Canmetcon
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Identification
HMDB Protein ID HMDBP00636
Secondary Accession Numbers
  • 5908
  • HMDBP04369
Name cAMP-specific 3',5'-cyclic phosphodiesterase 4D
Synonyms
  1. DPDE3
  2. PDE43
Gene Name PDE4D
Protein Type Unknown
Biological Properties
General Function Involved in catalytic activity
Specific Function Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Pathways
  • 3',5'-cyclic AMP degradation
  • Adenine phosphoribosyltransferase deficiency (APRT)
  • Adenosine Deaminase Deficiency
  • Adenylosuccinate Lyase Deficiency
  • AICA-Ribosiduria
  • Azathioprine Action Pathway
  • Cilostazol Action Pathway
  • Dipyridamole (Antiplatelet) Action Pathway
  • Gout or Kelley-Seegmiller Syndrome
  • Lesch-Nyhan Syndrome (LNS)
  • Mercaptopurine Action Pathway
  • Mitochondrial DNA depletion syndrome
  • Molybdenum Cofactor Deficiency
  • Morphine addiction
  • Myoadenylate deaminase deficiency
  • Purine Metabolism
  • Purine metabolism
  • Purine Nucleoside Phosphorylase Deficiency
  • Thioguanine Action Pathway
  • Xanthine Dehydrogenase Deficiency (Xanthinuria)
  • Xanthinuria type I
  • Xanthinuria type II
Reactions
Adenosine 3',5'-cyclic phosphate + Water → Adenosine monophosphate details
Cyclic AMP + Water → Adenosine monophosphate details
Cyclic GMP + Water → Guanosine monophosphate details
GO Classification
Biological Process
signal transduction
cAMP catabolic process
establishment of endothelial barrier
smooth muscle contraction
Cellular Component
cytosol
membrane
microtubule organizing center
Function
hydrolase activity, acting on ester bonds
catalytic activity
hydrolase activity
cyclic-nucleotide phosphodiesterase activity
3',5'-cyclic-nucleotide phosphodiesterase activity
phosphoric ester hydrolase activity
phosphoric diester hydrolase activity
Molecular Function
metal ion binding
drug binding
cAMP binding
3',5'-cyclic-AMP phosphodiesterase activity
Process
biological regulation
regulation of biological process
regulation of cellular process
signal transduction
Cellular Location
  1. Cytoplasm
  2. Cytoplasm
  3. Cytoplasm
  4. Membrane
  5. cytoskeleton
  6. cytoskeleton
  7. centrosome
Gene Properties
Chromosome Location 5
Locus 5q12
SNPs PDE4D
Gene Sequence
>2430 bp
ATGGAGGCAGAGGGCAGCAGCGCGCCGGCCCGGGCGGGCAGCGGAGAGGGCAGCGACAGC
GCCGGCGGGGCCACGCTCAAAGCCCCCAAGCATCTCTGGAGGCACGAGCAGCACCACCAG
TACCCGCTCCGGCAGCCCCAGTTCCGCCTCCTGCATCCCCATCACCACCTGCCCCCGCCG
CCGCCACCCTCGCCCCAGCCCCAGCCCCAGTGTCCGCTACAGCCGCCGCCGCCGCCCCCC
CTGCCGCCGCCCCCGCCGCCGCCCGGGGCTGCCCGCGGCCGCTACGCCTCGAGCGGGGCC
ACCGGCCGCGTCCGGCATCGCGGCTACTCGGACACCGAGCGCTACCTGTACTGTCGCGCC
ATGGACCGCACCTCCTACGCGGTGGAGACCGGCCACCGGCCCGGCCTGAAGAAATCCAGG
ATGTCCTGGCCCTCCTCGTTCCAGGGACTCAGGCGTTTTGATGTGGACAATGGCACATCT
GCGGGACGGAGTCCCTTGGATCCCATGACCAGCCCAGGATCCGGGCTAATTCTCCAAGCA
AATTTTGTCCACAGTCAACGACGGGAGTCCTTCCTGTATCGATCCGACAGCGATTATGAC
CTCTCTCCAAAGTCTATGTCCCGGAACTCCTCCATTGCCAGTGATATACACGGAGATGAC
TTGATTGTGACTCCATTTGCTCAGGTCTTGGCCAGTCTGCGAACTGTACGAAACAACTTT
GCTGCATTAACTAATTTGCAAGATCGAGCACCTAGCAAAAGATCACCCATGTGCAACCAA
CCATCCATCAACAAAGCCACCATAACAGAGGAGGCCTACCAGAAACTGGCCAGCGAGACC
