PDE4D

Phosphodiesterase 4D, cAMP-specific

PDB rendering based on 1mkd.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1MKD, 1OYN, 1PTW, 1Q9M, 1TB7, 1TBB, 1XOM, 1XON, 1XOQ, 1XOR, 1Y2B, 1Y2C, 1Y2D, 1Y2E, 1Y2K, 1ZKN, 2FM0, 2FM5, 2PW3, 2QYN, 3G4G, 3G4I, 3G4K, 3G4L, 3G58, 3IAD, 3IAK, 3K4S, 3SL3, 3SL4, 3SL5, 3SL6, 3SL8, 3V9B

Identifiers

Symbols

PDE4D ; ACRDYS2; DPDE3; HSPDE4D; PDE43; PDE4DN2; STRK1

External IDs

OMIM: 600129 MGI: 99555 HomoloGene: 129755 IUPHAR: 1303 ChEMBL: 288 GeneCards: PDE4D Gene

EC number

3.1.4.53

Gene ontology
Molecular function	• 3',5'-cyclic-nucleotide phosphodiesterase activity • 3',5'-cyclic-AMP phosphodiesterase activity • protein binding • drug binding • enzyme binding • cAMP binding • ubiquitin protein ligase binding • beta-2 adrenergic receptor binding • ion channel binding • metal ion binding • ATPase binding • scaffold protein binding
Cellular component	• microtubule organizing center • cytosol • voltage-gated calcium channel complex • membrane • apical plasma membrane • calcium channel complex
Biological process	• regulation of heart rate • cAMP catabolic process • smooth muscle contraction • aging • regulation of receptor activity • regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum • cAMP-mediated signaling • neutrophil chemotaxis • positive regulation of interferon-gamma production • positive regulation of interleukin-2 production • positive regulation of interleukin-5 production • negative regulation of peptidyl-serine phosphorylation • multicellular organism growth • negative regulation of heart contraction • T cell receptor signaling pathway • regulation of ryanodine-sensitive calcium-release channel activity • establishment of endothelial barrier • cellular response to lipopolysaccharide • cellular response to cAMP • cellular response to epinephrine stimulus • adrenergic receptor signaling pathway • regulation of cardiac muscle cell contraction • adrenergic receptor signaling pathway involved in positive regulation of heart rate • regulation of cell communication by electrical coupling involved in cardiac conduction • negative regulation of relaxation of cardiac muscle
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 5:
58.26 – 59.82 Mb

Chr 13:
108.45 – 109.95 Mb

PubMed search

cAMP-specific 3',5'-cyclic phosphodiesterase 4D is an enzyme that in humans is encoded by the PDE4D gene.

The PDE4D gene is complex and has at least 9 different isoforms that encode functional proteins. These proteins degrade the second messenger cAMP, which is a key signal transduction molecule in multiple cell types, including vascular cells (Dominiczak and McBride, 2003).[supplied by OMIM]^[1]

Interactions

PDE4D has been shown to interact with myomegalin^[2] and GNB2L1.^[3]^[4]

Clinical relevance

Mutations in this gene have been associated to cases od acrodysostosis.^[5]

This is the subtype of PDE4 that appears to be involved in the emetic and antidepressant effects of PDE4 inhibitors.^[6]

References

↑ "Entrez Gene: PDE4D phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila)".
↑ Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D, Onuffer J, Jin SL, Conti M (April 2001). "Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase". J. Biol. Chem. 276 (14): 11189–98. doi:10.1074/jbc.M006546200. PMID 11134006.
↑ Yarwood SJ, Steele MR, Scotland G, Houslay MD, Bolger GB (May 1999). "The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform". J. Biol. Chem. 274 (21): 14909–17. doi:10.1074/jbc.274.21.14909. PMID 10329691.
↑ Steele MR, McCahill A, Thompson DS, MacKenzie C, Isaacs NW, Houslay MD, Bolger GB (July 2001). "Identification of a surface on the beta-propeller protein RACK1 that interacts with the cAMP-specific phosphodiesterase PDE4D5". Cell. Signal. 13 (7): 507–13. doi:10.1016/S0898-6568(01)00167-X. PMID 11516626.
↑ Michot, C; Le Goff, C, Goldenberg, A, Abhyankar, A, Klein, C, Kinning, E, Guerrot, AM, Flahaut, P, Duncombe, A, Baujat, G, Lyonnet, S, Thalassinos, C, Nitschke, P, Casanova, JL, Le Merrer, M, Munnich, A, Cormier-Daire, V (Mar 28, 2012). "Exome Sequencing Identifies PDE4D Mutations as Another Cause of Acrodysostosis.". American Journal of Human Genetics 90 (4): 740–5. doi:10.1016/j.ajhg.2012.03.003. PMID 22464250.
↑ Zhang, HT (2009). "Cyclic AMP-Specific Phosphodiesterase-4 as a Target for the Development of Antidepressant Drugs". Current Pharmaceutical Design 15 (14): 1688–1698. doi:10.2174/138161209788168092. PMID 19442182.

