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Protein

High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A

Gene

Pde9a

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes (PubMed:9624145). Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP. Specifically regulates natriuretic-peptide-dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart (PubMed:25799991). Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein (Probable). In brain, involved in cognitive function, such as learning and long-term memory (PubMed:22328573, PubMed:24746365).Curated4 Publications

Catalytic activityi

Guanosine 3',5'-cyclic phosphate + H2O = guanosine 5'-phosphate.1 Publication

Cofactori

Protein has several cofactor binding sites:
  • Zn2+By similarityNote: Binds 1 Zn2+ ion per subunit. Binds 2 divalent metal cations per subunit: site 1 preferentially binds zinc, while site 2 has a preference for magnesium. Tightly binds zinc.By similarity
  • Mg2+By similarityNote: Binds 1 Mg2+ ions per subunit. Binds 2 divalent metal cations per subunit: site 1 preferentially binds zinc, while site 2 has a preference for magnesium. Binds magnesium less tightly than zinc.By similarity

Enzyme regulationi

Inhibited by SCH 51866 and moderately, by zaprinast. Specifically inhibited by PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) (PubMed:22328573).2 Publications

Kineticsi

  1. KM=0.07 mM for cGMP1 Publication

    Pathway: 3',5'-cyclic GMP degradation

    This protein is involved in step 1 of the subpathway that synthesizes GMP from 3',5'-cyclic GMP.
    Proteins known to be involved in this subpathway in this organism are:
    1. cGMP-specific 3',5'-cyclic phosphodiesterase (Pde5a), High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (Pde9a), cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A (Pde10a)
    This subpathway is part of the pathway 3',5'-cyclic GMP degradation, which is itself part of Purine metabolism.
    View all proteins of this organism that are known to be involved in the subpathway that synthesizes GMP from 3',5'-cyclic GMP, the pathway 3',5'-cyclic GMP degradation and in Purine metabolism.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Active sitei251 – 2511Proton donorBy similarity
    Metal bindingi255 – 2551Zinc; via tele nitrogenBy similarity
    Metal bindingi291 – 2911Zinc; via tele nitrogenBy similarity
    Metal bindingi292 – 2921MagnesiumBy similarity
    Metal bindingi292 – 2921ZincBy similarity
    Binding sitei292 – 2921cGMPBy similarity
    Metal bindingi401 – 4011ZincBy similarity
    Binding sitei401 – 4011cGMPBy similarity
    Binding sitei423 – 4231cGMPBy similarity
    Binding sitei423 – 4231Inhibitor specific to Pde9aBy similarity
    Binding sitei452 – 4521InhibitorBy similarity

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi251 – 2555cGMPBy similarity
    Nucleotide bindingi451 – 4522cGMPBy similarity

    GO - Molecular functioni

    • 3',5'-cyclic-GMP phosphodiesterase activity Source: MGI
    • metal ion binding Source: UniProtKB-KW

    GO - Biological processi

    • cGMP catabolic process Source: UniProtKB-UniPathway
    • cGMP-mediated signaling Source: Ensembl
    • metabolic process Source: GOC
    Complete GO annotation...

    Keywords - Molecular functioni

    Hydrolase

    Keywords - Ligandi

    cGMP, Magnesium, Metal-binding, Zinc

    Enzyme and pathway databases

    BRENDAi3.1.4.35. 3474.
    ReactomeiREACT_311531. cGMP effects.
    UniPathwayiUPA00763; UER00748.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9ACurated (EC:3.1.4.351 Publication)
    Gene namesi
    Name:Pde9a
    Synonyms:Pde8b
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589 Componenti: Chromosome 17

    Organism-specific databases

    MGIiMGI:1277179. Pde9a.

    Subcellular locationi

    • Cell projectionruffle membrane By similarity
    • Cytoplasmperinuclear region By similarity
    • Golgi apparatus By similarity
    • Endoplasmic reticulum By similarity
    • Cell membranesarcolemma By similarity

    GO - Cellular componenti

    Complete GO annotation...

    Keywords - Cellular componenti

    Cell membrane, Cell projection, Cytoplasm, Endoplasmic reticulum, Golgi apparatus, Membrane

    Pathology & Biotechi

    Disruption phenotypei

    Mice hearts develop less dilation and dysfunction when exposed to sustained pressure overload.1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 534534High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9APRO_0000198842Add
    BLAST

    Proteomic databases

    MaxQBiO70628.
    PRIDEiO70628.