CTGGAGGAGCTGGACTGGTGTCTGGACCAGCTAGAGACCCTACAGACCAGGCACTCCGTC
AGTGAGATGGCCTCCAACAAGTTTAAAAGGATGCTTAATCGGGAGCTCACCCATCTCTCT
GAAATGAGTCGGTCTGGAAATCAAGTGTCAGAGTTTATATCAAACACATTCTTAGATAAG
CAACATGAAGTGGAAATTCCTTCTCCAACTCAGAAGGAAAAGGAGAAAAAGAAAAGACCA
ATGTCTCAGATCAGTGGAGTCAAGAAATTGATGCACAGCTCTAGTCTGACTAATTCAAGT
ATCCCAAGGTTTGGAGTTAAAACTGAACAAGAAGATGTCCTTGCCAAGGAACTAGAAGAT
GTGAACAAATGGGGTCTTCATGTTTTCAGAATAGCAGAGTTGTCTGGTAACCGGCCCTTG
ACTGTTATCATGCACACCATTTTTCAGGAACGGGATTTATTAAAAACATTTAAAATTCCA
GTAGATACTTTAATTACATATCTTATGACTCTCGAAGACCATTACCATGCTGATGTGGCC
TATCACAACAATATCCATGCTGCAGATGTTGTCCAGTCTACTCATGTGCTATTATCTACA
CCTGCTTTGGAGGCTGTGTTTACAGATTTGGAGATTCTTGCAGCAATTTTTGCCAGTGCA
ATACATGATGTAGATCATCCTGGTGTGTCCAATCAATTTCTGATCAATACAAACTCTGAA
CTTGCCTTGATGTACAATGATTCCTCAGTCTTAGAGAACCATCATTTGGCTGTGGGCTTT
AAATTGCTTCAGGAAGAAAACTGTGACATTTTCCAGAATTTGACCAAAAAACAAAGACAA
TCTTTAAGGAAAATGGTCATTGACATCGTACTTGCAACAGATATGTCAAAACACATGAAT
CTACTGGCTGATTTGAAGACTATGGTTGAAACTAAGAAAGTGACAAGCTCTGGAGTTCTT
CTTCTTGATAATTATTCCGATAGGATTCAGGTTCTTCAGAATATGGTGCACTGTGCAGAT
CTGAGCAACCCAACAAAGCCTCTCCAGCTGTACCGCCAGTGGACGGACCGGATAATGGAG
GAGTTCTTCCGCCAAGGAGACCGAGAGAGGGAACGTGGCATGGAGATAAGCCCCATGTGT
GACAAGCACAATGCTTCCGTGGAAAAATCACAGGTGGGCTTCATAGACTATATTGTTCAT
CCCCTCTGGGAGACATGGGCAGACCTCGTCCACCCTGACGCCCAGGATATTTTGGACACT
TTGGAGGACAATCGTGAATGGTACCAGAGCACAATCCCTCAGAGCCCCTCTCCTGCACCT
GATGACCCAGAGGAGGGCCGGCAGGGTCAAACTGAGAAATTCCAGTTTGAACTAACTTTA
GAGGAAGATGGTGAGTCAGACACGGAAAAGGACAGTGGCAGTCAAGTGGAAGAAGACACT
AGCTGCAGTGACTCCAAGACTCTTTGTACTCAAGACTCAGAGTCTACTGAAATTCCCCTT
GATGAACAGGTTGAAGAGGAGGCAGTAGGGGAAGAAGAGGAAAGCCAGCCTGAAGCCTGT
GTCATAGATGATCGTTCTCCTGACACGTAA
Protein Properties
Number of Residues 809
Molecular Weight 91114.1
Theoretical pI 5.537
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence
>cAMP-specific 3',5'-cyclic phosphodiesterase 4D
MEAEGSSAPARAGSGEGSDSAGGATLKAPKHLWRHEQHHQYPLRQPQFRLLHPHHHLPPP
PPPSPQPQPQCPLQPPPPPPLPPPPPPPGAARGRYASSGATGRVRHRGYSDTERYLYCRA
MDRTSYAVETGHRPGLKKSRMSWPSSFQGLRRFDVDNGTSAGRSPLDPMTSPGSGLILQA
NFVHSQRRESFLYRSDSDYDLSPKSMSRNSSIASDIHGDDLIVTPFAQVLASLRTVRNNF
AALTNLQDRAPSKRSPMCNQPSINKATITEEAYQKLASETLEELDWCLDQLETLQTRHSV
SEMASNKFKRMLNRELTHLSEMSRSGNQVSEFISNTFLDKQHEVEIPSPTQKEKEKKKRP
MSQISGVKKLMHSSSLTNSSIPRFGVKTEQEDVLAKELEDVNKWGLHVFRIAELSGNRPL
TVIMHTIFQERDLLKTFKIPVDTLITYLMTLEDHYHADVAYHNNIHAADVVQSTHVLLST
PALEAVFTDLEILAAIFASAIHDVDHPGVSNQFLINTNSELALMYNDSSVLENHHLAVGF
KLLQEENCDIFQNLTKKQRQSLRKMVIDIVLATDMSKHMNLLADLKTMVETKKVTSSGVL
LLDNYSDRIQVLQNMVHCADLSNPTKPLQLYRQWTDRIMEEFFRQGDRERERGMEISPMC
DKHNASVEKSQVGFIDYIVHPLWETWADLVHPDAQDILDTLEDNREWYQSTIPQSPSPAP
DDPEEGRQGQTEKFQFELTLEEDGESDTEKDSGSQVEEDTSCSDSKTLCTQDSESTEIPL
DEQVEEEAVGEEEESQPEACVIDDRSPDT
GenBank ID Protein 157277988
UniProtKB/Swiss-Prot ID Q08499
UniProtKB/Swiss-Prot Entry Name PDE4D_HUMAN
PDB IDs
GenBank Gene ID NM_001104631.1
GeneCard ID PDE4D
GenAtlas ID PDE4D
HGNC ID HGNC:8783
References
General References
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  2. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. [PubMed:18669648 ]
  3. Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M: Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell. 2008 Aug 8;31(3):438-48. doi: 10.1016/j.molcel.2008.07.007. [PubMed:18691976 ]
