Phosphodiesterases and

FIGURE 11.31 Snake venom phosphodiesterase and spleen phosphodiesterase are exonncleases that degrade polynncleotides from opposite ends. 

Synthesized by soluble guanylyl cyclase and particulate guanylyl cyclase from guanosine triphosphate (GTP). Nitric oxide activates soluble guanylyl cyclase to enhance cyclic GMP production that contributes to various NO actions. Cyclic GMP is hydrolyzed by phosphodiesterases. Cyclic GMP binds to and activates cGMP-dependent protein kinase, phosphodiesterases, and Cyclic Nucleotide-regulated Cation Channels. 

Soderling SH, Beavo JA (2000) Regulation of cAMP and cGMP signaling new phosphodiesterases and new functions. Curr Opin Cell Biol 12 174—179... 

Effects on Ena e Activities. MTX at concentrations up to 10" g/mL had no effect on the enzymes related to the possible mechanism of cardioexcitatory action, such as cardiac Na ,K - ATPase, cyclic AMP phosphodiesterase, and sarcoplasmic reticulum Ca -ATPase. 

MTX caused a contraction of vascular smooth muscle and positive inotropic, positive chronotropic and arrhythmogenic effects on cardiac muscle. The effect of MTX was little affected by various receptor blockers, a Na channel blocker or a catecholamine depleting agent. Further, MTX had no effect on the enzymes which were related to Ca movements, such as Na , K -ATPase, cyclic AMP phosphodiesterase, and sarcoplasmic reticulum Ca -ATPase. These results would eliminate the possible involvement of an indirect action elicited by the release of chemical mediators and direct modifications of their receptors, Na channels, or various enzymes as a major mechanism of action of MTX. 

Theophylline is also considered an alternative to inhaled corticosteroids for the treatment of mild persistent asthma however, limited efficacy compared to inhaled corticosteroids, a narrow therapeutic index with life-threatening toxicity, and multiple clinically important drug interactions have severely limited its use. Theophylline causes bronchodilation through inhibition of phosphodiesterase and antagonism of adenosine and appears to have anti-inflammatory and immunomodulatory properties as well.36... 

Caturla, F., Enjo, J., Bemabeu, M. C. and Le Serre, S. (2004). New fluorescent probes for testing combinatorial catalysts with phosphodiesterase and esterase activities. Tetrahedron 60, 1903-1911. 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

A further characteristic of this principle is that, if the activity of phosphodiesterase is decreased, the concentration of cyclic GMP will increase to an extent dependent upon the extent of the decrease in activity. This characteristic has been made use of by the pharmaceutical industry. Cyclic GMP has a vasodilatory effect and this is the case for the arterioles that supply blood to the corpus cavemosum in the penis, which controls the erection of the penis. Drugs were developed (e.g. sildenafil) that inhibits cyclic GMP phosphodiesterase and hence increases the cyclic GMP level which resnlts in vasodilation of the arterioles and an increase in the snpply of blood to the spongy tissue of the corpus cavemosum, which expands resulting in erection. This dmg has been found to be effective in some patients snffering from erectile dysfunction. This can be a particular problem in diabetic patients and more elderly men (Chapter 19). 

Figure 14.13 The kinetic sequence of reactions that control the cyclic AMP concentration, and its binding to the effector system, and the kinetic sequence that controls the concentration of a neurotransmitter and its binding to the receptor on the postsyn-aptic membrane. Processes (1) are reactions catalysed by adenyl cyclase, and exocytosis. Reactions (2) are catalysed by phosphodiesterase and, for example, acetylcholinesterase. Reactions (3) are the interactions between the messenger and the effector system both the latter are equilibrium binding processes. (See Chapter 12 (p. 266) for discussions of equilibrium binding.)...

Mata R, Gamboa A, Macias M, Santillan S, UUoa M, Gonzalez MC, Effect of selected phytotoxic agents from Guanomyces polythrix on the calmodulin-dependent activity of the enzymes cAMP phosphodiesterase and NAD-kinase, JAgricFood Chem 51 4559 562, 2003. 

A naturally occurring substance (1,3,7-trimethytxan-thine) that competitively inhibits 3, 5 -cyclic AMP phosphodiesterase and acts as a powerful central nervous system stimulant. The inhibitory effect can be reversed at high cAMP concentrations. A related substance, theophylline (also known as aminophylhne) has a similar mode of action. 

This enzyme [EC 3.1.4.10], also known as monophospha-tidyhnositol phosphodiesterase and phosphatidylinositol... 

Venom exonuclease [EC 3.1.15.1], also known as venom phosphodiesterase, catalyzes the exonucleolytic cleavage of RNA or DNA (preferring single-stranded substrates) in the 3 to 5 direction to yield 5 -phosphomononucleo-tides. Similar enzymes include hog kidney phosphodiesterase and the Lactobacillus exonuclease. See also specific phosphodiesterase J. A. Gerit (1992) The Enzymes, 3rd ed., 20, 95. 

Several methyixanthines produced by plants are inhibitors of cyclic AMP phosphodiesterase and thereby produce an elevation in cyclic AMP levels in cells throughout the body. 

C. Aspirin inhibits platelet cyclooxygenase. Abciximab, a monoclonal antibody, binds to and inhibits the platelet glycoprotein Ilb/IIIa receptor. Dipyridamole inhibits platelet cyclic AMP phosphodiesterase and raises cyclic AMP levels. Eptifibatide binds to the glycoprotein Ilb/IIIa complex. 

The determinants of calcium sensitivity, ie, the curve relating the shortening of cardiac myofibrils to the cytoplasmic calcium concentration, are incompletely understood, but several types of drugs can be shown to affect calcium sensitivity in vitro. Levosimendan is the most recent example of a drug that increases calcium sensitivity (it may also inhibit phosphodiesterase) and reduces symptoms in models of heart failure. 

The methylxanthines have positive chronotropic and inotropic effects. At low concentrations, these effects appear to result from inhibition of presynaptic adenosine receptors in sympathetic nerves increasing catecholamine release at nerve endings. The higher concentrations (more than 10 i mol/L, 2 mg/L) associated with inhibition of phosphodiesterase and increases in cAMP may result in increased influx of calcium. At much higher concentrations (more than 100 mol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired. 

Mehats, C., Andersen, . B., Filopanti, M., Jin, S. L. C., Conti, M. (2002) Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling. Trends Endocrinol Metab 13(1), 29-35. 

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