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High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (EC 3.1.4.35)

 PDE9A_HUMAN             Reviewed;         593 AA.
O76083; B2RBI5; B4DFI5; D3DSJ8; D3DSJ9; O75490; O75491; O95225;
Q53Y40; Q5QD39; Q86SF7; Q86SI6; Q86SJ3; Q86WN3; Q86WN4; Q86WN5;
Q86WN6; Q86WN7; Q86WN8; Q86WN9; Q86WP0;
15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
01-NOV-1998, sequence version 1.
25-OCT-2017, entry version 168.
RecName: Full=High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A {ECO:0000305};
EC=3.1.4.35 {ECO:0000269|PubMed:18757755, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:9624146};
Name=PDE9A {ECO:0000312|HGNC:HGNC:8795};
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE9A1), FUNCTION, CATALYTIC
ACTIVITY, ENZYME REGULATION, AND TISSUE SPECIFICITY.
TISSUE=Brain, Prostate, and Testis;
PubMed=9624146; DOI=10.1074/jbc.273.25.15559;
Fisher D.A., Smith J.F., Pillar J.S., St Denis S.H., Cheng J.B.;
"Isolation and characterization of PDE9A, a novel human cGMP-specific
phosphodiesterase.";
J. Biol. Chem. 273:15559-15564(1998).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS PDE9A1; PDE9A2;
PDE9A3 AND PDE9A4).
TISSUE=Fetal brain;
PubMed=9856478; DOI=10.1007/s004390050838;
Guipponi M., Scott H.S., Kudoh J., Kawasaki K., Shibuya K.,
Shintani A., Asakawa S., Chen H., Lalioti M.D., Rossier C.,
Minoshima S., Shimizu N., Antonarakis S.E.;
"Identification and characterization of a novel cyclic nucleotide
phosphodiesterase gene (PDE9A) that maps to 21q22.3: alternative
splicing of mRNA transcripts, genomic structure and sequence.";
Hum. Genet. 103:386-392(1998).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS PDE9A5; PDE9A6; PDE9A7; PDE9A9;
PDE9A10; PDE9A11; PDE9A12; PDE9A13; PDE9A16; PDE9A17 AND PDE9A18), AND
TISSUE SPECIFICITY.
PubMed=12565835; DOI=10.1016/S0006-291X(03)00021-4;
Rentero C., Monfort A., Puigdomenech P.;
"Identification and distribution of different mRNA variants produced
by differential splicing in the human phosphodiesterase 9A gene.";
Biochem. Biophys. Res. Commun. 301:686-692(2003).
[4]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE9A6).
TISSUE=Brain, Small intestine, and Spleen;
PubMed=14527714; DOI=10.1016/S0378-1119(03)00733-9;
Wang P., Wu P., Egan R.W., Billah M.M.;
"Identification and characterization of a new human type 9 cGMP-
specific phosphodiesterase splice variant (PDE9A5). Differential
tissue distribution and subcellular localization of PDE9A variants.";
Gene 314:15-27(2003).
[5]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE9A21), AND SUBCELLULAR
LOCATION.
PubMed=17090334; DOI=10.1186/1471-2199-7-39;
Rentero C., Puigdomenech P.;
"Specific use of start codons and cellular localization of splice
variants of human phosphodiesterase 9A gene.";
BMC Mol. Biol. 7:39-39(2006).
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS PDE9A1 AND PDE9A3).
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PDE9A2).
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
Phelan M., Farmer A.;
"Cloning of human full-length CDSs in BD Creator(TM) system donor
vector.";
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=10830953; DOI=10.1038/35012518;
Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
Lehrach H., Reinhardt R., Yaspo M.-L.;
"The DNA sequence of human chromosome 21.";
Nature 405:311-319(2000).
[9]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
[10]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PDE9A2).
TISSUE=Eye;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[11]
ENZYME REGULATION.
PubMed=16150925; DOI=10.1124/mol.105.017608;
Wunder F., Tersteegen A., Rebmann A., Erb C., Fahrig T., Hendrix M.;
"Characterization of the first potent and selective PDE9 inhibitor
using a cGMP reporter cell line.";
Mol. Pharmacol. 68:1775-1781(2005).
[12]
TISSUE SPECIFICITY.
PubMed=22328573; DOI=10.1124/jpet.111.191353;
Kleiman R.J., Chapin D.S., Christoffersen C., Freeman J.,
Fonseca K.R., Geoghegan K.F., Grimwood S., Guanowsky V., Hajos M.,
Harms J.F., Helal C.J., Hoffmann W.E., Kocan G.P., Majchrzak M.J.,
McGinnis D., McLean S., Menniti F.S., Nelson F., Roof R.,
Schmidt A.W., Seymour P.A., Stephenson D.T., Tingley F.D.,
Vanase-Frawley M., Verhoest P.R., Schmidt C.J.;
"Phosphodiesterase 9A regulates central cGMP and modulates responses
to cholinergic and monoaminergic perturbation in vivo.";
J. Pharmacol. Exp. Ther. 341:396-409(2012).
[13]
REVIEW.
PubMed=24746902; DOI=10.1016/j.lfs.2014.04.007;
Singh N., Patra S.;
"Phosphodiesterase 9: insights from protein structure and role in
therapeutics.";
Life Sci. 106:1-11(2014).
[14]
FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
AND INDUCTION.
PubMed=25799991; DOI=10.1038/nature14332;
Lee D.I., Zhu G., Sasaki T., Cho G.S., Hamdani N., Holewinski R.,
Jo S.H., Danner T., Zhang M., Rainer P.P., Bedja D., Kirk J.A.,
Ranek M.J., Dostmann W.R., Kwon C., Margulies K.B., Van Eyk J.E.,
Paulus W.J., Takimoto E., Kass D.A.;
"Phosphodiesterase 9A controls nitric-oxide-independent cGMP and
hypertrophic heart disease.";
Nature 519:472-476(2015).
[15]
X-RAY CRYSTALLOGRAPHY (2.23 ANGSTROMS) OF 241-566 IN COMPLEX WITH THE
INHIBITOR IBMX, AND SUBUNIT.