  4. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M: Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell. 2006 Nov 3;127(3):635-48. [PubMed:17081983 ]
  5. Yu LR, Zhu Z, Chan KC, Issaq HJ, Dimitrov DS, Veenstra TD: Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra. J Proteome Res. 2007 Nov;6(11):4150-62. Epub 2007 Oct 9. [PubMed:17924679 ]
  6. Zahedi RP, Lewandrowski U, Wiesner J, Wortelkamp S, Moebius J, Schutz C, Walter U, Gambaryan S, Sickmann A: Phosphoproteome of resting human platelets. J Proteome Res. 2008 Feb;7(2):526-34. Epub 2007 Dec 19. [PubMed:18088087 ]
  7. Beausoleil SA, Villen J, Gerber SA, Rush J, Gygi SP: A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat Biotechnol. 2006 Oct;24(10):1285-92. Epub 2006 Sep 10. [PubMed:16964243 ]
  8. Zhang KY, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S, Hsieh D, Neiman J, West BL, Zhang C, Milburn MV, Kim SH, Schlessinger J, Bollag G: A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol Cell. 2004 Jul 23;15(2):279-86. [PubMed:15260978 ]
  9. Bolger G, Michaeli T, Martins T, St John T, Steiner B, Rodgers L, Riggs M, Wigler M, Ferguson K: A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs. Mol Cell Biol. 1993 Oct;13(10):6558-71. [PubMed:8413254 ]
  10. Xu RX, Rocque WJ, Lambert MH, Vanderwall DE, Luther MA, Nolte RT: Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram. J Mol Biol. 2004 Mar 19;337(2):355-65. [PubMed:15003452 ]
  11. Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY: Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure. 2004 Dec;12(12):2233-47. [PubMed:15576036 ]
  12. Card GL, Blasdel L, England BP, Zhang C, Suzuki Y, Gillette S, Fong D, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY: A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design. Nat Biotechnol. 2005 Feb;23(2):201-7. Epub 2005 Jan 30. [PubMed:15685167 ]
  13. Wang H, Peng MS, Chen Y, Geng J, Robinson H, Houslay MD, Cai J, Ke H: Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochem J. 2007 Dec 1;408(2):193-201. [PubMed:17727341 ]
  14. Nemoz G, Zhang R, Sette C, Conti M: Identification of cyclic AMP-phosphodiesterase variants from the PDE4D gene expressed in human peripheral mononuclear cells. FEBS Lett. 1996 Apr 8;384(1):97-102. [PubMed:8797812 ]
  15. Baecker PA, Obernolte R, Bach C, Yee C, Shelton ER: Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phosphodiesterase (PDE IVD). Gene. 1994 Jan 28;138(1-2):253-6. [PubMed:8125310 ]
  16. Bolger GB, Erdogan S, Jones RE, Loughney K, Scotland G, Hoffmann R, Wilkinson I, Farrell C, Houslay MD: Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene. Biochem J. 1997 Dec 1;328 ( Pt 2):539-48. [PubMed:9371713 ]
  17. Miro X, Casacuberta JM, Gutierrez-Lopez MD, de Landazuri MO, Puigdomenech P: Phosphodiesterases 4D and 7A splice variants in the response of HUVEC cells to TNF-alpha(1). Biochem Biophys Res Commun. 2000 Aug 2;274(2):415-21. [PubMed:10913353 ]
  18. Wang D, Deng C, Bugaj-Gaweda B, Kwan M, Gunwaldsen C, Leonard C, Xin X, Hu Y, Unterbeck A, De Vivo M: Cloning and characterization of novel PDE4D isoforms PDE4D6 and PDE4D7. Cell Signal. 2003 Sep;15(9):883-91. [PubMed:12834813 ]
