Phosphoric diester hydrolase

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases (which all break the phosphodiester backbone of DNA or RNA), as well as numerous less-well-characterized small-molecule phosphodiesterases. A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases (which all break the phosphodiester backbone of DNA or RNA), as well as numerous less-well-characterized small-molecule phosphodiesterases. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules. These multiple forms (isoforms or subtypes) of phosphodiesterase were isolated from rat brain using polyacrylamide gel electrophoresis in the early 1970s, and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues. The potential for selective phosphodiesterase inhibitors to be used as therapeutic agents was predicted in the 1970s. This prediction has now come to pass in a variety of fields (e.g. sildenafil as a PDE5 inhibitor and Rolipram as a PDE4 inhibitor). The PDE nomenclature signifies the PDE family with an Arabic numeral, then a capital letter denotes the gene in that family, and a second and final Arabic numeral then indicates the splice variant derived from a single gene (e.g., PDE1C3: family 1, gene C, splicing variant 3). The superfamily of PDE enzymes is classified into 12 families, namely PDE1-PDE12 , in mammals. The classification is based on: Different PDEs of the same family are functionally related despite the fact that their amino acid sequences can show considerable divergence. PDEs have different substrate specificities. Some are cAMP-selective hydrolases (PDE4, 7 and 8); others are cGMP-selective (PDE5, 6, and 9). Others can hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10, and 11). PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase. Although PDE2 can hydrolyze both cyclic nucleotides, binding of cGMP to the regulatory GAF-B domain will increase cAMP affinity and hydrolysis to the detriment of cGMP. This mechanism, as well as others, allows for cross-regulation of the cAMP and cGMP pathways. PDE12 cleaves cAMP and oligoadenylates. Phosphodiesterase enzymes have been shown to be different in different types of cells, including normal and leukemic lymphocytes and are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors of PDE can prolong or enhance the effects of physiological processes mediated by cAMP or cGMP by inhibition of their degradation by PDE.