PubMed=15210993; DOI=10.1073/pnas.0401120101;
Huai Q., Wang H., Zhang W., Colman R.W., Robinson H., Ke H.;
"Crystal structure of phosphodiesterase 9 shows orientation variation
of inhibitor 3-isobutyl-1-methylxanthine binding.";
Proc. Natl. Acad. Sci. U.S.A. 101:9624-9629(2004).
[16]
X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 242-566 IN COMPLEX WITH
MAGNESIUM; ZINC; GMP AND CGMP, ACTIVE SITE, FUNCTION, CATALYTIC
ACTIVITY, COFACTOR, AND MUTAGENESIS OF HIS-312 AND HIS-356.
PubMed=18757755; DOI=10.1073/pnas.0708850105;
Liu S., Mansour M.N., Dillman K.S., Perez J.R., Danley D.E.,
Aeed P.A., Simons S.P., Lemotte P.K., Menniti F.S.;
"Structural basis for the catalytic mechanism of human
phosphodiesterase 9.";
Proc. Natl. Acad. Sci. U.S.A. 105:13309-13314(2008).
[17]
X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 241-566 IN COMPLEX WITH
ZINC.
RIKEN structural genomics initiative (RSGI);
"Crystal structure of the human phosphodiesterase 9a catalytic
domain.";
Submitted (FEB-2009) to the PDB data bank.
[18] {ECO:0000244|PDB:3JSI, ECO:0000244|PDB:3JSW}
X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 242-566 IN COMPLEX WITH
MAGNESIUM; ZINC AND PF-4181366 INHIBITOR, ENZYME REGULATION, AND
COFACTOR.
PubMed=19919087; DOI=10.1021/jm9015334;
Verhoest P.R., Proulx-Lafrance C., Corman M., Chenard L., Helal C.J.,
Hou X., Kleiman R., Liu S., Marr E., Menniti F.S., Schmidt C.J.,
Vanase-Frawley M., Schmidt A.W., Williams R.D., Nelson F.R.,
Fonseca K.R., Liras S.;
"Identification of a brain penetrant PDE9A inhibitor utilizing
prospective design and chemical enablement as a rapid lead
optimization strategy.";
J. Med. Chem. 52:7946-7949(2009).
[19] {ECO:0000244|PDB:3K3E, ECO:0000244|PDB:3K3H}
X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 241-566 IN COMPLEX WITH
MAGNESIUM; ZINC AND BAY-73-6691 INHIBITOR, ENZYME REGULATION,
COFACTOR, AND MUTAGENESIS OF MET-425; ILE-463; LEU-480; TYR-484;
PHE-501; GLN-513 AND PHE-516.
PubMed=20121115; DOI=10.1021/jm901519f;
Wang H., Luo X., Ye M., Hou J., Robinson H., Ke H.;
"Insight into binding of phosphodiesterase-9A selective inhibitors by
crystal structures and mutagenesis.";
J. Med. Chem. 53:1726-1731(2010).
[20] {ECO:0000244|PDB:3QI3, ECO:0000244|PDB:3QI4}
X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF MUTANT GLU-513 IN COMPLEX
WITH MAGNESIUM; ZINC AND (S)-BAY-73-6691 INHIBITOR, ENZYME REGULATION,
COFACTOR, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, BIOPHYSICOCHEMICAL
PROPERTIES, AND MUTAGENESIS OF GLU-466 AND GLN-513.
PubMed=21483814; DOI=10.1371/journal.pone.0018092;
Hou J., Xu J., Liu M., Zhao R., Luo H.B., Ke H.;
"Structural asymmetry of phosphodiesterase-9, potential protonation of
a glutamic acid, and role of the invariant glutamine.";
PLoS ONE 6:E18092-E18092(2011).
[21] {ECO:0000244|PDB:4GH6}
X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 241-566 IN COMPLEX WITH
MAGNESIUM; ZINC AND INHIBITOR 28, COFACTOR, AND ENZYME REGULATION.
PubMed=22985069; DOI=10.1021/jm301189c;
Meng F., Hou J., Shao Y.X., Wu P.Y., Huang M., Zhu X., Cai Y., Li Z.,
Xu J., Liu P., Luo H.B., Wan Y., Ke H.;
"Structure-based discovery of highly selective phosphodiesterase-9A
inhibitors and implications for inhibitor design.";
J. Med. Chem. 55:8549-8558(2012).
[22] {ECO:0000244|PDB:4E90, ECO:0000244|PDB:4G2J, ECO:0000244|PDB:4G2L}
X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 242-566 IN COMPLEX WITH
MAGNESIUM; ZINC AND INHIBITOR, COFACTOR, AND ENZYME REGULATION.
PubMed=23025719; DOI=10.1021/jm3009635;
Claffey M.M., Helal C.J., Verhoest P.R., Kang Z., Fors K.S., Jung S.,
Zhong J., Bundesmann M.W., Hou X., Lui S., Kleiman R.J.,
Vanase-Frawley M., Schmidt A.W., Menniti F., Schmidt C.J.,
Hoffman W.E., Hajos M., McDowell L., O'Connor R.E.,
Macdougall-Murphy M., Fonseca K.R., Becker S.L., Nelson F.R.,
Liras S.;
"Application of structure-based drug design and parallel chemistry to
identify selective, brain penetrant, in vivo active phosphodiesterase
9A inhibitors.";
J. Med. Chem. 55:9055-9068(2012).
-!- FUNCTION: Specifically hydrolyzes the second messenger cGMP, which
is a key regulator of many important physiological processes.
Highly specific: compared to other members of the cyclic
nucleotide phosphodiesterase family, has the highest affinity and
selectivity for cGMP (PubMed:9624146, PubMed:18757755,
PubMed:21483814). Specifically regulates natriuretic-peptide-
dependent cGMP signaling in heart, acting as a regulator of
cardiac hypertrophy in myocytes and muscle. Does not regulate
nitric oxide-dependent cGMP in heart (PubMed:25799991). Additional
experiments are required to confirm whether its ability to
hydrolyze natriuretic-peptide-dependent cGMP is specific to heart
or is a general feature of the protein (Probable). In brain,
involved in cognitive function, such as learning and long-term
memory (By similarity). {ECO:0000250|UniProtKB:Q8QZV1,
ECO:0000269|PubMed:18757755, ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146,
ECO:0000305}.
