ID PDE9A_HUMAN Reviewed; 593 AA.
AC O76083; B2RBI5; B4DFI5; D3DSJ8; D3DSJ9; O75490; O75491; O95225; Q53Y40;
AC Q5QD39; Q86SF7; Q86SI6; Q86SJ3; Q86WN3; Q86WN4; Q86WN5; Q86WN6; Q86WN7;
AC Q86WN8; Q86WN9; Q86WP0;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 1.
DT 27-MAR-2024, entry version 207.
DE RecName: Full=High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A {ECO:0000305};
DE EC=3.1.4.35 {ECO:0000269|PubMed:18757755, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:9624146};
GN Name=PDE9A {ECO:0000312|HGNC:HGNC:8795};
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] (ISOFORM PDE9A1), FUNCTION, CATALYTIC ACTIVITY,
RP ACTIVITY REGULATION, AND TISSUE SPECIFICITY.
RC TISSUE=Brain, Prostate, and Testis;
RX PubMed=9624146; DOI=10.1074/jbc.273.25.15559;
RA Fisher D.A., Smith J.F., Pillar J.S., St Denis S.H., Cheng J.B.;
RT "Isolation and characterization of PDE9A, a novel human cGMP-specific
RT phosphodiesterase.";
RL J. Biol. Chem. 273:15559-15564(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS PDE9A1; PDE9A2; PDE9A3
RP AND PDE9A4).
RC TISSUE=Fetal brain;
RX PubMed=9856478; DOI=10.1007/s004390050838;
RA Guipponi M., Scott H.S., Kudoh J., Kawasaki K., Shibuya K., Shintani A.,
RA Asakawa S., Chen H., Lalioti M.D., Rossier C., Minoshima S., Shimizu N.,
RA Antonarakis S.E.;
RT "Identification and characterization of a novel cyclic nucleotide
RT phosphodiesterase gene (PDE9A) that maps to 21q22.3: alternative splicing
RT of mRNA transcripts, genomic structure and sequence.";
RL Hum. Genet. 103:386-392(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS PDE9A5; PDE9A6; PDE9A7; PDE9A9;
RP PDE9A10; PDE9A11; PDE9A12; PDE9A13; PDE9A16; PDE9A17 AND PDE9A18), AND
RP TISSUE SPECIFICITY.
RX PubMed=12565835; DOI=10.1016/s0006-291x(03)00021-4;
RA Rentero C., Monfort A., Puigdomenech P.;
RT "Identification and distribution of different mRNA variants produced by
RT differential splicing in the human phosphodiesterase 9A gene.";
RL Biochem. Biophys. Res. Commun. 301:686-692(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE9A6).
RC TISSUE=Brain, Small intestine, and Spleen;
RX PubMed=14527714; DOI=10.1016/s0378-1119(03)00733-9;
RA Wang P., Wu P., Egan R.W., Billah M.M.;
RT "Identification and characterization of a new human type 9 cGMP-specific
RT phosphodiesterase splice variant (PDE9A5). Differential tissue distribution
RT and subcellular localization of PDE9A variants.";
RL Gene 314:15-27(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE9A21), AND SUBCELLULAR LOCATION.
RX PubMed=17090334; DOI=10.1186/1471-2199-7-39;
RA Rentero C., Puigdomenech P.;
RT "Specific use of start codons and cellular localization of splice variants
RT of human phosphodiesterase 9A gene.";
RL BMC Mol. Biol. 7:39-39(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS PDE9A1 AND PDE9A3).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PDE9A2).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S.,
RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M.,
RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U.,
RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A.,
RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J.,
RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K.,
RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G.,
RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J.,
RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S.,
RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K.,
RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [9]
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PDE9A2).
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 [11]
RP ACTIVITY REGULATION.
RX PubMed=16150925; DOI=10.1124/mol.105.017608;
RA Wunder F., Tersteegen A., Rebmann A., Erb C., Fahrig T., Hendrix M.;
RT "Characterization of the first potent and selective PDE9 inhibitor using a
RT cGMP reporter cell line.";
RL Mol. Pharmacol. 68:1775-1781(2005).
RN [12]
RP TISSUE SPECIFICITY.
RX PubMed=22328573; DOI=10.1124/jpet.111.191353;
RA Kleiman R.J., Chapin D.S., Christoffersen C., Freeman J., Fonseca K.R.,
RA Geoghegan K.F., Grimwood S., Guanowsky V., Hajos M., Harms J.F.,
RA Helal C.J., Hoffmann W.E., Kocan G.P., Majchrzak M.J., McGinnis D.,
RA McLean S., Menniti F.S., Nelson F., Roof R., Schmidt A.W., Seymour P.A.,
RA Stephenson D.T., Tingley F.D., Vanase-Frawley M., Verhoest P.R.,
RA Schmidt C.J.;
RT "Phosphodiesterase 9A regulates central cGMP and modulates responses to
RT cholinergic and monoaminergic perturbation in vivo.";
RL J. Pharmacol. Exp. Ther. 341:396-409(2012).
RN [13]
RP REVIEW.
RX PubMed=24746902; DOI=10.1016/j.lfs.2014.04.007;
RA Singh N., Patra S.;
RT "Phosphodiesterase 9: insights from protein structure and role in
RT therapeutics.";
RL Life Sci. 106:1-11(2014).
RN [14]
RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP AND INDUCTION.
RX PubMed=25799991; DOI=10.1038/nature14332;
RA Lee D.I., Zhu G., Sasaki T., Cho G.S., Hamdani N., Holewinski R., Jo S.H.,
RA Danner T., Zhang M., Rainer P.P., Bedja D., Kirk J.A., Ranek M.J.,
RA Dostmann W.R., Kwon C., Margulies K.B., Van Eyk J.E., Paulus W.J.,
RA Takimoto E., Kass D.A.;
RT "Phosphodiesterase 9A controls nitric-oxide-independent cGMP and
RT hypertrophic heart disease.";
RL Nature 519:472-476(2015).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.23 ANGSTROMS) OF 241-566 IN COMPLEX WITH THE
RP INHIBITOR IBMX, AND SUBUNIT.
RX PubMed=15210993; DOI=10.1073/pnas.0401120101;
RA Huai Q., Wang H., Zhang W., Colman R.W., Robinson H., Ke H.;
RT "Crystal structure of phosphodiesterase 9 shows orientation variation of
RT inhibitor 3-isobutyl-1-methylxanthine binding.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:9624-9629(2004).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 242-566 IN COMPLEX WITH
RP MAGNESIUM; ZINC; GMP AND CGMP, ACTIVE SITE, FUNCTION, CATALYTIC ACTIVITY,
RP COFACTOR, AND MUTAGENESIS OF HIS-312 AND HIS-356.
RX PubMed=18757755; DOI=10.1073/pnas.0708850105;
RA Liu S., Mansour M.N., Dillman K.S., Perez J.R., Danley D.E., Aeed P.A.,
RA Simons S.P., Lemotte P.K., Menniti F.S.;
RT "Structural basis for the catalytic mechanism of human phosphodiesterase
RT 9.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:13309-13314(2008).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 241-566 IN COMPLEX WITH ZINC.