  19. Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, Gudmundsdottir T, Bjarnadottir SM, Einarsson OB, Gudjonsdottir HM, Hawkins M, Gudmundsson G, Gudmundsdottir H, Andrason H, Gudmundsdottir AS, Sigurdardottir M, Chou TT, Nahmias J, Goss S, Sveinbjornsdottir S, Valdimarsson EM, Jakobsson F, Agnarsson U, Gudnason V, Thorgeirsson G, Fingerle J, Gurney M, Gudbjartsson D, Frigge ML, Kong A, Stefansson K, Gulcher JR: The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003 Oct;35(2):131-8. Epub 2003 Sep 21. [PubMed:14517540 ]
  20. Bolger GB, McCahill A, Yarwood SJ, Steele MR, Warwicker J, Houslay MD: Delineation of RAID1, the RACK1 interaction domain located within the unique N-terminal region of the cAMP-specific phosphodiesterase, PDE4D5. BMC Biochem. 2002 Aug 23;3:24. [PubMed:12193273 ]
  21. Bolger GB, McCahill A, Huston E, Cheung YF, McSorley T, Baillie GS, Houslay MD: The unique amino-terminal region of the PDE4D5 cAMP phosphodiesterase isoform confers preferential interaction with beta-arrestins. J Biol Chem. 2003 Dec 5;278(49):49230-8. Epub 2003 Sep 18. [PubMed:14500724 ]
  22. Richter W, Conti M: The oligomerization state determines regulatory properties and inhibitor sensitivity of type 4 cAMP-specific phosphodiesterases. J Biol Chem. 2004 Jul 16;279(29):30338-48. Epub 2004 May 6. [PubMed:15131123 ]
  23. Rosand J, Bayley N, Rost N, de Bakker PI: Many hypotheses but no replication for the association between PDE4D and stroke. Nat Genet. 2006 Oct;38(10):1091-2; author reply 1092-3. [PubMed:17006457 ]
  24. Lee ME, Markowitz J, Lee JO, Lee H: Crystal structure of phosphodiesterase 4D and inhibitor complex(1). FEBS Lett. 2002 Oct 23;530(1-3):53-8. [PubMed:12387865 ]
  25. Huai Q, Colicelli J, Ke H: The crystal structure of AMP-bound PDE4 suggests a mechanism for phosphodiesterase catalysis. Biochemistry. 2003 Nov 18;42(45):13220-6. [PubMed:14609333 ]
  26. Huai Q, Wang H, Sun Y, Kim HY, Liu Y, Ke H: Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity. Structure. 2003 Jul;11(7):865-73. [PubMed:12842049 ]
  27. Huai Q, Liu Y, Francis SH, Corbin JD, Ke H: Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity. J Biol Chem. 2004 Mar 26;279(13):13095-101. Epub 2003 Dec 10. [PubMed:14668322 ]
  28. Huai Q, Sun Y, Wang H, Macdonald D, Aspiotis R, Robinson H, Huang Z, Ke H: Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase. J Med Chem. 2006 Mar 23;49(6):1867-73. [PubMed:16539372 ]
  29. Smith KJ, Baillie GS, Hyde EI, Li X, Houslay TM, McCahill A, Dunlop AJ, Bolger GB, Klussmann E, Adams DR, Houslay MD: 1H NMR structural and functional characterisation of a cAMP-specific phosphodiesterase-4D5 (PDE4D5) N-terminal region peptide that disrupts PDE4D5 interaction with the signalling scaffold proteins, beta-arrestin and RACK1. Cell Signal. 2007 Dec;19(12):2612-24. Epub 2007 Sep 1. [PubMed:17900862 ]
  30. Wang H, Robinson H, Ke H: The molecular basis for different recognition of substrates by phosphodiesterase families 4 and 10. J Mol Biol. 2007 Aug 10;371(2):302-7. Epub 2007 May 26. [PubMed:17582435 ]