic DNA. Translation: EAX00613.1 .
    CH471053 Genomic DNA. Translation: EAX00614.1 .
    BC014178 mRNA. Translation: AAH14178.2 .
    BC065510 mRNA. Translation: AAH65510.1 .
    M38561 Genomic DNA. Translation: AAA51907.1 .
    CCDSi CCDS1742.1.
    PIRi A36240.
    RefSeqi NP_004332.2. NM_004341.3.
    UniGenei Hs.377010.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    4BY3 X-ray 1.73 A 1456-1846 [» ]
    4C6B X-ray 1.66 A 1456-1846 [» ]
    4C6C X-ray 1.45 A 1456-1846 [» ]
    4C6D X-ray 1.30 A 1456-1846 [» ]
    4C6E X-ray 1.26 A 1456-1846 [» ]
    4C6F X-ray 1.26 A 1456-1846 [» ]
    4C6I X-ray 1.35 A 1456-1846 [» ]
    4C6J X-ray 1.30 A 1456-1846 [» ]
    4C6K X-ray 1.48 A 1456-1846 [» ]
    4C6L X-ray 1.55 A 1456-1846 [» ]
    4C6M X-ray 1.62 A 1456-1846 [» ]
    4C6N X-ray 1.90 A 1456-1846 [» ]
    4C6O X-ray 1.65 A 1456-1846 [» ]
    4C6P X-ray 1.52 A 1456-1846 [» ]
    4C6Q X-ray 1.66 A 1456-1846 [» ]
    ProteinModelPortali P27708.
    SMRi P27708. Positions 2-359, 394-1823, 1923-2223.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 107243. 41 interactions.
    DIPi DIP-39484N.
    IntActi P27708. 23 interactions.
    MINTi MINT-5000537.
    STRINGi 9606.ENSP00000264705.

    Chemistry

    BindingDBi P27708.
    ChEMBLi CHEMBL3093.
    DrugBanki DB00128. L-Aspartic Acid.
    DB00130. L-Glutamine.

    Protein family/group databases

    MEROPSi C26.952.

    PTM databases

    PhosphoSitei P27708.

    Polymorphism databases

    DMDMi 50403731.

    Proteomic databases

    MaxQBi P27708.
    PaxDbi P27708.
    PeptideAtlasi P27708.
    PRIDEi P27708.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000264705 ; ENSP00000264705 ; ENSG00000084774 .
    GeneIDi 790.
    KEGGi hsa:790.
    UCSCi uc002rji.3. human.

    Organism-specific databases

    CTDi 790.
    GeneCardsi GC02P027440.
    HGNCi HGNC:1424. CAD.
    HPAi CAB007781.
    MIMi 114010. gene.
    neXtProti NX_P27708.
    PharmGKBi PA26023.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0458.
    HOGENOMi HOG000234584.
    HOVERGENi HBG000279.
    InParanoidi P27708.
    KOi K11540.
    OMAi ACLQCWI.
    OrthoDBi EOG7M6D6F.
    PhylomeDBi P27708.
    TreeFami TF105604.

    Enzyme and pathway databases

    UniPathwayi UPA00070 ; UER00115 .
    UPA00070 ; UER00116 .
    UPA00070 ; UER00117 .
    BioCyci MetaCyc:ENSG00000084774-MONOMER.
    BRENDAi 3.5.2.3. 2681.
    Reactomei REACT_21376. Pyrimidine biosynthesis.

    Miscellaneous databases

    ChiTaRSi cad. human.
    GenomeRNAii 790.
    NextBioi 3214.
    PMAP-CutDB P27708.
    PROi P27708.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P27708.
    Bgeei P27708.
    CleanExi HS_CAD.
    Genevestigatori P27708.