RG RIKEN structural genomics initiative (RSGI);
RT "Crystal structure of the human phosphodiesterase 9a catalytic domain.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [18] {ECO:0007744|PDB:3JSI, ECO:0007744|PDB:3JSW}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 242-566 IN COMPLEX WITH
RP MAGNESIUM; ZINC AND PF-4181366 INHIBITOR, ACTIVITY REGULATION, AND
RP COFACTOR.
RX PubMed=19919087; DOI=10.1021/jm9015334;
RA Verhoest P.R., Proulx-Lafrance C., Corman M., Chenard L., Helal C.J.,
RA Hou X., Kleiman R., Liu S., Marr E., Menniti F.S., Schmidt C.J.,
RA Vanase-Frawley M., Schmidt A.W., Williams R.D., Nelson F.R., Fonseca K.R.,
RA Liras S.;
RT "Identification of a brain penetrant PDE9A inhibitor utilizing prospective
RT design and chemical enablement as a rapid lead optimization strategy.";
RL J. Med. Chem. 52:7946-7949(2009).
RN [19] {ECO:0007744|PDB:3K3E, ECO:0007744|PDB:3K3H}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 241-566 IN COMPLEX WITH
RP MAGNESIUM; ZINC AND BAY-73-6691 INHIBITOR, ACTIVITY REGULATION, COFACTOR,
RP AND MUTAGENESIS OF MET-425; ILE-463; LEU-480; TYR-484; PHE-501; GLN-513 AND
RP PHE-516.
RX PubMed=20121115; DOI=10.1021/jm901519f;
RA Wang H., Luo X., Ye M., Hou J., Robinson H., Ke H.;
RT "Insight into binding of phosphodiesterase-9A selective inhibitors by
RT crystal structures and mutagenesis.";
RL J. Med. Chem. 53:1726-1731(2010).
RN [20] {ECO:0007744|PDB:3QI3, ECO:0007744|PDB:3QI4}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF MUTANT GLU-513 IN COMPLEX WITH
RP MAGNESIUM; ZINC AND (S)-BAY-73-6691 INHIBITOR, ACTIVITY REGULATION,
RP COFACTOR, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND MUTAGENESIS OF GLU-466 AND GLN-513.
RX PubMed=21483814; DOI=10.1371/journal.pone.0018092;
RA Hou J., Xu J., Liu M., Zhao R., Luo H.B., Ke H.;
RT "Structural asymmetry of phosphodiesterase-9, potential protonation of a
RT glutamic acid, and role of the invariant glutamine.";
RL PLoS ONE 6:E18092-E18092(2011).
RN [21] {ECO:0007744|PDB:4GH6}
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 241-566 IN COMPLEX WITH
RP MAGNESIUM; ZINC AND INHIBITOR 28, COFACTOR, AND ACTIVITY REGULATION.
RX PubMed=22985069; DOI=10.1021/jm301189c;
RA Meng F., Hou J., Shao Y.X., Wu P.Y., Huang M., Zhu X., Cai Y., Li Z.,
RA Xu J., Liu P., Luo H.B., Wan Y., Ke H.;
RT "Structure-based discovery of highly selective phosphodiesterase-9A
RT inhibitors and implications for inhibitor design.";
RL J. Med. Chem. 55:8549-8558(2012).
RN [22] {ECO:0007744|PDB:4E90, ECO:0007744|PDB:4G2J, ECO:0007744|PDB:4G2L}
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 242-566 IN COMPLEX WITH
RP MAGNESIUM; ZINC AND INHIBITOR, COFACTOR, AND ACTIVITY REGULATION.
RX PubMed=23025719; DOI=10.1021/jm3009635;
RA Claffey M.M., Helal C.J., Verhoest P.R., Kang Z., Fors K.S., Jung S.,
RA Zhong J., Bundesmann M.W., Hou X., Lui S., Kleiman R.J., Vanase-Frawley M.,
RA Schmidt A.W., Menniti F., Schmidt C.J., Hoffman W.E., Hajos M.,
RA McDowell L., O'Connor R.E., Macdougall-Murphy M., Fonseca K.R.,
RA Becker S.L., Nelson F.R., Liras S.;
RT "Application of structure-based drug design and parallel chemistry to
RT identify selective, brain penetrant, in vivo active phosphodiesterase 9A
RT inhibitors.";
RL J. Med. Chem. 55:9055-9068(2012).
CC -!- FUNCTION: Specifically hydrolyzes the second messenger cGMP, which is a
CC key regulator of many important physiological processes. Highly
CC specific: compared to other members of the cyclic nucleotide
CC phosphodiesterase family, has the highest affinity and selectivity for
CC cGMP (PubMed:9624146, PubMed:18757755, PubMed:21483814). Specifically
CC regulates natriuretic-peptide-dependent cGMP signaling in heart, acting
CC as a regulator of cardiac hypertrophy in myocytes and muscle. Does not
CC regulate nitric oxide-dependent cGMP in heart (PubMed:25799991).
CC Additional experiments are required to confirm whether its ability to
CC hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is
CC a general feature of the protein (Probable). In brain, involved in
CC cognitive function, such as learning and long-term memory (By
CC similarity). {ECO:0000250|UniProtKB:Q8QZV1,
CC ECO:0000269|PubMed:18757755, ECO:0000269|PubMed:21483814,
CC ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146, ECO:0000305}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3',5'-cyclic GMP + H2O = GMP + H(+); Xref=Rhea:RHEA:16957,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57746,
CC ChEBI:CHEBI:58115; EC=3.1.4.35;
CC Evidence={ECO:0000269|PubMed:18757755, ECO:0000269|PubMed:21483814,
CC ECO:0000269|PubMed:9624146};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
CC ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
CC ECO:0000269|PubMed:23025719, ECO:0000305|PubMed:18757755};
CC Note=Binds 1 Zn(2+) ion per subunit. Binds 2 divalent metal cations per
CC subunit: site 1 preferentially binds zinc, while site 2 has a
CC preference for magnesium. Tightly binds zinc.
CC {ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
CC ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
CC ECO:0000269|PubMed:23025719, ECO:0000305|PubMed:18757755};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
CC ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
CC ECO:0000269|PubMed:23025719, ECO:0000305|PubMed:18757755};
CC Note=Binds 1 Mg(2+) ions per subunit. Binds 2 divalent metal cations
CC per subunit: site 1 preferentially binds zinc, while site 2 has a
CC preference for magnesium. Binds magnesium less tightly than zinc.