    PTM databases

    PhosphoSiteiO70628.

    Expressioni

    Tissue specificityi

    Highly expressed in kidney. Lower levels in liver, lung and brain (PubMed:9624145). Widely expressed in brain, with highest expression in cerebellar Purkinje cells (PubMed:14501210). Present in heart (at protein level) (PubMed:25799991).3 Publications

    Gene expression databases

    BgeeiO70628.
    CleanExiMM_PDE9A.
    ExpressionAtlasiO70628. baseline and differential.
    GenevisibleiO70628. MM.

    Interactioni

    Subunit structurei

    Homodimer.By similarity

    Protein-protein interaction databases

    STRINGi10090.ENSMUSP00000038005.

    Structurei

    3D structure databases

    ProteinModelPortaliO70628.
    SMRiO70628. Positions 181-504.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni227 – 489263CatalyticBy similarityAdd
    BLAST

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiNOG268427.
    GeneTreeiENSGT00760000118889.
    HOGENOMiHOG000008058.
    HOVERGENiHBG053545.
    InParanoidiO70628.
    KOiK13761.
    OMAiPRAFKIN.
    OrthoDBiEOG7DFXC4.
    PhylomeDBiO70628.
    TreeFamiTF314638.

    Family and domain databases

    Gene3Di1.10.1300.10. 1 hit.
    InterProiIPR003607. HD/PDEase_dom.
    IPR023088. PDEase.
    IPR002073. PDEase_catalytic_dom.
    IPR023174. PDEase_CS.
    [Graphical view]
    PfamiPF00233. PDEase_I. 1 hit.
    [Graphical view]
    PRINTSiPR00387. PDIESTERASE1.
    SMARTiSM00471. HDc. 1 hit.
    [Graphical view]
    PROSITEiPS00126. PDEASE_I. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    This entry describes 1 isoform i produced by alternative splicing. AlignAdd to basket

    Note: A number of isoforms are produced.

    Isoform 1 (identifier: O70628-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MGAGSSSYRP KAIYLDIDGR IQKVVFSKYC NSSDIMDLFC IATGLPRNTT
    60 70 80 90 100
    ISLLTTDDAM VSIDPTMPAN SERTPYKVRP VAVKQVSERE ELIQGVLAQV
    110 120 130 140 150
    AEQFSRAFKI NELKAEVANH LAVLEKRVEL EGLKVVEIEK CKSDIKKMRE
    160 170 180 190 200
    ELAARNSRTN CPCKYSFLDN KKLTPRRDVP TYPKYLLSPE TIEALRKPTF
    210 220 230 240 250
    DVWLWEPNEM LSCLEHMYHD LGLVRDFSIN PITLRRWLLC VHDNYRNNPF
    260 270 280 290 300
    HNFRHCFCVT QMMYSMVWLC GLQEKFSQMD ILVLMTAAIC HDLDHPGYNN
    310 320 330 340 350
    TYQINARTEL AVRYNDISPL ENHHCAIAFQ ILARPECNIF ASVPPEGFRQ
    360 370 380 390 400
    IRQGMITLIL ATDMARHAEI MDSFKEKMEN FDYSNEEHLT LLKMILIKCC
    410 420 430 440 450
    DISNEVRPME VAEPWVDCLL EEYFMQSDRE KSEGLPVAPF MDRDKVTKAT
    460 470 480 490 500
    AQIGFIKFVL IPMFETVTKL FPVVEETMLR PLWESREHYE ELKQLDDAMK
    510 520 530
    ELQKKTESLT SGAPENTTEK NRDAKDSEGH SPPN
    Length:534
    Mass (Da):61,636
    Last modified:August 1, 1998 - v1
    Checksum:i28126C7BB7375241
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF031147 mRNA. Translation: AAC24344.1.
    AF068247 mRNA. Translation: AAC23996.1.
    BC061163 mRNA. Translation: AAH61163.1.
    CCDSiCCDS28605.1. [O70628-1]
    RefSeqiNP_001157220.1. NM_001163748.1. [O70628-1]
    NP_032830.3. NM_008804.4. [O70628-1]
    UniGeneiMm.10812.