-!- CATALYTIC ACTIVITY: Guanosine 3',5'-cyclic phosphate + H(2)O =
guanosine 5'-phosphate. {ECO:0000269|PubMed:18757755,
ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:9624146}.
-!- COFACTOR:
Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
Evidence={ECO:0000269|PubMed:19919087,
ECO:0000269|PubMed:20121115, ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069, ECO:0000269|PubMed:23025719,
ECO:0000305|PubMed:18757755};
Note=Binds 1 Zn(2+) ion per subunit. Binds 2 divalent metal
cations per subunit: site 1 preferentially binds zinc, while site
2 has a preference for magnesium. Tightly binds zinc.
{ECO:0000269|PubMed:19919087, ECO:0000269|PubMed:20121115,
ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:22985069,
ECO:0000269|PubMed:23025719, ECO:0000305|PubMed:18757755};
-!- COFACTOR:
Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
Evidence={ECO:0000269|PubMed:19919087,
ECO:0000269|PubMed:20121115, ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069, ECO:0000269|PubMed:23025719,
ECO:0000305|PubMed:18757755};
Note=Binds 1 Mg(2+) ions per subunit. Binds 2 divalent metal
cations per subunit: site 1 preferentially binds zinc, while site
2 has a preference for magnesium. Binds magnesium less tightly
than zinc. {ECO:0000269|PubMed:19919087,
ECO:0000269|PubMed:20121115, ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069, ECO:0000269|PubMed:23025719,
ECO:0000305|PubMed:18757755};
-!- ENZYME REGULATION: Inhibited by zaprinast; inhibitor is however
not specific to PDE9A (PubMed:9624146). Specifically inhibited by
BAY-73-6691 (1-(2-chlorophenyl)-6-((2R)-3,3,3- trifluoro-2-
methylpropyl)-1,5-dihydro-4H-pyrazolo(3,4-d)pyrimidine-4-one)
(PubMed:16150925). BAY-73-9961 has two enantiomers, (R) and (S),
due to the presence of a chiral center, and both forms vary in
their pattern of interaction (PubMed:20121115, PubMed:21483814).
Specifically inhibited by PF-4181366 (4H-Pyrazolo[3,4-d]pyrimidin-
4-one, 1- cyclopentyl-1,5-dihydro-6-[(3S,4S)-4-methyl- 1-(6-
quinoxalinylmethyl)-3-pyrrolidinyl]-one) (PubMed:19919087).
Specifically inhibited by PF-4449613 ((R)-6-(1-(3-phenoxyazetidin-
1-yl)ethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-
d]pyrimidin- 4(5H)-one) (PubMed:25799991). Specifically inhibited
by inhibitor 28 (2-((1-(2-Chlorophenyl)-4-hydroxy-1Hpyrazolo[ 3,4-
d]pyrimidin-6-yl)amino)-N-(4- methoxyphenyl)propanamide):
inhibitor forms a hydrogen bond with Tyr-484 and Gln-513
(PubMed:22985069). Specifically inhibited by 1-Cyclopentyl-6-
[(1r)-1-(3-phenoxyazetidin- 1-Yl)ethyl]-1,5-dihydro-4h-
pyrazolo[3,4-D] pyrimidin-4-one: inhibitor forms a hydrogen bond
with Tyr-484 and Gln-513 (PubMed:23025719).
{ECO:0000269|PubMed:16150925, ECO:0000269|PubMed:19919087,
ECO:0000269|PubMed:20121115, ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069, ECO:0000269|PubMed:23025719,
ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146,
ECO:0000303|PubMed:24746902}.
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
KM=0.113 uM for cGMP {ECO:0000269|PubMed:21483814};
KM=501 uM for cAMP {ECO:0000269|PubMed:21483814};
Vmax=0.285 umol/min/mg enzyme with cGMP as substrate
{ECO:0000269|PubMed:21483814};
Vmax=3.7 umol/min/mg enzyme with cAMP as substrate
{ECO:0000269|PubMed:21483814};
Note=kcat is 0.18 sec(-1) for cGMP. kcat is 2.37 sec(-1) for
cAMP. {ECO:0000269|PubMed:21483814};
-!- PATHWAY: Purine metabolism; 3',5'-cyclic GMP degradation; GMP from
3',5'-cyclic GMP: step 1/1.
-!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:15210993,
ECO:0000269|PubMed:21483814}.
-!- INTERACTION:
O95817:BAG3; NbExp=3; IntAct=EBI-742764, EBI-747185;
A2RU00:C9orf106; NbExp=3; IntAct=EBI-742764, EBI-10173129;
P49759:CLK1; NbExp=3; IntAct=EBI-742764, EBI-473775;
Q49AN0:CRY2; NbExp=3; IntAct=EBI-742764, EBI-2212355;
Q9H8Y8:GORASP2; NbExp=3; IntAct=EBI-742764, EBI-739467;
Q15051-2:IQCB1; NbExp=4; IntAct=EBI-11524542, EBI-11944935;
O76011:KRT34; NbExp=4; IntAct=EBI-11524542, EBI-1047093;
P60410:KRTAP10-8; NbExp=3; IntAct=EBI-742764, EBI-10171774;
Q9BYR5:KRTAP4-2; NbExp=3; IntAct=EBI-742764, EBI-10172511;
Q9BYQ4:KRTAP9-2; NbExp=3; IntAct=EBI-742764, EBI-1044640;
Q14657:LAGE3; NbExp=3; IntAct=EBI-742764, EBI-1052105;
P25791:LMO2; NbExp=3; IntAct=EBI-742764, EBI-739696;
Q9BRA0:NAA38; NbExp=3; IntAct=EBI-742764, EBI-9106509;
Q7Z3S9:NOTCH2NL; NbExp=3; IntAct=EBI-742764, EBI-945833;
Q96FC7:PHYHIPL; NbExp=4; IntAct=EBI-11524542, EBI-748888;
Q96FC7-2:PHYHIPL; NbExp=3; IntAct=EBI-742764, EBI-10285660;
P49888:SULT1E1; NbExp=3; IntAct=EBI-742764, EBI-712512;
Q13049:TRIM32; NbExp=8; IntAct=EBI-11524542, EBI-742790;
Q9Y260:TRPV6; NbExp=3; IntAct=EBI-742764, EBI-750052;
Q9BRU9:UTP23; NbExp=3; IntAct=EBI-742764, EBI-5457544;
-!- SUBCELLULAR LOCATION: Isoform PDE9A1: Cell projection, ruffle
membrane {ECO:0000269|PubMed:17090334}. Cytoplasm, perinuclear
region {ECO:0000269|PubMed:17090334}. Golgi apparatus
{ECO:0000269|PubMed:17090334}. Endoplasmic reticulum
{ECO:0000269|PubMed:17090334}. Cell membrane, sarcolemma
{ECO:0000269|PubMed:25799991}.