CC {ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
CC ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
CC ECO:0000269|PubMed:23025719, ECO:0000305|PubMed:18757755};
CC -!- ACTIVITY REGULATION: Inhibited by zaprinast; inhibitor is however not
CC specific to PDE9A (PubMed:9624146). Specifically inhibited by BAY-73-
CC 6691 (1-(2-chlorophenyl)-6-((2R)-3,3,3- trifluoro-2-methylpropyl)-1,5-
CC dihydro-4H-pyrazolo(3,4-d)pyrimidine-4-one) (PubMed:16150925). BAY-73-
CC 9961 has two enantiomers, (R) and (S), due to the presence of a chiral
CC center, and both forms vary in their pattern of interaction
CC (PubMed:20121115, PubMed:21483814). Specifically inhibited by PF-
CC 4181366 (4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1- cyclopentyl-1,5-dihydro-
CC 6-[(3S,4S)-4-methyl- 1-(6-quinoxalinylmethyl)-3-pyrrolidinyl]-one)
CC (PubMed:19919087). Specifically inhibited by PF-4449613 ((R)-6-(1-(3-
CC phenoxyazetidin-1-yl)ethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-
CC pyrazolo[3,4-d]pyrimidin- 4(5H)-one) (PubMed:25799991). Specifically
CC inhibited by inhibitor 28 (2-((1-(2-Chlorophenyl)-4-hydroxy-1Hpyrazolo[
CC 3,4-d]pyrimidin-6-yl)amino)-N-(4- methoxyphenyl)propanamide): inhibitor
CC forms a hydrogen bond with Tyr-484 and Gln-513 (PubMed:22985069).
CC Specifically inhibited by 1-Cyclopentyl-6-[(1r)-1-(3-
CC phenoxyazetidin- 1-Yl)ethyl]-1,5-dihydro-4h-pyrazolo[3,4-D] pyrimidin-
CC 4-one: inhibitor forms a hydrogen bond with Tyr-484 and Gln-513
CC (PubMed:23025719). {ECO:0000269|PubMed:16150925,
CC ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
CC ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
CC ECO:0000269|PubMed:23025719, ECO:0000269|PubMed:25799991,
CC ECO:0000269|PubMed:9624146, ECO:0000303|PubMed:24746902}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.113 uM for cGMP {ECO:0000269|PubMed:21483814};
CC KM=501 uM for cAMP {ECO:0000269|PubMed:21483814};
CC Vmax=0.285 umol/min/mg enzyme with cGMP as substrate
CC {ECO:0000269|PubMed:21483814};
CC Vmax=3.7 umol/min/mg enzyme with cAMP as substrate
CC {ECO:0000269|PubMed:21483814};
CC Note=kcat is 0.18 sec(-1) for cGMP. kcat is 2.37 sec(-1) for cAMP.
CC {ECO:0000269|PubMed:21483814};
CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic GMP degradation; GMP from
CC 3',5'-cyclic GMP: step 1/1.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:15210993,
CC ECO:0000269|PubMed:21483814}.
CC -!- INTERACTION:
CC O76083; O95817: BAG3; NbExp=3; IntAct=EBI-742764, EBI-747185;
CC O76083; P49759: CLK1; NbExp=3; IntAct=EBI-742764, EBI-473775;
CC O76083; Q49AN0: CRY2; NbExp=3; IntAct=EBI-742764, EBI-2212355;
CC O76083; Q9H8Y8: GORASP2; NbExp=4; IntAct=EBI-742764, EBI-739467;
CC O76083; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-742764, EBI-10171774;
CC O76083; Q9BYR5: KRTAP4-2; NbExp=3; IntAct=EBI-742764, EBI-10172511;
CC O76083; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-742764, EBI-1044640;
CC O76083; Q14657: LAGE3; NbExp=3; IntAct=EBI-742764, EBI-1052105;
CC O76083; Q8NAJ2: LINC02913; NbExp=3; IntAct=EBI-742764, EBI-10173129;
CC O76083; P25791: LMO2; NbExp=3; IntAct=EBI-742764, EBI-739696;
CC O76083; Q9BRA0: NAA38; NbExp=3; IntAct=EBI-742764, EBI-9106509;
CC O76083; Q7Z3S9: NOTCH2NLA; NbExp=4; IntAct=EBI-742764, EBI-945833;
CC O76083; O76083-2: PDE9A; NbExp=3; IntAct=EBI-742764, EBI-11524542;
CC O76083; Q96FC7-2: PHYHIPL; NbExp=3; IntAct=EBI-742764, EBI-10285660;
CC O76083; P49888: SULT1E1; NbExp=3; IntAct=EBI-742764, EBI-712512;
CC O76083; Q13049: TRIM32; NbExp=10; IntAct=EBI-742764, EBI-742790;
CC O76083; Q9BRU9: UTP23; NbExp=3; IntAct=EBI-742764, EBI-5457544;
CC O76083; Q9Y260: ZFAB; NbExp=3; IntAct=EBI-742764, EBI-750052;
CC O76083-2; O95817: BAG3; NbExp=3; IntAct=EBI-11524542, EBI-747185;
CC O76083-2; Q16543: CDC37; NbExp=3; IntAct=EBI-11524542, EBI-295634;
CC O76083-2; P49759-3: CLK1; NbExp=3; IntAct=EBI-11524542, EBI-11981867;
CC O76083-2; Q49AN0: CRY2; NbExp=3; IntAct=EBI-11524542, EBI-2212355;
CC O76083-2; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-11524542, EBI-3867333;
CC O76083-2; Q15051-2: IQCB1; NbExp=5; IntAct=EBI-11524542, EBI-11944935;
CC O76083-2; Q63ZY3: KANK2; NbExp=3; IntAct=EBI-11524542, EBI-2556193;
CC O76083-2; O76011: KRT34; NbExp=5; IntAct=EBI-11524542, EBI-1047093;
CC O76083-2; Q07627: KRTAP1-1; NbExp=3; IntAct=EBI-11524542, EBI-11959885;
CC O76083-2; Q8IUG1: KRTAP1-3; NbExp=3; IntAct=EBI-11524542, EBI-11749135;
CC O76083-2; P60409: KRTAP10-7; NbExp=3; IntAct=EBI-11524542, EBI-10172290;
CC O76083-2; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-11524542, EBI-10171774;
CC O76083-2; P60411: KRTAP10-9; NbExp=3; IntAct=EBI-11524542, EBI-10172052;
CC O76083-2; P59991: KRTAP12-2; NbExp=3; IntAct=EBI-11524542, EBI-10176379;
CC O76083-2; P60328: KRTAP12-3; NbExp=3; IntAct=EBI-11524542, EBI-11953334;
CC O76083-2; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-11524542, EBI-3958099;
CC O76083-2; Q14657: LAGE3; NbExp=3; IntAct=EBI-11524542, EBI-1052105;
CC O76083-2; Q16649: NFIL3; NbExp=3; IntAct=EBI-11524542, EBI-3951858;
CC O76083-2; O76083-2: PDE9A; NbExp=3; IntAct=EBI-11524542, EBI-11524542;
CC O76083-2; Q96FC7: PHYHIPL; NbExp=3; IntAct=EBI-11524542, EBI-748888;
CC O76083-2; Q99633: PRPF18; NbExp=3; IntAct=EBI-11524542, EBI-2798416;
CC O76083-2; O00560: SDCBP; NbExp=3; IntAct=EBI-11524542, EBI-727004;
CC O76083-2; P49888: SULT1E1; NbExp=3; IntAct=EBI-11524542, EBI-712512;
CC O76083-2; Q13049: TRIM32; NbExp=10; IntAct=EBI-11524542, EBI-742790;
CC O76083-2; O15205: UBD; NbExp=3; IntAct=EBI-11524542, EBI-6657186;
CC O76083-2; P61964: WDR5; NbExp=3; IntAct=EBI-11524542, EBI-540834;
CC O76083-4; O76083-2: PDE9A; NbExp=3; IntAct=EBI-16433425, EBI-11524542;
CC O76083-4; Q13049: TRIM32; NbExp=3; IntAct=EBI-16433425, EBI-742790;
CC -!- SUBCELLULAR LOCATION: [Isoform PDE9A1]: Cell projection, ruffle
CC membrane {ECO:0000269|PubMed:17090334}. Cytoplasm, perinuclear region
CC {ECO:0000269|PubMed:17090334}. Golgi apparatus
CC {ECO:0000269|PubMed:17090334}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:17090334}. Cell membrane, sarcolemma
CC {ECO:0000269|PubMed:25799991}.
