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PDE5A  -  phosphodiesterase 5A, cGMP-specific

Bos taurus

 
 
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Disease relevance of PDE5A

  • A fully functional chimeric PDE6alpha'/PDE5 enzyme containing the PDE6alpha' noncatalytic cGMP-binding sites, and the PDE5 catalytic domain has been efficiently expressed in the baculovirus/High Five cell system [1].
  • This PDE5-dependent ANP resistance may represent an important contributor to the sodium retention of liver disease [2].
 

High impact information on PDE5A

 

Biological context of PDE5A

  • Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation [7].
  • A deletion mutant of cGMP-binding cGMP-specific PDE (PDE5), encoding the 357 carboxyl-terminal amino acids including the catalytic domain, has been generated, expressed, and purified [5].
  • The regulatory domain of the cGMP-binding cGMP-specific 3':5'-cyclic nucleotide phosphodiesterase (PDE5) contains two homologous segments of amino acid sequence that encode allosteric cyclic nucleotide-binding sites, referred to as site a and site b, which are highly selective for cGMP over cAMP [6].
  • Sildenafil (Viagra), a specific PDE5 inhibitor, promotes penile erection by blocking the activity of PDE5, which causes cGMP to accumulate in the corpus cavernosum [8].
  • The results indicate that cGMP bound to allosteric cGMP-binding sites of PKG is protected from hydrolysis by PDE5 and that persistent protection of cGMP by either non-phosphorylated or autophosphorylated PKGs may be a positive-feedback control to sustain cGMP signalling [9].
 

Anatomical context of PDE5A

  • Chimeric cGMP phosphodiesterases (PDEs) have been constructed using components of the cGMP-binding PDE (PDE5) and cone photoreceptor phosphodiesterase (PDE6alpha') in order to study structure and function of the photoreceptor enzyme [1].
  • The cGMP-binding cGMP-specific phosphodiesterase (PDE5) degrades cGMP and regulates the intracellular level of cGMP in many tissues, including the smooth muscle of the corpus cavernosum of the penis [8].
  • Hybridization on total RNA extracted from dibutyryl-cAMP-treated NG108-15 cells shows a 5-fold increase of PDE5 9 kb mRNA: such an increase is not observed in N18TG2 although we observed a similar increase in the enzymatic activity of both cell lines [10].
  • Primary cultures of bovine aortic endothelial cells (BAEC) express cyclic nucleotide phosphodiesterase (CN PDE) isozymes of the PDE2, PDE4 and PDE5 gene families [11].
  • The increase in recombinant PDE5 catalytic activity brought about by phosphorylation was time-dependent and was obtained with 0.2-0.5 microM PKG subunit, which is approximately the cellular level of this enzyme in vascular smooth muscle [12].
 

Associations of PDE5A with chemical compounds

 

Analytical, diagnostic and therapeutic context of PDE5A

References

  1. Probing domain functions of chimeric PDE6alpha'/PDE5 cGMP-phosphodiesterase. Granovsky, A.E., Natochin, M., McEntaffer, R.L., Haik, T.L., Francis, S.H., Corbin, J.D., Artemyev, N.O. J. Biol. Chem. (1998) [Pubmed]
  2. Increased cGMP phosphodiesterase activity mediates renal resistance to ANP in rats with bile duct ligation. Ni, X.P., Safai, M., Gardner, D.G., Humphreys, M.H. Kidney Int. (2001) [Pubmed]
  3. Ectopic expression of bovine type 5 phosphodiesterase confers a renal phenotype in Drosophila. Broderick, K.E., Kean, L., Dow, J.A., Pyne, N.J., Davies, S.A. J. Biol. Chem. (2004) [Pubmed]
  4. The GAFa domains of rod cGMP-phosphodiesterase 6 determine the selectivity of the enzyme dimerization. Muradov, K.G., Boyd, K.K., Martinez, S.E., Beavo, J.A., Artemyev, N.O. J. Biol. Chem. (2003) [Pubmed]
  5. Expression of an active, monomeric catalytic domain of the cGMP-binding cGMP-specific phosphodiesterase (PDE5). Fink, T.L., Francis, S.H., Beasley, A., Grimes, K.A., Corbin, J.D. J. Biol. Chem. (1999) [Pubmed]
  6. Studies of the molecular mechanism of discrimination between cGMP and cAMP in the allosteric sites of the cGMP-binding cGMP-specific phosphodiesterase (PDE5). Turko, I.V., Francis, S.H., Corbin, J.D. J. Biol. Chem. (1999) [Pubmed]
  7. Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. Turko, I.V., Francis, S.H., Corbin, J.D. Biochem. J. (1998) [Pubmed]
  8. Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. Turko, I.V., Ballard, S.A., Francis, S.H., Corbin, J.D. Mol. Pharmacol. (1999) [Pubmed]
  9. cGMP-dependent protein kinase protects cGMP from hydrolysis by phosphodiesterase-5. Kotera, J., Grimes, K.A., Corbin, J.D., Francis, S.H. Biochem. J. (2003) [Pubmed]
  10. cAMP-dependent induction of PDE5 expression in murine neuroblastoma cell differentiation. Giordano, D., Giorgi, M., Sette, C., Biagioni, S., Augusti-Tocco, G. FEBS Lett. (1999) [Pubmed]
  11. Altered expression of cyclic nucleotide phosphodiesterase isozymes during culture of aortic endothelial cells. Ashikaga, T., Strada, S.J., Thompson, W.J. Biochem. Pharmacol. (1997) [Pubmed]
  12. Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Corbin, J.D., Turko, I.V., Beasley, A., Francis, S.H. Eur. J. Biochem. (2000) [Pubmed]
  13. Antimitogenic actions of organic nitrates are potentiated by sildenafil and mediated via activation of protein kinase A. Osinski, M.T., Rauch, B.H., Schrör, K. Mol. Pharmacol. (2001) [Pubmed]
  14. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues. Daugan, A., Grondin, P., Ruault, C., Le Monnier de Gouville, A.C., Coste, H., Linget, J.M., Kirilovsky, J., Hyafil, F., Labaudinière, R. J. Med. Chem. (2003) [Pubmed]
  15. Activation of phosphodiesterase 5 and inhibition of guanylate cyclase by cGMP-dependent protein kinase in smooth muscle. Murthy, K.S. Biochem. J. (2001) [Pubmed]
  16. A photoaffinity probe covalently modifies the catalytic site of the cGMP-binding cGMP-specific phosphodiesterase (PDE-5). Corbin, J.D., Beasley, A., Turko, I.V., Haik, T.L., Mangum, K.A., Wells, J.N., Francis, S.H., Sekhar, K.R. Cell Biochem. Biophys. (1998) [Pubmed]
 
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