-!- SUBCELLULAR LOCATION: Isoform PDE9A2: Cell projection, ruffle
membrane {ECO:0000269|PubMed:17090334}. Cytoplasm, perinuclear
region {ECO:0000269|PubMed:17090334}.
-!- SUBCELLULAR LOCATION: Isoform PDE9A3: Cytoplasm
{ECO:0000269|PubMed:17090334}. Endoplasmic reticulum
{ECO:0000269|PubMed:17090334}.
-!- SUBCELLULAR LOCATION: Isoform PDE9A17: Cytoplasm
{ECO:0000269|PubMed:17090334}. Endoplasmic reticulum
{ECO:0000269|PubMed:17090334}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=16;
Name=PDE9A1;
IsoId=O76083-1; Sequence=Displayed;
Name=PDE9A2;
IsoId=O76083-2; Sequence=VSP_004599;
Name=PDE9A3;
IsoId=O76083-3; Sequence=VSP_004598, VSP_004599;
Name=PDE9A4;
IsoId=O76083-4; Sequence=VSP_004600;
Name=PDE9A5;
IsoId=O76083-5; Sequence=VSP_017309;
Name=PDE9A6; Synonyms=PDE9A5;
IsoId=O76083-6; Sequence=VSP_017305, VSP_004599;
Name=PDE9A7; Synonyms=PDE9A8, PDE9A14, PDE9A19, PDE9A20;
IsoId=O76083-7; Sequence=VSP_017303;
Name=PDE9A9;
IsoId=O76083-8; Sequence=VSP_017307, VSP_004599;
Name=PDE9A10;
IsoId=O76083-9; Sequence=VSP_017304, VSP_017310;
Name=PDE9A11; Synonyms=PDE9A15;
IsoId=O76083-10; Sequence=VSP_017302, VSP_017311;
Name=PDE9A12;
IsoId=O76083-11; Sequence=VSP_017305, VSP_017308;
Name=PDE9A13;
IsoId=O76083-12; Sequence=VSP_017306;
Name=PDE9A16;
IsoId=O76083-13; Sequence=VSP_004598;
Name=PDE9A17;
IsoId=O76083-14; Sequence=VSP_017305;
Name=PDE9A18;
IsoId=O76083-15; Sequence=VSP_017307;
Name=PDE9A21;
IsoId=O76083-16; Sequence=VSP_038647, VSP_004599;
-!- TISSUE SPECIFICITY: Expressed in all tissues examined (testis,
brain, small intestine, skeletal muscle, heart, lung, thymus,
spleen, placenta, kidney, liver, pancreas, ovary and prostate)
except blood (PubMed:9624146). Highest levels in brain, heart,
kidney, spleen, prostate and colon. Isoform PDE9A12 is found in
prostate (PubMed:12565835). In brain, present in the cortex,
cerebellum, and subiculum (at protein level) (PubMed:22328573). In
heart, primarily localizes to myocytes (PubMed:25799991).
{ECO:0000269|PubMed:12565835, ECO:0000269|PubMed:22328573,
ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146}.
-!- INDUCTION: Up-regulated in left ventricular hypertrophy from
aortic stenosis and following heart failure with preserved
ejection fraction (at protein level).
{ECO:0000269|PubMed:25799991}.
-!- MISCELLANEOUS: PDE9A is a potential target for treatment of
diseases such as stress-induced heart disease or long-term memory
defects. Specific inhibitors, such as BAY-73-6691 or PF-4449613
are promising candidates for clinical tests.
{ECO:0000303|PubMed:24746902, ECO:0000305|PubMed:25799991}.
-!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase
family. PDE9 subfamily. {ECO:0000305}.
-----------------------------------------------------------------------
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-----------------------------------------------------------------------
EMBL; AF048837; AAC39778.1; -; mRNA.
EMBL; AB017602; BAA88847.1; -; Genomic_DNA.
EMBL; AF067223; AAC26723.1; -; mRNA.
EMBL; AF067224; AAC26724.1; -; mRNA.
EMBL; AF067225; AAC26725.1; -; mRNA.
EMBL; AF067226; AAC26726.1; -; mRNA.
EMBL; AY196299; AAO34685.1; -; mRNA.
EMBL; AY196300; AAO34686.1; -; mRNA.
EMBL; AY196301; AAO34687.1; -; mRNA.
EMBL; AY196302; AAO34688.1; -; mRNA.
EMBL; AY196303; AAO34689.1; -; mRNA.
EMBL; AY196304; AAO34690.1; -; mRNA.
EMBL; AY196305; AAO34691.1; -; mRNA.
EMBL; AY196306; AAO34692.1; -; mRNA.
EMBL; AY196307; AAO34693.1; -; mRNA.
EMBL; AY196308; AAO34694.1; -; mRNA.
EMBL; AY196309; AAO34695.1; -; mRNA.
EMBL; AY196310; AAO34696.1; -; mRNA.
EMBL; AY196311; AAO34697.1; -; mRNA.
EMBL; AY196312; AAO34698.1; -; mRNA.
EMBL; AY196313; AAO34699.1; -; mRNA.
EMBL; AY196314; AAO34700.1; -; mRNA.
EMBL; AY242121; AAO88210.1; -; mRNA.
EMBL; AY701187; AAV84271.1; -; mRNA.
EMBL; AK294112; BAG57446.1; -; mRNA.
EMBL; AK314679; BAG37232.1; -; mRNA.
EMBL; BT007016; AAP35662.1; -; mRNA.
