Phosphodiesterase 239462 225712711 2008-07-15T01:08:37Z Benjamin Weiss 2406249 /* History */ [[Image:CGMP.png|thumb|[[Cyclic guanosine monophosphate|cGMP]]]] [[Image:CAMP.svg|thumb|[[cyclic adenosine monophosphate|cAMP]]]] A phosphodiesterase is any [[enzyme]] that breaks a [[phosphodiester bond]]. Usually, people speaking of ''phosphodiesterase'' are referring to [[cyclic nucleotide]] phosphodiesterases, which have great clinical significance and are described below. However, many other enzyme families are, in the technical sense, phosphodiesterases, including [[phospholipase]]s [[phospholipase C|C]] and [[phospholipase D|D]], [[autotaxin]], [[sphingomyelin phosphodiesterase]], [[DNAse]]s, [[RNAse]]s, and [[restriction endonuclease]]s (which all break the phosphodiester backbone of [[DNA]] or [[RNA]]), as well as numerous less-well-characterized small-molecule phosphodiesterases. '''The remainder of this article discusses the cyclic nucleotide phosphodiesterases:''' The '''cyclic nucleotide phosphodiesterase'''s (PDE) comprise a group of [[enzymes]] that degrade the [[phosphodiester bond]] in the [[second messenger]] molecules [[cyclic adenosine monophosphate|cAMP]] and [[Cyclic guanosine monophosphate|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. ==History== These multiple forms (isoforms or subtypes) of phosphodiesterase were isolated from rat brain using polyacrylamide gel electrophoresis in the early 1970s<ref>Uzunov, P. and Weiss, B.: Separation of multiple molecular forms of cyclic adenosine 3',5'-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis. Biochim. Biophys. Acta 284:220-226, 1972.</ref><ref>Strada, S.J., Uzunov, P. and Weiss, B.: Ontogenetic development of a phosphodiesterase activator and the multiple forms of cyclic AMP phosphodiesterase of rat brain. J. Neurochem. 23:1097-1103, 1974.</ref> and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues.<ref> Weiss, B.: Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase. Adv. Cycl. Nucl. Res. 5:195-211, 1975.</ref><ref>Fertel, R. and Weiss, B.: Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung. Mol. Pharmacol. 12:678-687, 1976.</ref> The potential for selective phosphodiesterase inhibitors to be used as therapeutic agents was predicted as early as 1977 by Weiss and Hait.<ref>Weiss, B. and Hait, W.N.: Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents. Ann. Rev. Pharmacol. Toxicol. 17:441-477, 1977.</ref> This prediction has now come to pass in a variety of fields. ==Classification and nomenclature== The PDE superfamily of enzymes is classified into 11 families, namely [[PDE1]]-PDE11, in [[mammals]]. The classification is based on: * [[amino acid]] sequences * substrate specificities * regulatory properties * pharmacological properties * tissue distribution. Different PDEs of the same family are functionally related despite the fact that their amino acid sequences can show considerable divergence <ref name=Iffland_2005>{{cite news|author=Iffland, A et al|title=Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system|date=2005|publisher=Biochemistry. 44(23): p. 8312-25.}}</ref>. PDEs have different substrate specificities. Some are cAMP selective hydrolases (PDE 4, -7 and -8), others are cGMP selective(PDE 5, -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 other, allows for cross-regulation of the cAMP and cGMP pathways. The nomenclature for PDE indicates ''PDE family'' by an Arabic numeral that is followed by a capital letter to denote the ''gene within a family''. A second Arabic numeral indicates the ''splice variant'' derived from a single gene (e.g., PDE1C3: family 1, gene C, splicing variant 3)<ref>Conti M. (2000) [http://mend.endojournals.org/cgi/content/full/14/9/1317 ''Phosphodiesterases and Cyclic Nucleotide Signaling in Endocrine Cells''] Molecular Endocrinology 14 (9): 1317-1327.</ref> ==Clinical significance== PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. <ref>{{cite journal |author=Jeon Y, Heo Y, Kim C, Hyun Y, Lee T, Ro S, Cho J |title=Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development |journal=Cell Mol Life Sci |volume=62 |issue=11 |pages=1198–220 |year=2005 |pmid=15798894 |doi=10.1007/s00018-005-4533-5}}</ref> [[Phosphodiesterase inhibitor|Inhibitors of PDE]] can prolong or enhance the effects of physiological processes mediated by [[cAMP]] or [[cGMP]] by inhibition of their degradation by PDE. Sildenafil ([[Viagra]]) is an inhibitor of [[cGMP-specific phosphodiesterase type 5]], which enhances the vasodilatory effects of cGMP in the [[corpus cavernosum]] and is used to treat [[erectile dysfunction]]. PDE inhibitors have been identified as new potential therapeutics in areas such as pulmonary arterial [[hypertension]], [[coronary heart disease]], [[dementia]], [[depression (mood)|depression]], and [[schizophrenia]]. Cilostazol ([[Pletal]]) inhibits [[PDE3]]. This inhibition allows [[Red Blood Cells]] to be more able to bend. This is useful in conditions such as [[intermittent claudication]], as the cells can maneuver through constricted veins and arteries more easily. ==References== {{Reflist|2}} ==External links== * {{MeshName|Phosphoric+Diester+Hydrolases}} {{Esterases}} [[Category:EC 3.1.4]] [[Category:Molecular biology]] [[de:Phosphodiesterase]] [[fr:Phosphodiestérase]] [[ja:ホスホジエステラーゼ]] [[ru:Фосфодиэстераза]] [[zh:磷酸二酯酶]]