    Family and domain databases

    Gene3Di 1.10.1030.10. 1 hit.
    3.30.1490.20. 1 hit.
    3.30.470.20. 2 hits.
    3.40.50.1370. 2 hits.
    3.40.50.1380. 1 hit.
    3.40.50.20. 2 hits.
    3.40.50.880. 1 hit.
    3.50.30.20. 1 hit.
    HAMAPi MF_00001. Asp_carb_tr.
    MF_01209. CPSase_S_chain.
    InterProi IPR006132. Asp/Orn_carbamoyltranf_P-bd.
    IPR006130. Asp/Orn_carbamoylTrfase.
    IPR002082. Asp_carbamoyltransf.
    IPR006131. Asp_carbamoyltransf_Asp/Orn-bd.
    IPR011761. ATP-grasp.
    IPR013815. ATP_grasp_subdomain_1.
    IPR013816. ATP_grasp_subdomain_2.
    IPR006275. CarbamoylP_synth_lsu.
    IPR005481. CarbamoylP_synth_lsu_N.
    IPR005480. CarbamoylP_synth_lsu_oligo.
    IPR006274. CarbamoylP_synth_ssu.
    IPR002474. CarbamoylP_synth_ssu_N.
    IPR005479. CbamoylP_synth_lsu-like_ATP-bd.
    IPR005483. CbamoylP_synth_lsu_CPSase_dom.
    IPR029062. Class_I_gatase-like.
    IPR002195. Dihydroorotase_CS.
    IPR017926. GATASE.
    IPR011059. Metal-dep_hydrolase_composite.
    IPR011607. MGS-like_dom.
    IPR016185. PreATP-grasp_dom.
    [Graphical view ]
    Pfami PF00289. CPSase_L_chain. 2 hits.
    PF02786. CPSase_L_D2. 2 hits.
    PF02787. CPSase_L_D3. 1 hit.
    PF00988. CPSase_sm_chain. 1 hit.
    PF00117. GATase. 1 hit.
    PF02142. MGS. 1 hit.
    PF00185. OTCace. 1 hit.
    PF02729. OTCace_N. 1 hit.
    [Graphical view ]
    PRINTSi PR00100. AOTCASE.
    PR00101. ATCASE.
    PR00098. CPSASE.
    SMARTi SM01096. CPSase_L_D3. 1 hit.
    SM01097. CPSase_sm_chain. 1 hit.
    SM00851. MGS. 1 hit.
    [Graphical view ]
    SUPFAMi SSF48108. SSF48108. 1 hit.
    SSF51338. SSF51338. 1 hit.
    SSF52021. SSF52021. 1 hit.
    SSF52317. SSF52317. 1 hit.
    SSF52335. SSF52335. 1 hit.
    SSF52440. SSF52440. 2 hits.
    SSF53671. SSF53671. 1 hit.
    TIGRFAMsi TIGR00670. asp_carb_tr. 1 hit.
    TIGR01369. CPSaseII_lrg. 1 hit.
    TIGR01368. CPSaseIIsmall. 1 hit.
    PROSITEi PS50975. ATP_GRASP. 2 hits.
    PS00097. CARBAMOYLTRANSFERASE. 1 hit.
    PS00866. CPSASE_1. 2 hits.
    PS00867. CPSASE_2. 2 hits.
    PS00482. DIHYDROOROTASE_1. 1 hit.
    PS00483. DIHYDROOROTASE_2. 1 hit.
    PS51273. GATASE_TYPE_1. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Molecular cloning of a human cDNA encoding a trifunctional enzyme of carbamoyl-phosphate synthetase-aspartate transcarbamoylase-dihydroorotase in de Novo pyrimidine synthesis."
      Iwahana H., Fujimura M., Ii S., Kondo M., Moritani M., Takahashi Y., Yamaoka T., Yoshimoto K., Itakura M.
      Biochem. Biophys. Res. Commun. 219:249-255(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Fetal lung fibroblast.
    2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Eye.
    4. Cited for: PROTEIN SEQUENCE OF 2-13; 157-165; 169-177; 359-371; 501-516; 548-555; 599-606; 697-719; 761-778; 843-854; 932-944; 1034-1048; 1067-1075; 1110-1127; 1229-1240; 1263-1270; 1313-1323; 1326-1333; 1658-1667; 1723-1731; 1840-1848; 1976-1986; 2025-2036; 2103-2110; 2179-2187 AND 2215-2225, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY.
      Tissue: Colon adenocarcinoma and Hepatoma.
    5. "Organization and nucleotide sequence of the 3' end of the human CAD gene."
      Davidson J.N., Rao G.N., Niswander L., Andreano C., Tamer C., Chen K.C.
      DNA Cell Biol. 9:667-676(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1752-2225.
    6. "Function of conserved histidine residues in mammalian dihydroorotase."
      Zimmermann B.H., Kemling N.M., Evans D.R.
      Biochemistry 34:7038-7046(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: MUTAGENESIS OF HIS-1471; HIS-1473; ASP-1512; HIS-1590; HIS-1642 AND HIS-1690, COFACTOR, ZINC-BINDING SITES.
    7. "Growth-dependent regulation of mammalian pyrimidine biosynthesis by the protein kinase A and MAPK signaling cascades."
      Sigoillot F.D., Evans D.R., Guy H.I.
      J. Biol. Chem. 277:15745-15751(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: ENZYME REGULATION.
    8. "Nuclear localization and mitogen-activated protein kinase phosphorylation of the multifunctional protein CAD."
      Sigoillot F.D., Kotsis D.H., Serre V., Sigoillot S.M., Evans D.R., Guy H.I.
      J. Biol. Chem. 280:25611-25620(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION.
    9. "Transcriptional repression of human cad gene by hypoxia inducible factor-1alpha."
      Chen K.F., Lai Y.Y., Sun H.S., Tsai S.J.
      Nucleic Acids Res. 33:5190-5198(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INDUCTION.
    10. "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
      Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.
      Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    11. "A probability-based approach for high-throughput protein phosphorylation analysis and site localization."
      Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.
      Nat. Biotechnol. 24:1285-1292(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    12. "Protein kinase C modulates the up-regulation of the pyrimidine biosynthetic complex, CAD, by MAP kinase."
      Sigoillot F.D., Kotsis D.H., Masko E.M., Bame M., Evans D.R., Evans H.I.
      Front. Biosci. 12:3892-3898(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-456; SER-1406; SER-1859 AND SER-1873, MUTAGENESIS OF SER-1873.
    13. "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
      Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
      Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859 AND THR-1884, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    14. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1884, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    15. "Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
      Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
      Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    16. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
      Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
      Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Leukemic T-cell.
    17. "Lysine acetylation targets protein complexes and co-regulates major cellular functions."
      Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
      Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-747 AND LYS-1411, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    18. "Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
      Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
      Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1859; SER-1900 AND THR-1906, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    19. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    20. "System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
      Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
      Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1406 AND SER-1859, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    21. "Comparative large-scale characterisation of plant vs. mammal proteins reveals similar and idiosyncratic N-alpha acetylation features."
      Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., Giglione C.
      Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    22. Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    23. "Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis."
      Robitaille A.M., Christen S., Shimobayashi M., Cornu M., Fava L.L., Moes S., Prescianotto-Baschong C., Sauer U., Jenoe P., Hall M.N.
      Science 339:1320-1323(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-1859.
    24. "Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1."
      Ben-Sahra I., Howell J.J., Asara J.M., Manning B.D.
      Science 339:1323-1328(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-1859 AND SER-1900.
    25. "Structure, functional characterization, and evolution of the dihydroorotase domain of human CAD."
      Grande-Garcia A., Lallous N., Diaz-Tejada C., Ramon-Maiques S.
      Structure 22:185-198(2014) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) OF 1456-1846 IN COMPLEX WITH DIHYDROOROTATE; N-CARBAMOYL-L-ASPARTIC ACID AND ZINC, COFACTOR, CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF HIS-1471; THR-1562; PHE-1563; HIS-1590; CYS-1613; HIS-1614; GLU-1637 AND ASP-1686, CARBAMYLATION AT LYS-1556.
    26. Cited for: VARIANTS [LARGE SCALE ANALYSIS] GLN-177 AND CYS-735.

    Entry informationi

    Entry nameiPYR1_HUMAN
    AccessioniPrimary (citable) accession number: P27708
    Secondary accession number(s): D6W552, Q6P0Q0, Q96CK3
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: August 1, 1992
    Last sequence update: July 19, 2004
    Last modified: October 1, 2014
    This is version 171 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Miscellaneous

    GATase (glutamine amidotransferase) and CPSase (carbamoyl phosphate synthase) form together the glutamine-dependent CPSase (GD-CPSase) (EC 6.3.5.5).

    Keywords - Technical termi

    3D-structure, Allosteric enzyme, Complete proteome, Direct protein sequencing, Multifunctional enzyme, Reference proteome

    Documents

    1. Human chromosome 2
      Human chromosome 2: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    6. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    7. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3