EMBL; AP001747; BAA95552.1; -; Genomic_DNA.
EMBL; CH471079; EAX09544.1; -; Genomic_DNA.
EMBL; CH471079; EAX09536.1; -; Genomic_DNA.
EMBL; CH471079; EAX09537.1; -; Genomic_DNA.
EMBL; CH471079; EAX09541.1; -; Genomic_DNA.
EMBL; CH471079; EAX09542.1; -; Genomic_DNA.
EMBL; CH471079; EAX09546.1; -; Genomic_DNA.
EMBL; CH471079; EAX09540.1; -; Genomic_DNA.
EMBL; CH471079; EAX09548.1; -; Genomic_DNA.
EMBL; CH471079; EAX09549.1; -; Genomic_DNA.
EMBL; BC009047; AAH09047.1; -; mRNA.
CCDS; CCDS13690.1; -. [O76083-1]
CCDS; CCDS33567.1; -. [O76083-5]
CCDS; CCDS33568.1; -. [O76083-2]
CCDS; CCDS33569.1; -. [O76083-15]
CCDS; CCDS33570.1; -. [O76083-12]
CCDS; CCDS33571.1; -. [O76083-4]
CCDS; CCDS42941.1; -. [O76083-8]
CCDS; CCDS42942.1; -. [O76083-14]
CCDS; CCDS42943.1; -. [O76083-6]
CCDS; CCDS42944.1; -. [O76083-11]
CCDS; CCDS42945.1; -. [O76083-13]
CCDS; CCDS42946.1; -. [O76083-3]
CCDS; CCDS42947.1; -. [O76083-9]
RefSeq; NP_001001567.1; NM_001001567.1. [O76083-2]
RefSeq; NP_001001568.1; NM_001001568.1. [O76083-3]
RefSeq; NP_001001569.1; NM_001001569.1. [O76083-4]
RefSeq; NP_001001570.1; NM_001001570.1. [O76083-5]
RefSeq; NP_001001571.1; NM_001001571.1. [O76083-6]
RefSeq; NP_001001572.1; NM_001001572.1. [O76083-7]
RefSeq; NP_001001573.1; NM_001001573.1. [O76083-7]
RefSeq; NP_001001574.1; NM_001001574.1. [O76083-8]
RefSeq; NP_001001575.1; NM_001001575.1. [O76083-9]
RefSeq; NP_001001576.1; NM_001001576.1. [O76083-10]
RefSeq; NP_001001577.1; NM_001001577.1. [O76083-11]
RefSeq; NP_001001578.1; NM_001001578.1. [O76083-12]
RefSeq; NP_001001579.1; NM_001001579.1. [O76083-7]
RefSeq; NP_001001580.1; NM_001001580.1. [O76083-10]
RefSeq; NP_001001581.1; NM_001001581.1. [O76083-13]
RefSeq; NP_001001582.1; NM_001001582.1. [O76083-14]
RefSeq; NP_001001583.1; NM_001001583.1. [O76083-15]
RefSeq; NP_001001584.1; NM_001001584.2. [O76083-7]
RefSeq; NP_001001585.1; NM_001001585.1. [O76083-7]
RefSeq; NP_001302462.1; NM_001315533.1. [O76083-16]
RefSeq; NP_002597.1; NM_002606.2. [O76083-1]
RefSeq; XP_016883855.1; XM_017028366.1. [O76083-7]
UniGene; Hs.473927; -.
PDB; 2HD1; X-ray; 2.23 A; A/B=241-566.
PDB; 2YY2; X-ray; 2.80 A; A/B=241-566.
PDB; 3DY8; X-ray; 2.15 A; A/B=242-566.
PDB; 3DYL; X-ray; 2.70 A; A/B=242-566.
PDB; 3DYN; X-ray; 2.10 A; A/B=242-566.
PDB; 3DYQ; X-ray; 2.50 A; A/B=242-566.
PDB; 3DYS; X-ray; 2.30 A; A/B=242-566.
PDB; 3JSI; X-ray; 2.72 A; A/B=242-566.
PDB; 3JSW; X-ray; 2.30 A; A/B=242-566.
PDB; 3K3E; X-ray; 2.70 A; A/B=241-566.
PDB; 3K3H; X-ray; 2.50 A; A/B=241-566.
PDB; 3N3Z; X-ray; 2.75 A; A/B=241-566.
PDB; 3QI3; X-ray; 2.30 A; A/B=1-593.
PDB; 3QI4; X-ray; 2.50 A; A/B=1-593.
PDB; 4E90; X-ray; 2.50 A; A/B=242-566.
PDB; 4G2J; X-ray; 2.40 A; A/B=242-566.
PDB; 4G2L; X-ray; 3.00 A; A/B=242-566.
PDB; 4GH6; X-ray; 2.70 A; A/B=241-566.
PDB; 4Y86; X-ray; 2.01 A; A/B=1-593.
PDB; 4Y87; X-ray; 3.10 A; A/B=1-593.
PDB; 4Y8C; X-ray; 2.70 A; A/B=1-593.
PDBsum; 2HD1; -.
PDBsum; 2YY2; -.
PDBsum; 3DY8; -.
PDBsum; 3DYL; -.
PDBsum; 3DYN; -.
PDBsum; 3DYQ; -.
PDBsum; 3DYS; -.
PDBsum; 3JSI; -.
PDBsum; 3JSW; -.
PDBsum; 3K3E; -.
PDBsum; 3K3H; -.
PDBsum; 3N3Z; -.
PDBsum; 3QI3; -.
PDBsum; 3QI4; -.
PDBsum; 4E90; -.
PDBsum; 4G2J; -.
PDBsum; 4G2L; -.
PDBsum; 4GH6; -.
PDBsum; 4Y86; -.
PDBsum; 4Y87; -.
PDBsum; 4Y8C; -.
ProteinModelPortal; O76083; -.
SMR; O76083; -.
BioGrid; 111178; 25.
IntAct; O76083; 33.
MINT; MINT-1444906; -.
STRING; 9606.ENSP00000291539; -.
BindingDB; O76083; -.
ChEMBL; CHEMBL3535; -.
DrugBank; DB07954; 3-isobutyl-1-methyl-7H-xanthine.
