Phosphodiesterase

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spinqualitylabelsall models Yeast phosphodiesterase 1 complex with GMP, MPD and Zn+2 (grey) ions (PDB entry 4ojx) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Function 3'5'-cyclic nucleotide phosphodiesterases (PDE) are enzymes that hydrolyze the 3',5'-phosphodiester bond in cyclic nucleotides (e.g., cAMP, cGMP). PDEs operate in concert with cyclases (adenylate cyclase or guanylate cyclase) to regulate the cellular concentration of cyclic nucleotides. cAMP and cGMP serve as intracellular second messengers for a multitude of signaling pathways, including sensory transduction, hormone signaling, and neurotransmitter signaling. In mammals, 11 distinct families of PDEs have been identified which share a highly homologous catalytic domain (pfam:00233, PDEase_I). See details on PDE 6 in User:Rick H. Cote/PDE6. Tyrosyl-DNA PDE hydrolyzes phosphodiester bond at the 3’-end of DNA linked to a tyrosyl moiety. Glycerophosphodiester PDE hydrolyzes various glycerophosphodiesters to release glycerol-3-phosphate and alcohol. PDE 1 is calcium/calmodulin dependent[1]. PDE 2 is cGMP-dependent 3’,5’-cyclic PDE[2]. PDE 3 is expressed in vascular smooth muscle cells[3]. PDE 4a-d are cCMP-specific and regulate cAMP levels and signaling. PDE4s are expressed differently in different cell types but posses similar catalytic and regulatory domains. PDE 5 is cGMP-specific. PDE 6 is the primary effector of retinal phototransduction[4]. PDE 7 is expressed in lymphocytes and certain brain regions and is involved in pre inflammatory processes[5]. PDE 8 regulates chemotaxis of activated lymphocytes[6]. PDE 9 regulates cGMP levels[7]. PDE 10 is expressed in striatum[8]. Specific phosphodiesterases are in C-di-GMP specific phosphodiesterases. Relevance PDE4 inhibitors are used in the treatment of chronic inflammatory diseases[9]. PDE5 inhibitors like viagra are used for premature ejaculation[10]. PDE7 inhibitors are tested as potential drugs for neurological disorders. PDE10 inhibitors are tested as modifiers of Parkinson disease[11]. Structural highlights The yeast PDE 1 is located between 2 monomers and contains [12]. Water molecules shown as red spheres.

3D Structures of phosphodiesterase

Updated on 31-August-2017

References

1. ↑ Schermuly RT, Pullamsetti SS, Kwapiszewska G, Dumitrascu R, Tian X, Weissmann N, Ghofrani HA, Kaulen C, Dunkern T, Schudt C, Voswinckel R, Zhou J, Samidurai A, Klepetko W, Paddenberg R, Kummer W, Seeger W, Grimminger F. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy. Circulation. 2007 May 1;115(17):2331-9. Epub 2007 Apr 16. PMID:17438150 doi:http://dx.doi.org/10.1161/CIRCULATIONAHA.106.676809
2. ↑ Whalin ME, Scammell JG, Strada SJ, Thompson WJ. Phosphodiesterase II, the cGMP-activatable cyclic nucleotide phosphodiesterase, regulates cyclic AMP metabolism in PC12 cells. Mol Pharmacol. 1991 Jun;39(6):711-7. PMID:1646946
3. ↑ Tilley DG, Maurice DH. Vascular smooth muscle cell phosphodiesterase (PDE) 3 and PDE4 activities and levels are regulated by cyclic AMP in vivo. Mol Pharmacol. 2002 Sep;62(3):497-506. PMID:12181425
4. ↑ Morin F, Lugnier C, Kameni J, Voisin P. Expression and role of phosphodiesterase 6 in the chicken pineal gland. J Neurochem. 2001 Jul;78(1):88-99. PMID:11432976
5. ↑ Redondo M, Brea J, Perez DI, Soteras I, Val C, Perez C, Morales-Garcia JA, Alonso-Gil S, Paul-Fernandez N, Martin-Alvarez R, Cadavid MI, Loza MI, Perez-Castillo A, Mengod G, Campillo NE, Martinez A, Gil C. Effect of phosphodiesterase 7 (PDE7) inhibitors in experimental autoimmune encephalomyelitis mice. Discovery of a new chemically diverse family of compounds. J Med Chem. 2012 Apr 12;55(7):3274-84. doi: 10.1021/jm201720d. Epub 2012 Mar 16. PMID:22385507 doi:http://dx.doi.org/10.1021/jm201720d
6. ↑ Dong H, Osmanova V, Epstein PM, Brocke S. Phosphodiesterase 8 (PDE8) regulates chemotaxis of activated lymphocytes. Biochem Biophys Res Commun. 2006 Jun 30;345(2):713-9. Epub 2006 May 3. PMID:16696947 doi:http://dx.doi.org/10.1016/j.bbrc.2006.04.143
7. ↑ 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. PMID:24746902 doi:http://dx.doi.org/10.1016/j.lfs.2014.04.007
8. ↑ Qiu Y, Yanase T, Hu H, Tanaka T, Nishi Y, Liu M, Sueishi K, Sawamura T, Nawata H. Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development. Endocrinology. 2010 Jul;151(7):3307-16. doi: 10.1210/en.2009-1268. Epub 2010 Apr , 28. PMID:20427482 doi:http://dx.doi.org/10.1210/en.2009-1268
9. ↑ Jin SL, Ding SL, Lin SC. Phosphodiesterase 4 and its inhibitors in inflammatory diseases. Chang Gung Med J. 2012 May-Jun;35(3):197-210. PMID:22735051
10. ↑ Reffelmann T, Kloner RA. Cardiovascular effects of phosphodiesterase 5 inhibitors. Curr Pharm Des. 2006;12(27):3485-94. PMID:17017941
11. ↑ Garcia AM, Redondo M, Martinez A, Gil C. Phosphodiesterase 10 inhibitors: new disease modifying drugs for Parkinson's disease? Curr Med Chem. 2014 Apr;21(10):1171-87. PMID:24372206
12. ↑ Tian Y, Cui W, Huang M, Robinson H, Wan Y, Wang Y, Ke H. Dual specificity and novel structural folding of yeast phosphodiesterase-1 for hydrolysis of second messengers cyclic adenosine and guanosine 3',5'-monophosphate. Biochemistry. 2014 Aug 5;53(30):4938-45. doi: 10.1021/bi500406h. Epub 2014 Jul, 22. PMID:25050706 doi:http://dx.doi.org/10.1021/bi500406h