CC -!- SUBCELLULAR LOCATION: [Isoform PDE9A2]: Cell projection, ruffle
CC membrane {ECO:0000269|PubMed:17090334}. Cytoplasm, perinuclear region
CC {ECO:0000269|PubMed:17090334}.
CC -!- SUBCELLULAR LOCATION: [Isoform PDE9A3]: Cytoplasm
CC {ECO:0000269|PubMed:17090334}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:17090334}.
CC -!- SUBCELLULAR LOCATION: [Isoform PDE9A17]: Cytoplasm
CC {ECO:0000269|PubMed:17090334}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:17090334}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=16;
CC Name=PDE9A1;
CC IsoId=O76083-1; Sequence=Displayed;
CC Name=PDE9A2;
CC IsoId=O76083-2; Sequence=VSP_004599;
CC Name=PDE9A3;
CC IsoId=O76083-3; Sequence=VSP_004598, VSP_004599;
CC Name=PDE9A4;
CC IsoId=O76083-4; Sequence=VSP_004600;
CC Name=PDE9A5;
CC IsoId=O76083-5; Sequence=VSP_017309;
CC Name=PDE9A6; Synonyms=PDE9A5;
CC IsoId=O76083-6; Sequence=VSP_017305, VSP_004599;
CC Name=PDE9A7; Synonyms=PDE9A8, PDE9A14, PDE9A19, PDE9A20;
CC IsoId=O76083-7; Sequence=VSP_017303;
CC Name=PDE9A9;
CC IsoId=O76083-8; Sequence=VSP_017307, VSP_004599;
CC Name=PDE9A10;
CC IsoId=O76083-9; Sequence=VSP_017304, VSP_017310;
CC Name=PDE9A11; Synonyms=PDE9A15;
CC IsoId=O76083-10; Sequence=VSP_017302, VSP_017311;
CC Name=PDE9A12;
CC IsoId=O76083-11; Sequence=VSP_017305, VSP_017308;
CC Name=PDE9A13;
CC IsoId=O76083-12; Sequence=VSP_017306;
CC Name=PDE9A16;
CC IsoId=O76083-13; Sequence=VSP_004598;
CC Name=PDE9A17;
CC IsoId=O76083-14; Sequence=VSP_017305;
CC Name=PDE9A18;
CC IsoId=O76083-15; Sequence=VSP_017307;
CC Name=PDE9A21;
CC IsoId=O76083-16; Sequence=VSP_038647, VSP_004599;
CC -!- TISSUE SPECIFICITY: Expressed in all tissues examined (testis, brain,
CC small intestine, skeletal muscle, heart, lung, thymus, spleen,
CC placenta, kidney, liver, pancreas, ovary and prostate) except blood
CC (PubMed:9624146). Highest levels in brain, heart, kidney, spleen,
CC prostate and colon. Isoform PDE9A12 is found in prostate
CC (PubMed:12565835). In brain, present in the cortex, cerebellum, and
CC subiculum (at protein level) (PubMed:22328573). In heart, primarily
CC localizes to myocytes (PubMed:25799991). {ECO:0000269|PubMed:12565835,
CC ECO:0000269|PubMed:22328573, ECO:0000269|PubMed:25799991,
CC ECO:0000269|PubMed:9624146}.
CC -!- INDUCTION: Up-regulated in left ventricular hypertrophy from aortic
CC stenosis and following heart failure with preserved ejection fraction
CC (at protein level). {ECO:0000269|PubMed:25799991}.
CC -!- MISCELLANEOUS: PDE9A is a potential target for treatment of diseases
CC such as stress-induced heart disease or long-term memory defects.
CC Specific inhibitors, such as BAY-73-6691 or PF-4449613 are promising
CC candidates for clinical tests. {ECO:0000303|PubMed:24746902,
CC ECO:0000305|PubMed:25799991}.
CC -!- MISCELLANEOUS: N-(4-methoxyphenyl)-N~2~-[1-(2-methylphenyl)-4-oxo-4,5-
CC dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-L-alaninamide correspond to
CC compound 28. {ECO:0000305|PubMed:22985069}.
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC PDE9 subfamily. {ECO:0000305}.
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DR EMBL; AF048837; AAC39778.1; -; mRNA.
DR EMBL; AB017602; BAA88847.1; -; Genomic_DNA.
DR EMBL; AF067223; AAC26723.1; -; mRNA.
DR EMBL; AF067224; AAC26724.1; -; mRNA.
DR EMBL; AF067225; AAC26725.1; -; mRNA.
DR EMBL; AF067226; AAC26726.1; -; mRNA.
DR EMBL; AY196299; AAO34685.1; -; mRNA.
DR EMBL; AY196300; AAO34686.1; -; mRNA.
DR EMBL; AY196301; AAO34687.1; -; mRNA.
DR EMBL; AY196302; AAO34688.1; -; mRNA.
DR EMBL; AY196303; AAO34689.1; -; mRNA.
DR EMBL; AY196304; AAO34690.1; -; mRNA.
DR EMBL; AY196305; AAO34691.1; -; mRNA.
DR EMBL; AY196306; AAO34692.1; -; mRNA.
DR EMBL; AY196307; AAO34693.1; -; mRNA.
DR EMBL; AY196308; AAO34694.1; -; mRNA.
DR EMBL; AY196309; AAO34695.1; -; mRNA.
DR EMBL; AY196310; AAO34696.1; -; mRNA.
DR EMBL; AY196311; AAO34697.1; -; mRNA.
DR EMBL; AY196312; AAO34698.1; -; mRNA.
DR EMBL; AY196313; AAO34699.1; -; mRNA.
DR EMBL; AY196314; AAO34700.1; -; mRNA.
