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

Details

Name
High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Synonyms
  • 3.1.4.35
Gene Name
PDE9A
Organism
Humans
Amino acid sequence
>lcl|BSEQ0006116|High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
MGSGSSSYRPKAIYLDIDGRIQKVIFSKYCNSSDIMDLFCIATGLPRNTTISLLTTDDAM
VSIDPTMPANSERTPYKVRPVAIKQLSAGVEDKRTTSRGQSAERPLRDRRVVGLEQPRRE
GAFESGQVEPRPREPQGCYQEGQRIPPEREELIQSVLAQVAEQFSRAFKINELKAEVANH
LAVLEKRVELEGLKVVEIEKCKSDIKKMREELAARSSRTNCPCKYSFLDNHKKLTPRRDV
PTYPKYLLSPETIEALRKPTFDVWLWEPNEMLSCLEHMYHDLGLVRDFSINPVTLRRWLF
CVHDNYRNNPFHNFRHCFCVAQMMYSMVWLCSLQEKFSQTDILILMTAAICHDLDHPGYN
NTYQINARTELAVRYNDISPLENHHCAVAFQILAEPECNIFSNIPPDGFKQIRQGMITLI
LATDMARHAEIMDSFKEKMENFDYSNEEHMTLLKMILIKCCDISNEVRPMEVAEPWVDCL
LEEYFMQSDREKSEGLPVAPFMDRDKVTKATAQIGFIKFVLIPMFETVTKLFPMVEEIML
QPLWESRDRYEELKRIDDAMKELQKKTDSLTSGATEKSRERSRDVKNSEGDCA
Number of residues
593
Molecular Weight
68491.95
Theoretical pI
6.1
GO Classification
Functions
3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase activity / metal ion binding
Processes
blood coagulation / cGMP catabolic process / cGMP metabolic process / positive regulation of cardiac muscle hypertrophy / signal transduction
Components
cytosol / endoplasmic reticulum / Golgi apparatus / perinuclear region of cytoplasm / ruffle membrane / sarcolemma
General Function
Metal ion binding
Specific 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).
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Cell projection
Gene sequence
>lcl|BSEQ0021351|High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A)
ATGGGATCCGGCTCCTCCAGCTACCGGCCCAAGGCCATCTACCTGGACATCGATGGACGC
ATTCAGAAGGTAATCTTCAGCAAGTACTGCAACTCCAGCGACATCATGGACCTGTTCTGC
ATCGCCACCGGCCTGCCTCGGAACACGACCATCTCCCTGCTGACCACCGACGACGCCATG
GTCTCCATCGACCCCACCATGCCCGCGAATTCAGAACGCACTCCGTACAAAGTGAGACCT
GTGGCCATCAAGCAACTCTCCGAGAGAGAAGAATTAATCCAGAGCGTGCTGGCGCAGGTT
GCAGAGCAGTTCTCAAGAGCATTCAAAATCAATGAACTGAAAGCTGAAGTTGCAAATCAC
TTGGCTGTCCTAGAGAAACGCGTGGAATTGGAAGGACTAAAAGTGGTGGAGATTGAGAAA
TGCAAGAGTGACATTAAGAAGATGAGGGAGGAGCTGGCGGCCAGAAGCAGCAGGACCAAC
TGCCCCTGTAAGTACAGTTTTTTGGATAACCACAAGAAGTTGACTCCTCGACGCGATGTT
CCCACTTACCCCAAGTACCTGCTCTCTCCAGAGACCATCGAGGCCCTGCGGAAGCCGACC
TTTGACGTCTGGCTTTGGGAGCCCAATGAGATGCTGAGCTGCCTGGAGCACATGTACCAC
GACCTCGGGCTGGTCAGGGACTTCAGCATCAACCCTGTCACCCTCAGGAGGTGGCTGTTC
TGCGTCCACGACAACTACAGAAACAACCCCTTCCACAACTTCCGGCACTGCTTCTGCGTG
GCCCAGATGATGTACAGCATGGTCTGGCTCTGCAGTCTCCAGGAGAAGTTCTCACAAACG
GATATCCTGATCCTAATGACAGCGGCCATCTGCCACGATCTGGACCATCCCGGCTACAAC
AACACGTACCAGATCAATGCCCGCACAGAGCTGGCGGTCCGCTACAATGACATCTCACCG
CTGGAGAACCACCACTGCGCCGTGGCCTTCCAGATCCTCGCCGAGCCTGAGTGCAACATC
TTCTCCAACATCCCACCTGATGGGTTCAAGCAGATCCGACAGGGAATGATCACATTAATC
TTGGCCACTGACATGGCAAGACATGCAGAAATTATGGATTCTTTCAAAGAGAAAATGGAG
AATTTTGACTACAGCAACGAGGAGCACATGACCCTGCTGAAGATGATTTTGATAAAATGC
TGTGATATCTCTAACGAGGTCCGTCCAATGGAAGTCGCAGAGCCTTGGGTGGACTGTTTA
TTAGAGGAATATTTTATGCAGAGCGACCGTGAGAAGTCAGAAGGCCTTCCTGTGGCACCG
TTCATGGACCGAGACAAAGTGACCAAGGCCACAGCCCAGATTGGGTTCATCAAGTTTGTC
CTGATCCCAATGTTTGAAACAGTGACCAAGCTCTTCCCCATGGTTGAGGAGATCATGCTG
CAGCCACTTTGGGAATCCCGAGATCGCTACGAGGAGCTGAAGCGGATAGATGACGCCATG
AAAGAGTTACAGAAGAAGACTGACAGCTTGACGTCTGGGGCCACCGAGAAGTCCAGAGAG
AGAAGCAGAGATGTGAAAAACAGTGAAGGAGACTGTGCCTGA
Chromosome Location
21
Locus
Not Available
External Identifiers
ResourceLink
UniProtKB IDO76083
UniProtKB Entry NamePDE9A_HUMAN
GenBank Gene IDAF048837
GenAtlas IDPDE9A
HGNC IDHGNC:8795
General References
  1. Fisher DA, Smith JF, Pillar JS, St Denis SH, Cheng JB: Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase. J Biol Chem. 1998 Jun 19;273(25):15559-64. [PubMed:9624146]
  2. Guipponi M, Scott HS, Kudoh J, Kawasaki K, Shibuya K, Shintani A, Asakawa S, Chen H, Lalioti MD, Rossier C, Minoshima S, Shimizu N, Antonarakis SE: 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. 1998 Oct;103(4):386-92. [PubMed:9856478]
