Sandbox Reserved 957: Difference between revisions
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Sekiguchi M, Hoshizaki H, Adachi H, Ohshima S, Taniguchi K, Kurabayashi M. Effects of antiplatelet agents on subacute thrombosis and restenosis after successful coronary stenting: a randomized comparison of ticlopidine and cilostazol. Circ J 68: 610–614, 2004. | Sekiguchi M, Hoshizaki H, Adachi H, Ohshima S, Taniguchi K, Kurabayashi M. Effects of antiplatelet agents on subacute thrombosis and restenosis after successful coronary stenting: a randomized comparison of ticlopidine and cilostazol. Circ J 68: 610–614, 2004. | ||
Sopory S, Kaur T, Visweswariah SS. The cGMP-binding, cGMPspecific phosphodiesterase (PDE5): intestinal cell expression, regulation and role in fluid secretion. Cell Signal 16: 681–692, 2004.<br \> | Sopory S, Kaur T, Visweswariah SS. The cGMP-binding, cGMPspecific phosphodiesterase (PDE5): intestinal cell expression, regulation and role in fluid secretion. Cell Signal 16: 681–692, 2004.<br \> | ||
Zhu B, Strada S, Stevens T. Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 289: L196–L206, 2005.<br \></ref> and platelets and Corpus Cavernosum. In particular, it is implied in the NO pathway of penile erection and so in the Erectile Dysfunction (ED) <ref> | Zhu B, Strada S, Stevens T. Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 289: L196–L206, 2005.<br \></ref> and platelets and Corpus Cavernosum. In particular, it is implied in the NO pathway of penile erection and so in the Erectile Dysfunction (ED) <ref>JD Corbin, Mechanisms of action of PDE5 inhibition in erectile dysfunction, International Journal of Impotence Research (2004) 16, S4–S7</ref>.<br \> | ||
There are 11 families of PDE (from 1 to 9), there is 21 genes for PDE which code 60 different PDE. For the PDE5A, the only PDE5 subcategory, there are 4 isoforms but their catalytic domain is the same <ref>Byung-Je Sung, Kwang Yeon Hwang, Young Ho Jeon, Jae Il Lee, Yong-Seok Heo, Jin Hwan Kim, Jinho Moon, Jung Min Yoon, Young-Lan Hyun, Eunmi Kim, Sung Jin Eum, Sam-Yong Park, Jie-Oh Lee, Tae Gyu Lee, Seonggu Ro & Joong Myung Cho, Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules, NATURE, VOL 425, 4 SEPTEMBER 2003</ref>.<br \> | There are 11 families of PDE (from 1 to 9), there is 21 genes for PDE which code 60 different PDE. For the PDE5A, the only PDE5 subcategory, there are 4 isoforms but their catalytic domain is the same <ref>Byung-Je Sung, Kwang Yeon Hwang, Young Ho Jeon, Jae Il Lee, Yong-Seok Heo, Jin Hwan Kim, Jinho Moon, Jung Min Yoon, Young-Lan Hyun, Eunmi Kim, Sung Jin Eum, Sam-Yong Park, Jie-Oh Lee, Tae Gyu Lee, Seonggu Ro & Joong Myung Cho, Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules, NATURE, VOL 425, 4 SEPTEMBER 2003</ref>.<br \> | ||
The catalytic reaction is the hydrolysis of guanosine cyclic monophosphate into linear guanosine monophosphate. This cGMP-specific enzyme have 3 domains (from N terminal to C terminal) : GAF A, GAF B and a conserved catalytic domain regard to other PDEs of the family. Only cGMP can bind GAF A or GAF B and it stimulates the hydrolysis.<br \> | The catalytic reaction is the hydrolysis of guanosine cyclic monophosphate into linear guanosine monophosphate. This cGMP-specific enzyme have 3 domains (from N terminal to C terminal) : GAF A, GAF B and a conserved catalytic domain regard to other PDEs of the family. Only cGMP can bind GAF A or GAF B and it stimulates the hydrolysis.<br \> | ||
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As it is written over, there are 2 regulatory domains (GAF A and GAF B). In cGMP pathway, PDE5 allows a negative feedback of the molecule: first, in presence of cGMP, it binds GAF A which stimulates the catalysis in the active site, and vice versa. Moreover, cGMP actives PKG which phophorylates PDE5, that is stimulated by the presence of cGMP on the GAF A or/and the active site. If the protein is not binding with cGMP but it is phophorylated, that stimulates the binding of cGMP on GAF A and the catalytic site. So cGMP presence overstimulates the catalysis <ref>Okada D, Asakawa S. Allosteric activation of cGMP-specific, cGMP-binding phosphodiesterase (PDE5) by cGMP. Biochemistry 41: 9672–9679, 2002 | As it is written over, there are 2 regulatory domains (GAF A and GAF B). In cGMP pathway, PDE5 allows a negative feedback of the molecule: first, in presence of cGMP, it binds GAF A which stimulates the catalysis in the active site, and vice versa. Moreover, cGMP actives PKG which phophorylates PDE5, that is stimulated by the presence of cGMP on the GAF A or/and the active site. If the protein is not binding with cGMP but it is phophorylated, that stimulates the binding of cGMP on GAF A and the catalytic site. So cGMP presence overstimulates the catalysis <ref>Okada D, Asakawa S. Allosteric activation of cGMP-specific, cGMP-binding phosphodiesterase (PDE5) by cGMP. Biochemistry 41: 9672–9679, 2002 | ||
Weber G. Energetics of ligand binding to protein. Adv Protein Chem 29: 1–83, 1975. | Weber G. Energetics of ligand binding to protein. Adv Protein Chem 29: 1–83, 1975. | ||
Bessay EP, Blount MA, Zoraghi R, Beasley A, Grimes KA, Francis SH, Corbin JD. Phosphorylation increases affinity of the phosphodiesterase-5 catalytic site for tadalafil. J Pharmacol Exp Ther 325: 62–68, 2008.</ref>. And it also increase inhibitor's affinity<ref>Bessay EP, Zoraghi R, Blount MA, Grimes KA, Beasley A, Francis SH, Corbin JD. Phosphorylation of phosphodiesterase-5 is promoted by a conformational change induced by sildenafil, vardenafil, or tadalafil. Front Biosci 12: 1899–1910, 2007.</ref> and without cGMP, inhibitor don’t bind the PDE5 <ref> | Bessay EP, Blount MA, Zoraghi R, Beasley A, Grimes KA, Francis SH, Corbin JD. Phosphorylation increases affinity of the phosphodiesterase-5 catalytic site for tadalafil. J Pharmacol Exp Ther 325: 62–68, 2008.</ref>. And it also increase inhibitor's affinity<ref>Bessay EP, Zoraghi R, Blount MA, Grimes KA, Beasley A, Francis SH, Corbin JD. Phosphorylation of phosphodiesterase-5 is promoted by a conformational change induced by sildenafil, vardenafil, or tadalafil. Front Biosci 12: 1899–1910, 2007.</ref> and without cGMP, inhibitor don’t bind the PDE5 <ref>JD Corbin, Mechanisms of action of PDE5 inhibition in erectile dysfunction, International Journal of Impotence Research (2004) 16, S4–S7</ref>.<br \> | ||
== The NO Pathway == | == The NO Pathway == | ||