Phosphodiesterase enzyme system

Another receptor-enzyme system was elucidated, which forms a guanylate cyclase. This enzyme converts GTP to cGMP upon receptor binding on the outer surface. The resulting cGMP activates either a protein kinase or a phosphodiesterase. 

Relaxation of smooth mnscles is controlled by the concentration of cyclic GMP in the muscle. This is regulated by the activities of the enzyme that forms cyclic GMP (i.e. gnanyl cyclase) and the enzyme that degrades cyclic GMP, that is, cyclic GMP phosphodiesterase (see Box 12.2). This is analogons to the enzyme system that regulates the concentration of cyclic AMP, by the activities of adenyl cyclase and phosphodiesterase ... 

Plenty of biological activities have been attributed to derivatives of ring systems 1-50 in the patent and published literature. New substituted pyrazolo[4,3- pyrimidines have been synthesized and claimed to be useful for treatment of male erectile dysfunction due to the inhibitory action they exerted on phosphodiesterase enzymes <1998EPP995750, 2000USP6066722>. Diverse biological activities have been attributed to pyrazolo[3,4-, pyrimidines... 

The regulatory role of calcium ions in intermediary metabolism is well documented. Calcium has been shown to be involved in activation or inhibition of specific enzyme systems [105], For example, it activates cyclic nucleotide phosphodiesterase, phosphofructokinase, fructose 1 6 biphosphatase, glycerol phosphate dehydrogenase, pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase. Calcium ions inhibit pyruvate kinase, pyruvate carboxylase, Na+/K+-AT-Pase and adenylate cyclase. 

The degradation of cyclic AMP is catalyzed by a specific phosphodiesterase which converts it to adenylic acid " (Figure l). Again, the effect of nucleotide analogues or other potential inhibitors on the degradation of cyclic AMP can be studied vitro in this enzyme system, and the possible significance of such agents will be discussed below. 

Analogues of cyclic AMP per se may also be worthy of investigation in view of the fact that a specific enzyme synthesizes this compound. The enzyme may be localized selectively in various tissues and a specific cyclic phosphodiesterase inactivates the substance by forming 5 -AMP. Thus, enzyme systems in which the medicinal chemist can evaluate compounds in a direct manner for their ability to act in place of cyclic AMP or inhibit its action or degradation... 

The phosphopantetheine prosthetic group of ACP, fatty acid synthetase complexes, and presumably other enzyme systems, turn over rapidly, possibly as part of a cellular control mechanism. A specific phosphodiesterase cleaves holo-ACP to 4 -phosphopantetheine and the apoprotein ... 

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

Another important group of hydrolytic enzymes are phospho- and cyclophosphodiesterases. They catalyze the hydrolysis of phospho-diester bonds and many of the most relevant biological substrates are nucleic acids. Phospholipase C and D are also important examples. Initial attempts to measure phosphodiesterase activity placed a phosphodiester between a fluorophore and a quencher and the probe was tested in vitro [146], This system was slightly modified by Caturla and used for the identification of catalysts with phosphodiesterase activity [147], More recently, Nagano and co-workers used a coumarin donor and fluorescein as a FRET... 

Action on the CNS depends directly on the dose of administered drug, and can be manifested as fatigue, anxiety, tremors, and even convulsions in relatively high doses. Theophylline acts on the cardiovascular system by displaying positive ionotropic and chronotropic effects on the heart, which, can likely be linked to the elevated influx of calcium ions by modulated cyclic adenosine monophosphate and its action on specific cardiac phosphodiesterases. In the gastrointestinal system, methylxanthines simultaneously stimulate secretion of both gastric juice and digestive enzymes. 

When the systemic need has been satisfied there should be a way of reversing the hormone triggered process. All of the effects we have seen are promptly reversed when the need for them has ended. Cyclic AMP is hydrolyzed to 5 -AMP by an enzyme called cyclic AMP phosphodiesterase, and protein phosphatases catalyze the hydrolytic re-... 

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