  3. 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. 2003 Feb 14;301(3):686-92. [PubMed:12565835]
  4. Wang P, Wu P, Egan RW, Billah MM: 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. 2003 Sep 18;314:15-27. [PubMed:14527714]
  5. Rentero C, Puigdomenech P: Specific use of start codons and cellular localization of splice variants of human phosphodiesterase 9A gene. BMC Mol Biol. 2006 Nov 8;7:39. [PubMed:17090334]
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  8. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334]
  9. 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. 2005 Dec;68(6):1775-81. Epub 2005 Sep 8. [PubMed:16150925]
  10. Kleiman RJ, Chapin DS, Christoffersen C, Freeman J, Fonseca KR, Geoghegan KF, Grimwood S, Guanowsky V, Hajos M, Harms JF, Helal CJ, Hoffmann WE, Kocan GP, Majchrzak MJ, McGinnis D, McLean S, Menniti FS, Nelson F, Roof R, Schmidt AW, Seymour PA, Stephenson DT, Tingley FD, Vanase-Frawley M, Verhoest PR, Schmidt CJ: Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo. J Pharmacol Exp Ther. 2012 May;341(2):396-409. doi: 10.1124/jpet.111.191353. Epub 2012 Feb 10. [PubMed:22328573]
  11. Singh N, Patra S: Phosphodiesterase 9: insights from protein structure and role in therapeutics. Life Sci. 2014 Jun 13;106(1-2):1-11. doi: 10.1016/j.lfs.2014.04.007. Epub 2014 Apr 16. [PubMed:24746902]
  12. Lee DI, Zhu G, Sasaki T, Cho GS, Hamdani N, Holewinski R, Jo SH, Danner T, Zhang M, Rainer PP, Bedja D, Kirk JA, Ranek MJ, Dostmann WR, Kwon C, Margulies KB, Van Eyk JE, Paulus WJ, Takimoto E, Kass DA: Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature. 2015 Mar 26;519(7544):472-6. doi: 10.1038/nature14332. Epub 2015 Mar 18. [PubMed:25799991]
  13. Huai Q, Wang H, Zhang W, Colman RW, 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. 2004 Jun 29;101(26):9624-9. Epub 2004 Jun 21. [PubMed:15210993]
  14. Liu S, Mansour MN, Dillman KS, Perez JR, Danley DE, Aeed PA, Simons SP, Lemotte PK, Menniti FS: Structural basis for the catalytic mechanism of human phosphodiesterase 9. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13309-14. doi: 10.1073/pnas.0708850105. Epub 2008 Aug 29. [PubMed:18757755]
  15. Verhoest PR, Proulx-Lafrance C, Corman M, Chenard L, Helal CJ, Hou X, Kleiman R, Liu S, Marr E, Menniti FS, Schmidt CJ, Vanase-Frawley M, Schmidt AW, Williams RD, Nelson FR, Fonseca KR, Liras S: Identification of a brain penetrant PDE9A inhibitor utilizing prospective design and chemical enablement as a rapid lead optimization strategy. J Med Chem. 2009 Dec 24;52(24):7946-9. doi: 10.1021/jm9015334. [PubMed:19919087]
  16. 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. 2010 Feb 25;53(4):1726-31. doi: 10.1021/jm901519f. [PubMed:20121115]
  17. Hou J, Xu J, Liu M, Zhao R, Luo HB, Ke H: Structural asymmetry of phosphodiesterase-9, potential protonation of a glutamic acid, and role of the invariant glutamine. PLoS One. 2011 Mar 31;6(3):e18092. doi: 10.1371/journal.pone.0018092. [PubMed:21483814]
  18. Meng F, Hou J, Shao YX, Wu PY, Huang M, Zhu X, Cai Y, Li Z, Xu J, Liu P, Luo HB, Wan Y, Ke H: Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design. J Med Chem. 2012 Oct 11;55(19):8549-58. doi: 10.1021/jm301189c. Epub 2012 Oct 1. [PubMed:22985069]
  19. Claffey MM, Helal CJ, Verhoest PR, Kang Z, Fors KS, Jung S, Zhong J, Bundesmann MW, Hou X, Lui S, Kleiman RJ, Vanase-Frawley M, Schmidt AW, Menniti F, Schmidt CJ, Hoffman WE, Hajos M, McDowell L, O'Connor RE, Macdougall-Murphy M, Fonseca KR, Becker SL, Nelson FR, 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. 2012 Nov 8;55(21):9055-68. doi: 10.1021/jm3009635. Epub 2012 Oct 12. [PubMed:23025719]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB03597Gamma-Glutamyl[S-(2-Iodobenzyl)Cysteinyl]GlycineexperimentalunknownDetails
DB079543-isobutyl-1-methyl-7H-xanthineexperimentalunknownDetails
DB00201CaffeineapprovedunknowninhibitorDetails
DB09283TrapidilexperimentalyesinhibitorDetails