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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; 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 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. DR Genevisible; O76083; HS. 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 //