Phosphodiesterase definition

An important observation linking Ca + to hormone action involved the definition of the intracellular targets of Ca action. The discovery of a Ca -dependent regulator of phosphodiesterase activity provided the basis for a broad understanding of how Ca and cAMP interact within cells. 

Phosphatases are numerous and important enzymes (see also Chapt. 2). They are classified as phosphoric monoester hydrolases (phosphatases, EC 3.1.3), phosphoric diester hydrolases (phosphodiesterases, EC 3.1.4), triphosphoric monoester hydrolases (EC 3.1.5), diphosphoric monoester hydrolases (pyrophosphatases, EC 3.1.7), and phosphoric triester hydrolases (EC 3.1.8) [21] [63]. Most of these enzymes have a narrow substrate specificity restricted to endogenous compounds. However, some of these enzymes are active toward xenobiotic organophosphorus compounds, e.g., alkaline phosphatase (EC 3.1.3.1), acid phosphatase (EC 3.1.3.2), aryldialkylphosphatase (para-oxonase (PON1), EC 3.1.8.1) and diisopropyl-fluorophosphatase (tabunase, somanase, EC 3.1.8.2) [64 - 70]. However, such a classification is far from definitive and will evolve with further biochemical findings. Thus, a good correlation has been found in human blood samples between somanase and sarinase activities on the one hand, and paraoxonase (PON1) type Q isozyme concentrations on the other [71]. 

The above-described data show that CRF added to cells of the rat Intermediate lobe In culture causes a rapid stimulation of oe-MSH release and cyclic AMP accumulation, thus demonstrating a direct action of the peptide on pars intermedia cells (15). It is however difficult, using intact cells, to dissociate between increases in cyclic AMP levels due to stimulation of adenylate cyclase activity or to Inhibition of cyclic nucleotide phosphodiesterase or to a combination of both effects. Definitive proof of the role of adenylate cyclase In the action of CRF In the intermediate lobe of the pituitary gland is provided by the following findings of a CRF-lnduced stimulation of adenylate cyclase activity in homogenate of rat and bovine pars Intermedia cells. 

Milrinone is an inhibitor of phosphodiesterase type III. Although the long-term oral use of such inhibitors is associated with an increase in mortality (SEDA-17, 217), milrinone has been used intravenously in patients with heart failure, both for short-term and longer-term therapy (SEDA-21, 196) (SEDA-22, 203) (SEDA-23, 109). It has been suggested to be particularly useful in tiding patients over while they are waiting for definitive treatment. 

As in the case of adenylate cyclase, the application of chiral phosphate and thiophosphate analysis techniques has yielded the most definitive evidence on the enzymic mechanism of cAMP phosphodiesterase. Eckstein and coworkers were able to determine the stereochemistry of the reaction of cAMP phosphodiesterase from beef heart using the phosphorothioate cAMP(S) substrate (Burgers et al., 1979b). This approach had been made possible by the development of the diastereomers of cAMP(S) by Stec (Baraniak et al., 1979). Phosphodiesterase-catalysed hydrolysis was carried... 

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