DrugBank; DB00201; Caffeine.
DrugBank; DB03597; Gamma-Glutamyl[S-(2-Iodobenzyl)Cysteinyl]Glycine.
GuidetoPHARMACOLOGY; 1309; -.
iPTMnet; O76083; -.
PhosphoSitePlus; O76083; -.
BioMuta; PDE9A; -.
PaxDb; O76083; -.
PeptideAtlas; O76083; -.
PRIDE; O76083; -.
DNASU; 5152; -.
Ensembl; ENST00000291539; ENSP00000291539; ENSG00000160191. [O76083-1]
Ensembl; ENST00000328862; ENSP00000328699; ENSG00000160191. [O76083-15]
Ensembl; ENST00000335440; ENSP00000335365; ENSG00000160191. [O76083-12]
Ensembl; ENST00000335512; ENSP00000335242; ENSG00000160191. [O76083-2]
Ensembl; ENST00000349112; ENSP00000344730; ENSG00000160191. [O76083-4]
Ensembl; ENST00000380328; ENSP00000369685; ENSG00000160191. [O76083-5]
Ensembl; ENST00000398224; ENSP00000381280; ENSG00000160191. [O76083-3]
Ensembl; ENST00000398225; ENSP00000381281; ENSG00000160191. [O76083-14]
Ensembl; ENST00000398227; ENSP00000381283; ENSG00000160191. [O76083-9]
Ensembl; ENST00000398229; ENSP00000381285; ENSG00000160191. [O76083-11]
Ensembl; ENST00000398232; ENSP00000381287; ENSG00000160191. [O76083-13]
Ensembl; ENST00000398234; ENSP00000381289; ENSG00000160191. [O76083-6]
Ensembl; ENST00000398236; ENSP00000381291; ENSG00000160191. [O76083-8]
GeneID; 5152; -.
KEGG; hsa:5152; -.
UCSC; uc002zbm.4; human. [O76083-1]
CTD; 5152; -.
DisGeNET; 5152; -.
EuPathDB; HostDB:ENSG00000160191.17; -.
GeneCards; PDE9A; -.
HGNC; HGNC:8795; PDE9A.
HPA; HPA011380; -.
MIM; 602973; gene.
neXtProt; NX_O76083; -.
OpenTargets; ENSG00000160191; -.
PharmGKB; PA33143; -.
eggNOG; KOG3689; Eukaryota.
eggNOG; ENOG410XRI7; LUCA.
GeneTree; ENSGT00760000119066; -.
HOVERGEN; HBG053545; -.
KO; K13761; -.
OMA; TQMMYSM; -.
OrthoDB; EOG091G082I; -.
PhylomeDB; O76083; -.
TreeFam; TF314638; -.
BRENDA; 3.1.4.35; 2681.
Reactome; R-HSA-418457; cGMP effects.
SABIO-RK; O76083; -.
UniPathway; UPA00763; UER00748.
ChiTaRS; PDE9A; human.
EvolutionaryTrace; O76083; -.
GeneWiki; PDE9A; -.
GenomeRNAi; 5152; -.
PRO; PR:O76083; -.
Proteomes; UP000005640; Chromosome 21.
Bgee; ENSG00000160191; -.
ExpressionAtlas; O76083; baseline and differential.
Genevisible; O76083; HS.
GO; GO:0005829; C:cytosol; IDA:UniProtKB.
GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
GO; GO:0043204; C:perikaryon; IEA:Ensembl.
GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
GO; GO:0042383; C:sarcolemma; IDA:UniProtKB.
GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IDA:UniProtKB.
GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; TAS:ProtInc.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0046069; P:cGMP catabolic process; IDA:UniProtKB.
GO; GO:0046068; P:cGMP metabolic process; IDA:UniProtKB.
GO; GO:0019934; P:cGMP-mediated signaling; IEA:Ensembl.
GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; ISS:UniProtKB.
GO; GO:0007165; P:signal transduction; TAS:ProtInc.
CDD; cd00077; HDc; 1.
Gene3D; 1.10.1300.10; -; 1.
InterPro; IPR003607; HD/PDEase_dom.
InterPro; IPR023088; PDEase.
InterPro; IPR002073; PDEase_catalytic_dom.
InterPro; IPR036971; PDEase_catalytic_dom_sf.
InterPro; IPR023174; PDEase_CS.
Pfam; PF00233; PDEase_I; 1.
PRINTS; PR00387; PDIESTERASE1.
SMART; SM00471; HDc; 1.
PROSITE; PS00126; PDEASE_I; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; Cell membrane; Cell projection;
cGMP; Complete proteome; Cytoplasm; Endoplasmic reticulum;
Golgi apparatus; Hydrolase; Magnesium; Membrane; Metal-binding;
Phosphoprotein; Reference proteome; Zinc.
CHAIN 1 593 High affinity cGMP-specific 3',5'-cyclic
phosphodiesterase 9A.
/FTId=PRO_0000198841.
NP_BIND 312 316 cGMP. {ECO:0000269|PubMed:18757755}.
NP_BIND 512 513 cGMP. {ECO:0000269|PubMed:18757755}.
REGION 288 550 Catalytic. {ECO:0000250}.
ACT_SITE 312 312 Proton donor.
{ECO:0000269|PubMed:18757755}.
METAL 316 316 Zinc; via tele nitrogen.
{ECO:0000244|PDB:2HD1,
ECO:0000244|PDB:2YY2,
ECO:0000244|PDB:3DYN,
ECO:0000244|PDB:3JSI,
ECO:0000244|PDB:3JSW,
ECO:0000244|PDB:3K3E,
ECO:0000244|PDB:3K3H,
ECO:0000244|PDB:3N3Z,
ECO:0000244|PDB:4E90,
ECO:0000244|PDB:4G2J,
ECO:0000244|PDB:4G2L,
ECO:0000244|PDB:4GH6,
ECO:0000269|PubMed:18757755,
ECO:0000269|PubMed:19919087,
ECO:0000269|PubMed:20121115,
ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069,
ECO:0000269|PubMed:23025719}.
METAL 352 352 Zinc; via tele nitrogen.