DR EMBL; AY242121; AAO88210.1; -; mRNA.
DR EMBL; AY701187; AAV84271.1; -; mRNA.
DR EMBL; AK294112; BAG57446.1; -; mRNA.
DR EMBL; AK314679; BAG37232.1; -; mRNA.
DR EMBL; BT007016; AAP35662.1; -; mRNA.
DR EMBL; AP001747; BAA95552.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09544.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09536.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09537.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09541.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09542.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09546.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09540.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09548.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09549.1; -; Genomic_DNA.
DR EMBL; BC009047; AAH09047.1; -; mRNA.
DR CCDS; CCDS13690.1; -. [O76083-1]
DR CCDS; CCDS33567.1; -. [O76083-5]
DR CCDS; CCDS33568.1; -. [O76083-2]
DR CCDS; CCDS33569.1; -. [O76083-15]
DR CCDS; CCDS33570.1; -. [O76083-12]
DR CCDS; CCDS33571.1; -. [O76083-4]
DR CCDS; CCDS42941.1; -. [O76083-8]
DR CCDS; CCDS42942.1; -. [O76083-14]
DR CCDS; CCDS42943.1; -. [O76083-6]
DR CCDS; CCDS42944.1; -. [O76083-11]
DR CCDS; CCDS42945.1; -. [O76083-13]
DR CCDS; CCDS42946.1; -. [O76083-3]
DR CCDS; CCDS42947.1; -. [O76083-9]
DR RefSeq; NP_001001567.1; NM_001001567.1. [O76083-2]
DR RefSeq; NP_001001568.1; NM_001001568.1. [O76083-3]
DR RefSeq; NP_001001569.1; NM_001001569.1. [O76083-4]
DR RefSeq; NP_001001570.1; NM_001001570.1. [O76083-5]
DR RefSeq; NP_001001571.1; NM_001001571.1. [O76083-6]
DR RefSeq; NP_001001572.1; NM_001001572.1. [O76083-7]
DR RefSeq; NP_001001573.1; NM_001001573.1. [O76083-7]
DR RefSeq; NP_001001574.1; NM_001001574.1. [O76083-8]
DR RefSeq; NP_001001575.1; NM_001001575.1. [O76083-9]
DR RefSeq; NP_001001576.1; NM_001001576.1. [O76083-10]
DR RefSeq; NP_001001577.1; NM_001001577.1. [O76083-11]
DR RefSeq; NP_001001578.1; NM_001001578.1. [O76083-12]
DR RefSeq; NP_001001579.1; NM_001001579.1. [O76083-7]
DR RefSeq; NP_001001580.1; NM_001001580.1. [O76083-10]
DR RefSeq; NP_001001581.1; NM_001001581.1. [O76083-13]
DR RefSeq; NP_001001582.1; NM_001001582.1. [O76083-14]
DR RefSeq; NP_001001583.1; NM_001001583.1. [O76083-15]
DR RefSeq; NP_001001584.1; NM_001001584.2. [O76083-7]
DR RefSeq; NP_001001585.1; NM_001001585.1. [O76083-7]
DR RefSeq; NP_001302462.1; NM_001315533.1. [O76083-16]
DR RefSeq; NP_002597.1; NM_002606.2. [O76083-1]
DR RefSeq; XP_016883855.1; XM_017028366.1. [O76083-7]
DR PDB; 2HD1; X-ray; 2.23 A; A/B=241-566.
DR PDB; 2YY2; X-ray; 2.80 A; A/B=241-566.
DR PDB; 3DY8; X-ray; 2.15 A; A/B=242-566.
DR PDB; 3DYL; X-ray; 2.70 A; A/B=242-566.
DR PDB; 3DYN; X-ray; 2.10 A; A/B=242-566.
DR PDB; 3DYQ; X-ray; 2.50 A; A/B=242-566.
DR PDB; 3DYS; X-ray; 2.30 A; A/B=242-566.
DR PDB; 3JSI; X-ray; 2.72 A; A/B=242-566.
DR PDB; 3JSW; X-ray; 2.30 A; A/B=242-566.
DR PDB; 3K3E; X-ray; 2.70 A; A/B=241-566.
DR PDB; 3K3H; X-ray; 2.50 A; A/B=241-566.
DR PDB; 3N3Z; X-ray; 2.75 A; A/B=241-566.
DR PDB; 3QI3; X-ray; 2.30 A; A/B=1-593.
DR PDB; 3QI4; X-ray; 2.50 A; A/B=1-593.
DR PDB; 4E90; X-ray; 2.50 A; A/B=242-566.
DR PDB; 4G2J; X-ray; 2.40 A; A/B=242-566.
DR PDB; 4G2L; X-ray; 3.00 A; A/B=242-566.
DR PDB; 4GH6; X-ray; 2.70 A; A/B=241-566.
DR PDB; 4Y86; X-ray; 2.01 A; A/B=1-593.
DR PDB; 4Y87; X-ray; 3.10 A; A/B=1-593.
DR PDB; 4Y8C; X-ray; 2.70 A; A/B=1-593.
DR PDB; 6A3N; X-ray; 2.60 A; A/B=245-566.
DR PDB; 6LZZ; X-ray; 2.40 A; A/B=245-566.
DR PDB; 7F0I; X-ray; 2.70 A; A/B=1-593.
DR PDB; 8BPY; X-ray; 3.30 A; A/B=247-561.
DR PDBsum; 2HD1; -.
DR PDBsum; 2YY2; -.
DR PDBsum; 3DY8; -.
DR PDBsum; 3DYL; -.
DR PDBsum; 3DYN; -.
DR PDBsum; 3DYQ; -.
DR PDBsum; 3DYS; -.
DR PDBsum; 3JSI; -.
DR PDBsum; 3JSW; -.
DR PDBsum; 3K3E; -.
DR PDBsum; 3K3H; -.
DR PDBsum; 3N3Z; -.
DR PDBsum; 3QI3; -.
DR PDBsum; 3QI4; -.
DR PDBsum; 4E90; -.
DR PDBsum; 4G2J; -.
DR PDBsum; 4G2L; -.
DR PDBsum; 4GH6; -.
DR PDBsum; 4Y86; -.
DR PDBsum; 4Y87; -.
DR PDBsum; 4Y8C; -.
DR PDBsum; 6A3N; -.
DR PDBsum; 6LZZ; -.
DR PDBsum; 7F0I; -.
DR PDBsum; 8BPY; -.
DR AlphaFoldDB; O76083; -.
DR SMR; O76083; -.
DR BioGRID; 111178; 57.
DR IntAct; O76083; 42.
DR MINT; O76083; -.
DR STRING; 9606.ENSP00000291539; -.
DR BindingDB; O76083; -.
DR ChEMBL; CHEMBL3535; -.
DR DrugBank; DB07954; 3-isobutyl-1-methyl-7H-xanthine.
DR DrugBank; DB00201; Caffeine.