Wang Q (2005). "Molecular genetics of coronary artery disease". Curr. Opin. Cardiol. 20 (3): 182–8. doi:10.1097/01.hco.0000160373.77190.f1. PMC 1579824. PMID 15861005.
Swinnen JV, Joseph DR, Conti M (1989). "The mRNA encoding a high-affinity cAMP phosphodiesterase is regulated by hormones and cAMP". Proc. Natl. Acad. Sci. U.S.A. 86 (21): 8197–201. doi:10.1073/pnas.86.21.8197. PMC 298247. PMID 2554303.
Milatovich A, Bolger G, Michaeli T, Francke U (1994). "Chromosome localizations of genes for five cAMP-specific phosphodiesterases in man and mouse". Somat. Cell Mol. Genet. 20 (2): 75–86. doi:10.1007/BF02290677. PMID 8009369.
Baecker PA, Obernolte R, Bach C et al. (1994). "Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phosphodiesterase (PDE IVD)". Gene 138 (1–2): 253–6. doi:10.1016/0378-1119(94)90818-4. PMID 8125310.
Bolger G, Michaeli T, Martins T et al. (1993). "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. 13 (10): 6558–71. PMC 364715. PMID 8413254.
Sette C, Conti M (1996). "Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. Involvement of serine 54 in the enzyme activation". J. Biol. Chem. 271 (28): 16526–34. doi:10.1074/jbc.271.28.16526. PMID 8663227.
Némoz G, Zhang R, Sette C, Conti M (1996). "Identification of cyclic AMP-phosphodiesterase variants from the PDE4D gene expressed in human peripheral mononuclear cells". FEBS Lett. 384 (1): 97–102. doi:10.1016/0014-5793(96)00300-6. PMID 8797812.
Bolger GB, Erdogan S, Jones RE et al. (1998). "Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene". Biochem. J. 328 (Pt 2): 539–48. PMC 1218953. PMID 9371713.
Hoffmann R, Baillie GS, MacKenzie SJ et al. (1999). "The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579". EMBO J. 18 (4): 893–903. doi:10.1093/emboj/18.4.893. PMC 1171182. PMID 10022832.
Yarwood SJ, Steele MR, Scotland G et al. (1999). "The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform". J. Biol. Chem. 274 (21): 14909–17. doi:10.1074/jbc.274.21.14909. PMID 10329691.
Beard MB, O'Connell JC, Bolger GB, Houslay MD (1999). "The unique N-terminal domain of the cAMP phosphodiesterase PDE4D4 allows for interaction with specific SH3 domains". FEBS Lett. 460 (1): 173–7. doi:10.1016/S0014-5793(99)01335-6. PMID 10571082.
MacKenzie SJ, Baillie GS, McPhee I et al. (2000). "ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions". J. Biol. Chem. 275 (22): 16609–17. doi:10.1074/jbc.275.22.16609. PMID 10828059.
Miró X, Casacuberta JM, Gutiérrez-López MD et al. (2000). "Phosphodiesterases 4D and 7A splice variants in the response of HUVEC cells to TNF-alpha(1)". Biochem. Biophys. Res. Commun. 274 (2): 415–21. doi:10.1006/bbrc.2000.3146. PMID 10913353.
Verde I, Pahlke G, Salanova M et al. (2001). "Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase". J. Biol. Chem. 276 (14): 11189–98. doi:10.1074/jbc.M006546200. PMID 11134006.
Zauli G, Milani D, Mirandola P et al. (2001). "HIV-1 Tat protein down-regulates CREB transcription factor expression in PC12 neuronal cells through a phosphatidylinositol 3-kinase/AKT/cyclic nucleoside phosphodiesterase pathway". FASEB J. 15 (2): 483–91. doi:10.1096/fj.00-0354com. PMID 11156964.
Dodge KL, Khouangsathiene S, Kapiloff MS et al. (2001). "mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module". EMBO J. 20 (8): 1921–30. doi:10.1093/emboj/20.8.1921. PMC 125429. PMID 11296225.
Steele MR, McCahill A, Thompson DS et al. (2001). "Identification of a surface on the beta-propeller protein RACK1 that interacts with the cAMP-specific phosphodiesterase PDE4D5". Cell. Signal. 13 (7): 507–13. doi:10.1016/S0898-6568(01)00167-X. PMID 11516626.
Gretarsdottir S, Sveinbjörnsdottir S, Jonsson HH et al. (2002). "Localization of a Susceptibility Gene for Common Forms of Stroke to 5q12". Am. J. Hum. Genet. 70 (3): 593–603. doi:10.1086/339252. PMC 384939. PMID 11833004.
Moon E, Lee R, Near R et al. (2002). "Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia". Clin. Cancer Res. 8 (2): 589–95. PMID 11839681.
Le Jeune IR, Shepherd M, Van Heeke G et al. (2002). "Cyclic AMP-dependent transcriptional up-regulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterization of a novel PDE4D5 promoter". J. Biol. Chem. 277 (39): 35980–9. doi:10.1074/jbc.M204832200. PMID 12121997.

PDB gallery

1mkd: crystal structure of PDE4D catalytic domain and zardaverine complex

1oyn: Crystal structure of PDE4D2 in complex with (R,S)-rolipram

1ptw: The Crystal Structure of AMP-Bound PDE4 Suggests a Mechanism for Phosphodiesterase Catalysis

1q9m: Three dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity

1tb7: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With AMP

1tbb: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Rolipram

1xom: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Cilomilast

1xon: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Piclamilast

1xoq: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Roflumilast

1xor: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Zardaverine

1y2b: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester

1y2c: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester

1y2d: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 1-(4-methoxy-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester

1y2e: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 1-(4-amino-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester

1y2k: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 3,5-dimethyl-1-(3-nitro-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

1zkn: Structure of PDE4D2-IBMX

2fm0: Crystal structure of PDE4D in complex with L-869298

2fm5: Crystal structure of PDE4D2 in complex with inhibitor L-869299

PDE4D

Interactions

Clinical relevance

References

Further reading