    Genome annotation databases

    EnsembliENSMUST00000047168; ENSMUSP00000038005; ENSMUSG00000041119. [O70628-1]
    ENSMUST00000127929; ENSMUSP00000117611; ENSMUSG00000041119. [O70628-1]
    GeneIDi18585.
    KEGGimmu:18585.
    UCSCiuc008buz.2. mouse. [O70628-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF031147 mRNA. Translation: AAC24344.1.
    AF068247 mRNA. Translation: AAC23996.1.
    BC061163 mRNA. Translation: AAH61163.1.
    CCDSiCCDS28605.1. [O70628-1]
    RefSeqiNP_001157220.1. NM_001163748.1. [O70628-1]
    NP_032830.3. NM_008804.4. [O70628-1]
    UniGeneiMm.10812.

    3D structure databases

    ProteinModelPortaliO70628.
    SMRiO70628. Positions 181-504.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    STRINGi10090.ENSMUSP00000038005.

    PTM databases

    PhosphoSiteiO70628.

    Proteomic databases

    MaxQBiO70628.
    PRIDEiO70628.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENSMUST00000047168; ENSMUSP00000038005; ENSMUSG00000041119. [O70628-1]
    ENSMUST00000127929; ENSMUSP00000117611; ENSMUSG00000041119. [O70628-1]
    GeneIDi18585.
    KEGGimmu:18585.
    UCSCiuc008buz.2. mouse. [O70628-1]

    Organism-specific databases

    CTDi5152.
    MGIiMGI:1277179. Pde9a.

    Phylogenomic databases

    eggNOGiNOG268427.
    GeneTreeiENSGT00760000118889.
    HOGENOMiHOG000008058.
    HOVERGENiHBG053545.
    InParanoidiO70628.
    KOiK13761.
    OMAiPRAFKIN.
    OrthoDBiEOG7DFXC4.
    PhylomeDBiO70628.
    TreeFamiTF314638.

    Enzyme and pathway databases

    UniPathwayiUPA00763; UER00748.
    BRENDAi3.1.4.35. 3474.
    ReactomeiREACT_311531. cGMP effects.

    Miscellaneous databases

    NextBioi294460.
    PROiO70628.
    SOURCEiSearch...

    Gene expression databases

    BgeeiO70628.
    CleanExiMM_PDE9A.
    ExpressionAtlasiO70628. baseline and differential.
    GenevisibleiO70628. MM.

    Family and domain databases

    Gene3Di1.10.1300.10. 1 hit.
    InterProiIPR003607. HD/PDEase_dom.
    IPR023088. PDEase.
    IPR002073. PDEase_catalytic_dom.
    IPR023174. PDEase_CS.
    [Graphical view]
    PfamiPF00233. PDEase_I. 1 hit.
    [Graphical view]
    PRINTSiPR00387. PDIESTERASE1.
    SMARTiSM00471. HDc. 1 hit.
    [Graphical view]
    PROSITEiPS00126. PDEASE_I. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Publicationsi

    « Hide 'large scale' publications
    1. "Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases."
      Soderling S.H., Bayuga S.J., Beavo J.A.
      J. Biol. Chem. 273:15553-15558(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, ENZYME REGULATION, TISSUE SPECIFICITY.
    2. "Identification and characterization of a novel cyclic nucleotide phosphodiesterase gene (PDE9A) that maps to 21q22.3: alternative splicing of mRNA transcripts, genomic structure and sequence."
      Guipponi M., Scott H.S., Kudoh J., Kawasaki K., Shibuya K., Shintani A., Asakawa S., Chen H., Lalioti M.D., Rossier C., Minoshima S., Shimizu N., Antonarakis S.E.
      Hum. Genet. 103:386-392(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    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] (ISOFORM 1).
      Tissue: Brain.
    4. "Cloning and localization of the cGMP-specific phosphodiesterase type 9 in the rat brain."
      van Staveren W.C., Glick J., Markerink-van Ittersum M., Shimizu M., Beavo J.A., Steinbusch H.W., de Vente J.
      J. Neurocytol. 31:729-741(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY.
    5. Cited for: FUNCTION, ENZYME REGULATION.
    6. "PDE9A inhibition rescues amyloid beta-induced deficits in synaptic plasticity and cognition."
      Kroker K.S., Mathis C., Marti A., Cassel J.C., Rosenbrock H., Dorner-Ciossek C.
      Neurobiol. Aging 35:2072-2078(2014) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    7. Cited for: FUNCTION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE.

    Entry informationi

    Entry nameiPDE9A_MOUSE
    AccessioniPrimary (citable) accession number: O70628
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 15, 1999
    Last sequence update: August 1, 1998
    Last modified: June 24, 2015
    This is version 120 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.