DR DrugBank; DB03597; gamma-Glutamyl[S-(2-iodobenzyl)cysteinyl]glycine.
DR DrugBank; DB09283; Trapidil.
DR DrugCentral; O76083; -.
DR GuidetoPHARMACOLOGY; 1309; -.
DR iPTMnet; O76083; -.
DR PhosphoSitePlus; O76083; -.
DR BioMuta; PDE9A; -.
DR EPD; O76083; -.
DR jPOST; O76083; -.
DR MassIVE; O76083; -.
DR PaxDb; 9606-ENSP00000291539; -.
DR PeptideAtlas; O76083; -.
DR ProteomicsDB; 50391; -. [O76083-1]
DR ProteomicsDB; 50392; -. [O76083-10]
DR ProteomicsDB; 50393; -. [O76083-11]
DR ProteomicsDB; 50394; -. [O76083-12]
DR ProteomicsDB; 50395; -. [O76083-13]
DR ProteomicsDB; 50396; -. [O76083-14]
DR ProteomicsDB; 50397; -. [O76083-15]
DR ProteomicsDB; 50398; -. [O76083-16]
DR ProteomicsDB; 50399; -. [O76083-2]
DR ProteomicsDB; 50400; -. [O76083-3]
DR ProteomicsDB; 50401; -. [O76083-4]
DR ProteomicsDB; 50402; -. [O76083-5]
DR ProteomicsDB; 50403; -. [O76083-6]
DR ProteomicsDB; 50404; -. [O76083-7]
DR ProteomicsDB; 50405; -. [O76083-8]
DR ProteomicsDB; 50406; -. [O76083-9]
DR Antibodypedia; 1648; 263 antibodies from 33 providers.
DR DNASU; 5152; -.
DR Ensembl; ENST00000291539.11; ENSP00000291539.6; ENSG00000160191.18. [O76083-1]
DR Ensembl; ENST00000328862.10; ENSP00000328699.6; ENSG00000160191.18. [O76083-15]
DR Ensembl; ENST00000335440.10; ENSP00000335365.6; ENSG00000160191.18. [O76083-12]
DR Ensembl; ENST00000335512.8; ENSP00000335242.4; ENSG00000160191.18. [O76083-2]
DR Ensembl; ENST00000349112.7; ENSP00000344730.3; ENSG00000160191.18. [O76083-4]
DR Ensembl; ENST00000380328.6; ENSP00000369685.2; ENSG00000160191.18. [O76083-5]
DR Ensembl; ENST00000398224.3; ENSP00000381280.3; ENSG00000160191.18. [O76083-3]
DR Ensembl; ENST00000398225.7; ENSP00000381281.3; ENSG00000160191.18. [O76083-14]
DR Ensembl; ENST00000398227.7; ENSP00000381283.3; ENSG00000160191.18. [O76083-9]
DR Ensembl; ENST00000398229.7; ENSP00000381285.3; ENSG00000160191.18. [O76083-11]
DR Ensembl; ENST00000398232.7; ENSP00000381287.3; ENSG00000160191.18. [O76083-13]
DR Ensembl; ENST00000398234.7; ENSP00000381289.3; ENSG00000160191.18. [O76083-6]
DR Ensembl; ENST00000398236.7; ENSP00000381291.3; ENSG00000160191.18. [O76083-8]
DR GeneID; 5152; -.
DR KEGG; hsa:5152; -.
DR MANE-Select; ENST00000291539.11; ENSP00000291539.6; NM_002606.3; NP_002597.1.
DR UCSC; uc002zbm.4; human. [O76083-1]
DR AGR; HGNC:8795; -.
DR CTD; 5152; -.
DR DisGeNET; 5152; -.
DR GeneCards; PDE9A; -.
DR HGNC; HGNC:8795; PDE9A.
DR HPA; ENSG00000160191; Tissue enhanced (intestine).
DR MIM; 602973; gene.
DR neXtProt; NX_O76083; -.
DR OpenTargets; ENSG00000160191; -.
DR PharmGKB; PA33143; -.
DR VEuPathDB; HostDB:ENSG00000160191; -.
DR eggNOG; KOG3689; Eukaryota.
DR GeneTree; ENSGT00940000155587; -.
DR HOGENOM; CLU_032104_1_0_1; -.
DR InParanoid; O76083; -.
DR OMA; HPGFNNY; -.
DR OrthoDB; 5479253at2759; -.
DR PhylomeDB; O76083; -.
DR TreeFam; TF314638; -.
DR BRENDA; 3.1.4.35; 2681.
DR PathwayCommons; O76083; -.
DR Reactome; R-HSA-418457; cGMP effects.
DR SABIO-RK; O76083; -.
DR SignaLink; O76083; -.
DR SIGNOR; O76083; -.
DR UniPathway; UPA00763; UER00748.
DR BioGRID-ORCS; 5152; 11 hits in 1151 CRISPR screens.
DR ChiTaRS; PDE9A; human.
DR EvolutionaryTrace; O76083; -.
DR GeneWiki; PDE9A; -.
DR GenomeRNAi; 5152; -.
DR Pharos; O76083; Tchem.
DR PRO; PR:O76083; -.
DR Proteomes; UP000005640; Chromosome 21.
DR RNAct; O76083; Protein.
DR Bgee; ENSG00000160191; Expressed in mucosa of transverse colon and 158 other cell types or tissues.
DR ExpressionAtlas; O76083; baseline and differential.
DR Genevisible; O76083; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0042383; C:sarcolemma; IDA:UniProtKB.
DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; TAS:ProtInc.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046069; P:cGMP catabolic process; IDA:UniProtKB.
DR GO; GO:0046068; P:cGMP metabolic process; IDA:UniProtKB.
DR GO; GO:2000178; P:negative regulation of neural precursor cell proliferation; IEA:Ensembl.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; ISS:UniProtKB.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR CDD; cd00077; HDc; 1.
DR Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 1.
DR InterPro; IPR003607; HD/PDEase_dom.
DR InterPro; IPR023088; PDEase.
DR InterPro; IPR002073; PDEase_catalytic_dom.
DR InterPro; IPR036971; PDEase_catalytic_dom_sf.
DR InterPro; IPR023174; PDEase_CS.
DR PANTHER; PTHR11347; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1.
DR PANTHER; PTHR11347:SF230; HIGH AFFINITY CGMP-SPECIFIC 3',5'-CYCLIC PHOSPHODIESTERASE 9A; 1.
DR Pfam; PF00233; PDEase_I; 1.
DR PRINTS; PR00387; PDIESTERASE1.
DR SMART; SM00471; HDc; 1.
DR SUPFAM; SSF109604; HD-domain/PDEase-like; 1.
DR PROSITE; PS00126; PDEASE_I_1; 1.
DR PROSITE; PS51845; PDEASE_I_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; cGMP;
KW Cytoplasm; Endoplasmic reticulum; Golgi apparatus; Hydrolase; Magnesium;
KW Membrane; Metal-binding; Phosphoprotein; Reference proteome; Zinc.
