Phosphodiesterase enzyme families

Several mechanisms have been proposed for the actions of methylxanthines, but none has been firmly established. At high concentrations, they can be shown in vitro to inhibit several members of the phosphodiesterase (PDE) enzyme family (Figure 20-3). Because the phosphodiesterases hydrolyze cyclic nucleotides, this inhibition results in higher concentrations of intracellular cyclic AMP (cAMP) and, in some tissues, cGMP. CAMP is responsible for a myriad of cellular functions including, but not limited to, stimulation of cardiac function, relaxation of smooth muscle, and reduction in the immune and inflammatory activity of specific cells. 

The predominant phosphodiesterase isozyme class in inflammatory cells is composed of the enzymes that belong to the phosphodiesterase IV family (Torphy and Undem 1991). This group of enzymes has a marked preference for cyclic AMP (JC = 3-10 iM) as a substrate and demonstrates httle if any catalytic activity against cyclic GMP. Furthermore, this enzymes are selectively inhibited by compounds such as rolipram and Ro 20-1724 (Torphy and Undem 1991, Giembycz 1992). 

Metabolism. The nucleotide cAMP (adenosine 3, 5 -cyclic monophosphate) is synthesized by membrane-bound adenylate cyclases [1] on the inside of the plasma membrane. The adenylate cyclases are a family of enzymes that cyclize ATP to cAMP by cleaving diphosphate (PPi). The degradation of cAMP to AMP is catalyzed by phosphodiesterases [2], which are inhibited by methylxanthines such as caffeine, for example. By contrast, insulin activates the esterase and thereby reduces the cAMP level (see p. 388). 

Hydrolysis of cAMP cAMP is rapidly hydrolyzed to 5-AMP by cAMP phosphodiesterase, one of a family of enzymes that cleave the cyclic 3 5 -phosphodiester bond. 5-AMP is not an intracellular signalling molecule. Thus, the effects of neurotransmitter- or hormone-mediated increases of cAMP are rapidly terminated if the extracellular signal is removed. [Note Phosphodiesterase is inhibited by methylxanthine derivatives, such as theophylline and caffeine.3]... 

No, there are no NO membrane receptors, in striking contrast to classical neurotransmitters, which have numerous types and subtypes of membrane receptors on neurons. Rather, the target of NO is iron in the active site of GC (Fig. 14—4). Once NO binds to the iron, GC is activated and cGMP is formed. The action of cGMP is terminated by a family of enzymes known as phosphodiesterases (PDEs), of which there are several forms, depending on the tissue (Fig. 14—3). 

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPPl), also known as plasma cell membrane glycoprotein 1 (PC-1), is a member of the NPP family of transmembrane enzymes that catalyzes the hydrolysis of extracellular nucleotides. Different family members demonstrate preference for distinct substrates, but share ability to hydrolyze phosphodiester and pyrophosphatase bonds [1]. ENPPl appears to have preference for ATP, but also demonstrates pyrophosphatase and phosphodiesterase activities toward pyrophosphate and ADP [1, 2],... 

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