{ECO:0000244|PDB:2HD1,
ECO:0000244|PDB:2YY2,
ECO:0000244|PDB:3DYN,
ECO:0000244|PDB:3JSI,
ECO:0000244|PDB:3JSW,
ECO:0000244|PDB:3K3E,
ECO:0000244|PDB:3K3H,
ECO:0000244|PDB:3N3Z,
ECO:0000244|PDB:4E90,
ECO:0000244|PDB:4G2J,
ECO:0000244|PDB:4G2L,
ECO:0000244|PDB:4GH6,
ECO:0000269|PubMed:18757755,
ECO:0000269|PubMed:19919087,
ECO:0000269|PubMed:20121115,
ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069,
ECO:0000269|PubMed:23025719}.
METAL 353 353 Magnesium. {ECO:0000244|PDB:2HD1,
ECO:0000244|PDB:2YY2,
ECO:0000244|PDB:3DYN,
ECO:0000244|PDB:3JSI,
ECO:0000244|PDB:3JSW,
ECO:0000244|PDB:3K3E,
ECO:0000244|PDB:3K3H,
ECO:0000244|PDB:3N3Z,
ECO:0000244|PDB:4E90,
ECO:0000244|PDB:4G2J,
ECO:0000244|PDB:4G2L,
ECO:0000244|PDB:4GH6,
ECO:0000269|PubMed:18757755,
ECO:0000269|PubMed:19919087,
ECO:0000269|PubMed:20121115,
ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069,
ECO:0000269|PubMed:23025719}.
METAL 353 353 Zinc. {ECO:0000244|PDB:2HD1,
ECO:0000244|PDB:2YY2,
ECO:0000244|PDB:3DYN,
ECO:0000244|PDB:3JSI,
ECO:0000244|PDB:3JSW,
ECO:0000244|PDB:3K3E,
ECO:0000244|PDB:3K3H,
ECO:0000244|PDB:3N3Z,
ECO:0000244|PDB:4E90,
ECO:0000244|PDB:4G2J,
ECO:0000244|PDB:4G2L,
ECO:0000244|PDB:4GH6,
ECO:0000269|PubMed:18757755,
ECO:0000269|PubMed:19919087,
ECO:0000269|PubMed:20121115,
ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069,
ECO:0000269|PubMed:23025719}.
METAL 462 462 Zinc. {ECO:0000244|PDB:2HD1,
ECO:0000244|PDB:2YY2,
ECO:0000244|PDB:3DYN,
ECO:0000244|PDB:3JSI,
ECO:0000244|PDB:3JSW,
ECO:0000244|PDB:3K3E,
ECO:0000244|PDB:3K3H,
ECO:0000244|PDB:3N3Z,
ECO:0000244|PDB:4E90,
ECO:0000244|PDB:4G2J,
ECO:0000244|PDB:4G2L,
ECO:0000244|PDB:4GH6,
ECO:0000269|PubMed:18757755,
ECO:0000269|PubMed:19919087,
ECO:0000269|PubMed:20121115,
ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069,
ECO:0000269|PubMed:23025719}.
BINDING 353 353 cGMP. {ECO:0000269|PubMed:18757755}.
BINDING 462 462 cGMP. {ECO:0000269|PubMed:18757755}.
BINDING 484 484 cGMP. {ECO:0000269|PubMed:18757755}.
BINDING 484 484 Inhibitor specific to PDE9A.
{ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069,
ECO:0000269|PubMed:23025719}.
BINDING 513 513 Inhibitor. {ECO:0000269|PubMed:19919087,
ECO:0000269|PubMed:20121115,
ECO:0000269|PubMed:21483814,
ECO:0000269|PubMed:22985069,
ECO:0000269|PubMed:23025719}.
MOD_RES 379 379 Phosphoserine.
{ECO:0000250|UniProtKB:Q8QZV1}.
VAR_SEQ 1 217 Missing (in isoform PDE9A11).
{ECO:0000303|PubMed:12565835}.
/FTId=VSP_017302.
VAR_SEQ 1 207 Missing (in isoform PDE9A7).
{ECO:0000303|PubMed:12565835}.
/FTId=VSP_017303.
VAR_SEQ 1 160 Missing (in isoform PDE9A10).
{ECO:0000303|PubMed:12565835}.
/FTId=VSP_017304.
VAR_SEQ 1 73 MGSGSSSYRPKAIYLDIDGRIQKVIFSKYCNSSDIMDLFCI
ATGLPRNTTISLLTTDDAMVSIDPTMPANSER -> MSSFS
IHHSVTCCFYLVRSHGRPTS (in isoform
PDE9A21). {ECO:0000303|PubMed:17090334}.
/FTId=VSP_038647.
VAR_SEQ 1 73 MGSGSSSYRPKAIYLDIDGRIQKVIFSKYCNSSDIMDLFCI
ATGLPRNTTISLLTTDDAMVSIDPTMPANSER -> MDAFR
S (in isoform PDE9A3 and isoform
PDE9A16). {ECO:0000303|PubMed:12565835,
ECO:0000303|PubMed:14702039,
ECO:0000303|PubMed:9856478}.
/FTId=VSP_004598.
VAR_SEQ 1 46 MGSGSSSYRPKAIYLDIDGRIQKVIFSKYCNSSDIMDLFCI
ATGLP -> MDAFR (in isoform PDE9A6,
isoform PDE9A12 and isoform PDE9A17).
{ECO:0000303|PubMed:12565835,
ECO:0000303|PubMed:14527714}.
/FTId=VSP_017305.
VAR_SEQ 24 165 VIFSKYCNSSDIMDLFCIATGLPRNTTISLLTTDDAMVSID
PTMPANSERTPYKVRPVAIKQLSAGVEDKRTTSRGQSAERP
LRDRRVVGLEQPRREGAFESGQVEPRPREPQGCYQEGQRIP
PEREELIQSVLAQVAEQFS -> EHDHLPADHRRRHGLHRP
HHAREFRTHSVQSETCGHQATL (in isoform
PDE9A13). {ECO:0000303|PubMed:12565835}.
/FTId=VSP_017306.