FT CHAIN 1..593
FT /note="High affinity cGMP-specific 3',5'-cyclic
FT phosphodiesterase 9A"
FT /id="PRO_0000198841"
FT DOMAIN 236..557
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT REGION 87..141
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 564..593
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 96..127
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 572..593
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 312
FT /note="Proton donor"
FT /evidence="ECO:0000269|PubMed:18757755"
FT BINDING 312..316
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000269|PubMed:18757755"
FT BINDING 316
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:18757755,
FT ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
FT ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
FT ECO:0000269|PubMed:23025719, ECO:0007744|PDB:2HD1,
FT ECO:0007744|PDB:2YY2, ECO:0007744|PDB:3DYN,
FT ECO:0007744|PDB:3JSI, ECO:0007744|PDB:3JSW,
FT ECO:0007744|PDB:3K3E, ECO:0007744|PDB:3K3H,
FT ECO:0007744|PDB:3N3Z, ECO:0007744|PDB:4E90,
FT ECO:0007744|PDB:4G2J, ECO:0007744|PDB:4G2L,
FT ECO:0007744|PDB:4GH6"
FT BINDING 352
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:18757755,
FT ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
FT ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
FT ECO:0000269|PubMed:23025719, ECO:0007744|PDB:2HD1,
FT ECO:0007744|PDB:2YY2, ECO:0007744|PDB:3DYN,
FT ECO:0007744|PDB:3JSI, ECO:0007744|PDB:3JSW,
FT ECO:0007744|PDB:3K3E, ECO:0007744|PDB:3K3H,
FT ECO:0007744|PDB:3N3Z, ECO:0007744|PDB:4E90,
FT ECO:0007744|PDB:4G2J, ECO:0007744|PDB:4G2L,
FT ECO:0007744|PDB:4GH6"
FT BINDING 353
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000269|PubMed:18757755"
FT BINDING 353
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:18757755,
FT ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
FT ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
FT ECO:0000269|PubMed:23025719, ECO:0007744|PDB:2HD1,
FT ECO:0007744|PDB:2YY2, ECO:0007744|PDB:3DYN,
FT ECO:0007744|PDB:3JSI, ECO:0007744|PDB:3JSW,
FT ECO:0007744|PDB:3K3E, ECO:0007744|PDB:3K3H,
FT ECO:0007744|PDB:3N3Z, ECO:0007744|PDB:4E90,
FT ECO:0007744|PDB:4G2J, ECO:0007744|PDB:4G2L,
FT ECO:0007744|PDB:4GH6"
FT BINDING 353
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:18757755,
FT ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
FT ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
FT ECO:0000269|PubMed:23025719, ECO:0007744|PDB:2HD1,
FT ECO:0007744|PDB:2YY2, ECO:0007744|PDB:3DYN,
FT ECO:0007744|PDB:3JSI, ECO:0007744|PDB:3JSW,
FT ECO:0007744|PDB:3K3E, ECO:0007744|PDB:3K3H,
FT ECO:0007744|PDB:3N3Z, ECO:0007744|PDB:4E90,
FT ECO:0007744|PDB:4G2J, ECO:0007744|PDB:4G2L,
FT ECO:0007744|PDB:4GH6"
FT BINDING 462
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000269|PubMed:18757755"
FT BINDING 462
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:18757755,
FT ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
FT ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
FT ECO:0000269|PubMed:23025719, ECO:0007744|PDB:2HD1,
FT ECO:0007744|PDB:2YY2, ECO:0007744|PDB:3DYN,
FT ECO:0007744|PDB:3JSI, ECO:0007744|PDB:3JSW,
FT ECO:0007744|PDB:3K3E, ECO:0007744|PDB:3K3H,
FT ECO:0007744|PDB:3N3Z, ECO:0007744|PDB:4E90,
FT ECO:0007744|PDB:4G2J, ECO:0007744|PDB:4G2L,
FT ECO:0007744|PDB:4GH6"
FT BINDING 484
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000269|PubMed:18757755"
FT BINDING 512..513
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000269|PubMed:18757755"
FT MOD_RES 379
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8QZV1"
FT VAR_SEQ 1..217
FT /note="Missing (in isoform PDE9A11)"
FT /evidence="ECO:0000303|PubMed:12565835"
FT /id="VSP_017302"
FT VAR_SEQ 1..207
FT /note="Missing (in isoform PDE9A7)"
FT /evidence="ECO:0000303|PubMed:12565835"
FT /id="VSP_017303"
FT VAR_SEQ 1..160
FT /note="Missing (in isoform PDE9A10)"
FT /evidence="ECO:0000303|PubMed:12565835"
FT /id="VSP_017304"
FT VAR_SEQ 1..73
FT /note="MGSGSSSYRPKAIYLDIDGRIQKVIFSKYCNSSDIMDLFCIATGLPRNTTIS
FT LLTTDDAMVSIDPTMPANSER -> MSSFSIHHSVTCCFYLVRSHGRPTS (in
FT isoform PDE9A21)"
FT /evidence="ECO:0000303|PubMed:17090334"
FT /id="VSP_038647"
FT VAR_SEQ 1..73
FT /note="MGSGSSSYRPKAIYLDIDGRIQKVIFSKYCNSSDIMDLFCIATGLPRNTTIS
FT LLTTDDAMVSIDPTMPANSER -> MDAFRS (in isoform PDE9A3 and
FT isoform PDE9A16)"
FT /evidence="ECO:0000303|PubMed:12565835,
FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:9856478"
FT /id="VSP_004598"
FT VAR_SEQ 1..46
FT /note="MGSGSSSYRPKAIYLDIDGRIQKVIFSKYCNSSDIMDLFCIATGLP -> MD
FT AFR (in isoform PDE9A6, isoform PDE9A12 and isoform
FT PDE9A17)"
FT /evidence="ECO:0000303|PubMed:12565835,
FT ECO:0000303|PubMed:14527714"
FT /id="VSP_017305"
FT VAR_SEQ 24..165
FT /note="VIFSKYCNSSDIMDLFCIATGLPRNTTISLLTTDDAMVSIDPTMPANSERTP
FT YKVRPVAIKQLSAGVEDKRTTSRGQSAERPLRDRRVVGLEQPRREGAFESGQVEPRPRE
FT PQGCYQEGQRIPPEREELIQSVLAQVAEQFS -> EHDHLPADHRRRHGLHRPHHAREF
FT RTHSVQSETCGHQATL (in isoform PDE9A13)"
FT /evidence="ECO:0000303|PubMed:12565835"
FT /id="VSP_017306"
FT VAR_SEQ 24..165
FT /note="VIFSKYCNSSDIMDLFCIATGLPRNTTISLLTTDDAMVSIDPTMPANSERTP
FT YKVRPVAIKQLSAGVEDKRTTSRGQSAERPLRDRRVVGLEQPRREGAFESGQVEPRPRE
FT PQGCYQEGQRIPPEREELIQSVLAQVAEQFS -> HSVQSETCGHQATL (in
FT isoform PDE9A4)"
FT /evidence="ECO:0000303|PubMed:9856478"
FT /id="VSP_004600"
FT VAR_SEQ 48..73
FT /note="Missing (in isoform PDE9A9 and isoform PDE9A18)"
FT /evidence="ECO:0000303|PubMed:12565835"
FT /id="VSP_017307"
FT VAR_SEQ 73..165
FT /note="Missing (in isoform PDE9A12)"
FT /evidence="ECO:0000303|PubMed:12565835"
FT /id="VSP_017308"
FT VAR_SEQ 74..165
FT /note="TPYKVRPVAIKQLSAGVEDKRTTSRGQSAERPLRDRRVVGLEQPRREGAFES
FT GQVEPRPREPQGCYQEGQRIPPEREELIQSVLAQVAEQFS -> NELILYTSLRNLLFL
FT PSKESWASHQHSVQSETCGHQATL (in isoform PDE9A5)"
FT /evidence="ECO:0000303|PubMed:12565835"
FT /id="VSP_017309"
FT VAR_SEQ 88..147
FT /note="Missing (in isoform PDE9A2, isoform PDE9A3, isoform
FT PDE9A6, isoform PDE9A9 and isoform PDE9A21)"
FT /evidence="ECO:0000303|PubMed:12565835,
FT ECO:0000303|PubMed:14527714, ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:17090334,
FT ECO:0000303|PubMed:9856478, ECO:0000303|Ref.7"
FT /id="VSP_004599"
FT VAR_SEQ 161..165
FT /note="AEQFS -> MDAFR (in isoform PDE9A10)"
FT /evidence="ECO:0000303|PubMed:12565835"
FT /id="VSP_017310"
FT VAR_SEQ 218
FT /note="R -> M (in isoform PDE9A11)"
FT /evidence="ECO:0000303|PubMed:12565835"
FT /id="VSP_017311"
FT MUTAGEN 312
FT /note="H->A: Completely abolishes catalytic activity."