VAR_SEQ 24 165 VIFSKYCNSSDIMDLFCIATGLPRNTTISLLTTDDAMVSID
PTMPANSERTPYKVRPVAIKQLSAGVEDKRTTSRGQSAERP
LRDRRVVGLEQPRREGAFESGQVEPRPREPQGCYQEGQRIP
PEREELIQSVLAQVAEQFS -> HSVQSETCGHQATL (in
isoform PDE9A4).
{ECO:0000303|PubMed:9856478}.
/FTId=VSP_004600.
VAR_SEQ 48 73 Missing (in isoform PDE9A9 and isoform
PDE9A18). {ECO:0000303|PubMed:12565835}.
/FTId=VSP_017307.
VAR_SEQ 73 165 Missing (in isoform PDE9A12).
{ECO:0000303|PubMed:12565835}.
/FTId=VSP_017308.
VAR_SEQ 74 165 TPYKVRPVAIKQLSAGVEDKRTTSRGQSAERPLRDRRVVGL
EQPRREGAFESGQVEPRPREPQGCYQEGQRIPPEREELIQS
VLAQVAEQFS -> NELILYTSLRNLLFLPSKESWASHQHS
VQSETCGHQATL (in isoform PDE9A5).
{ECO:0000303|PubMed:12565835}.
/FTId=VSP_017309.
VAR_SEQ 88 147 Missing (in isoform PDE9A2, isoform
PDE9A3, isoform PDE9A6, isoform PDE9A9
and isoform PDE9A21).
{ECO:0000303|PubMed:12565835,
ECO:0000303|PubMed:14527714,
ECO:0000303|PubMed:14702039,
ECO:0000303|PubMed:15489334,
ECO:0000303|PubMed:17090334,
ECO:0000303|PubMed:9856478,
ECO:0000303|Ref.7}.
/FTId=VSP_004599.
VAR_SEQ 161 165 AEQFS -> MDAFR (in isoform PDE9A10).
{ECO:0000303|PubMed:12565835}.
/FTId=VSP_017310.
VAR_SEQ 218 218 R -> M (in isoform PDE9A11).
{ECO:0000303|PubMed:12565835}.
/FTId=VSP_017311.
MUTAGEN 312 312 H->A: Completely abolishes catalytic
activity. {ECO:0000269|PubMed:18757755}.
MUTAGEN 356 356 H->A: Reduces catalytic activity, but has
no effect on substrate affinity.
{ECO:0000269|PubMed:18757755}.
MUTAGEN 425 425 M->A: Induces a 2 fold change in
inhibitory sensivity by BAY-73-9961.
{ECO:0000269|PubMed:20121115}.
MUTAGEN 463 463 I->A: Induces a 6-9 fold change in
inhibitory sensivity by BAY-73-9961.
{ECO:0000269|PubMed:20121115}.
MUTAGEN 466 466 E->A: Decreased affinity and catalytic
activity for cGMP and cAMP.
{ECO:0000269|PubMed:21483814}.
MUTAGEN 480 480 L->A: Induces a 6-9 fold change in
inhibitory sensivity by BAY-73-9961.
{ECO:0000269|PubMed:20121115}.
MUTAGEN 484 484 Y->A: Induces a 6-9 fold change in
inhibitory sensivity by BAY-73-9961.
{ECO:0000269|PubMed:20121115}.
MUTAGEN 501 501 F->A: Induces a 2 fold change in
inhibitory sensivity by BAY-73-9961.
{ECO:0000269|PubMed:20121115}.
MUTAGEN 513 513 Q->A: Induces a dramatic change in
inhibitory sensivity by BAY-73-9961.
{ECO:0000269|PubMed:20121115}.
MUTAGEN 513 513 Q->E: 2 fold decreased affinity and
catalytic activity for cGMP. 8 fold
decreased catalytic activity for cAMP
without affecting the affinity for cAMP.
{ECO:0000269|PubMed:21483814}.
MUTAGEN 516 516 F->A: Induces a dramatic change in
inhibitory sensivity by BAY-73-9961.
{ECO:0000269|PubMed:20121115}.
CONFLICT 79 79 R -> G (in Ref. 6; BAG57446).
{ECO:0000305}.
HELIX 250 255 {ECO:0000244|PDB:4Y86}.
HELIX 263 265 {ECO:0000244|PDB:3DYN}.
HELIX 268 281 {ECO:0000244|PDB:4Y86}.
HELIX 284 287 {ECO:0000244|PDB:4Y86}.
HELIX 292 304 {ECO:0000244|PDB:4Y86}.
STRAND 310 313 {ECO:0000244|PDB:4Y86}.
HELIX 314 330 {ECO:0000244|PDB:4Y86}.
HELIX 333 335 {ECO:0000244|PDB:4Y86}.
HELIX 339 351 {ECO:0000244|PDB:4Y86}.
TURN 352 355 {ECO:0000244|PDB:4Y86}.
HELIX 361 366 {ECO:0000244|PDB:4Y86}.
HELIX 370 374 {ECO:0000244|PDB:4Y86}.
TURN 375 377 {ECO:0000244|PDB:4Y86}.
HELIX 380 393 {ECO:0000244|PDB:4Y86}.
HELIX 396 398 {ECO:0000244|PDB:4Y86}.
TURN 400 403 {ECO:0000244|PDB:4Y86}.
HELIX 406 421 {ECO:0000244|PDB:4Y86}.
HELIX 425 427 {ECO:0000244|PDB:4Y86}.
HELIX 428 438 {ECO:0000244|PDB:4Y86}.
HELIX 439 441 {ECO:0000244|PDB:2HD1}.
HELIX 447 462 {ECO:0000244|PDB:4Y86}.
HELIX 465 467 {ECO:0000244|PDB:4Y86}.
HELIX 470 492 {ECO:0000244|PDB:4Y86}.
TURN 493 495 {ECO:0000244|PDB:4Y86}.
HELIX 500 502 {ECO:0000244|PDB:4Y86}.
TURN 504 506 {ECO:0000244|PDB:4Y86}.
HELIX 509 519 {ECO:0000244|PDB:4Y86}.
HELIX 521 531 {ECO:0000244|PDB:4Y86}.
HELIX 535 538 {ECO:0000244|PDB:4Y86}.
HELIX 540 562 {ECO:0000244|PDB:4Y86}.
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


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