FT /evidence="ECO:0000269|PubMed:18757755"
FT MUTAGEN 356
FT /note="H->A: Reduces catalytic activity, but has no effect
FT on substrate affinity."
FT /evidence="ECO:0000269|PubMed:18757755"
FT MUTAGEN 425
FT /note="M->A: Induces a 2 fold change in inhibitory
FT sensitivity by BAY-73-9961."
FT /evidence="ECO:0000269|PubMed:20121115"
FT MUTAGEN 463
FT /note="I->A: Induces a 6-9 fold change in inhibitory
FT sensitivity by BAY-73-9961."
FT /evidence="ECO:0000269|PubMed:20121115"
FT MUTAGEN 466
FT /note="E->A: Decreased affinity and catalytic activity for
FT cGMP and cAMP."
FT /evidence="ECO:0000269|PubMed:21483814"
FT MUTAGEN 480
FT /note="L->A: Induces a 6-9 fold change in inhibitory
FT sensitivity by BAY-73-9961."
FT /evidence="ECO:0000269|PubMed:20121115"
FT MUTAGEN 484
FT /note="Y->A: Induces a 6-9 fold change in inhibitory
FT sensitivity by BAY-73-9961."
FT /evidence="ECO:0000269|PubMed:20121115"
FT MUTAGEN 501
FT /note="F->A: Induces a 2 fold change in inhibitory
FT sensitivity by BAY-73-9961."
FT /evidence="ECO:0000269|PubMed:20121115"
FT MUTAGEN 513
FT /note="Q->A: Induces a dramatic change in inhibitory
FT sensitivity by BAY-73-9961."
FT /evidence="ECO:0000269|PubMed:20121115"
FT MUTAGEN 513
FT /note="Q->E: 2 fold decreased affinity and catalytic
FT activity for cGMP. 8 fold decreased catalytic activity for
FT cAMP without affecting the affinity for cAMP."
FT /evidence="ECO:0000269|PubMed:21483814"
FT MUTAGEN 516
FT /note="F->A: Induces a dramatic change in inhibitory
FT sensitivity by BAY-73-9961."
FT /evidence="ECO:0000269|PubMed:20121115"
FT CONFLICT 79
FT /note="R -> G (in Ref. 6; BAG57446)"
FT /evidence="ECO:0000305"
FT HELIX 250..255
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 263..265
FT /evidence="ECO:0007829|PDB:3DYN"
FT HELIX 268..281
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 284..287
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 292..304
FT /evidence="ECO:0007829|PDB:4Y86"
FT STRAND 310..313
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 314..330
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 333..335
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 339..351
FT /evidence="ECO:0007829|PDB:4Y86"
FT TURN 352..355
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 361..366
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 370..374
FT /evidence="ECO:0007829|PDB:4Y86"
FT TURN 375..377
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 380..393
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 396..398
FT /evidence="ECO:0007829|PDB:4Y86"
FT TURN 400..403
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 406..421
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 425..427
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 428..438
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 439..441
FT /evidence="ECO:0007829|PDB:2HD1"
FT HELIX 447..462
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 465..467
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 470..492
FT /evidence="ECO:0007829|PDB:4Y86"
FT TURN 493..495
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 500..502
FT /evidence="ECO:0007829|PDB:4Y86"
FT TURN 504..506
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 509..519
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 521..531
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 535..538
FT /evidence="ECO:0007829|PDB:4Y86"
FT HELIX 540..562
FT /evidence="ECO:0007829|PDB:4Y86"
SQ SEQUENCE 593 AA; 68493 MW; E2731C7C828C0994 CRC64;
MGSGSSSYRP KAIYLDIDGR IQKVIFSKYC NSSDIMDLFC IATGLPRNTT ISLLTTDDAM
VSIDPTMPAN SERTPYKVRP VAIKQLSAGV EDKRTTSRGQ SAERPLRDRR VVGLEQPRRE
GAFESGQVEP RPREPQGCYQ EGQRIPPERE ELIQSVLAQV AEQFSRAFKI NELKAEVANH
LAVLEKRVEL EGLKVVEIEK CKSDIKKMRE ELAARSSRTN CPCKYSFLDN HKKLTPRRDV
PTYPKYLLSP ETIEALRKPT FDVWLWEPNE MLSCLEHMYH DLGLVRDFSI NPVTLRRWLF
CVHDNYRNNP FHNFRHCFCV AQMMYSMVWL CSLQEKFSQT DILILMTAAI CHDLDHPGYN
NTYQINARTE LAVRYNDISP LENHHCAVAF QILAEPECNI FSNIPPDGFK QIRQGMITLI
LATDMARHAE IMDSFKEKME NFDYSNEEHM TLLKMILIKC CDISNEVRPM EVAEPWVDCL
LEEYFMQSDR EKSEGLPVAP FMDRDKVTKA TAQIGFIKFV LIPMFETVTK LFPMVEEIML
QPLWESRDRY EELKRIDDAM KELQKKTDSL TSGATEKSRE RSRDVKNSEG DCA
//
