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Technically, 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 technically 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 remainder of this article discusses the cyclic nucleotide phosphodiesterases:
The cyclic nucleotide phosphodiesterases (PDE) 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 initially isolated from rat brain by Uzunov and Weiss in 1972 and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues.
The potential for selective phosphodisterase inhibitors to be used as therapeutic agents was predicted as early as 1977 by Weiss and Hait. This prediction has now come to pass in a variety of fields.
Classification and nomenclature
The PDE superfamily of enzymes are 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
PDE3 is sometimes referred to as cGMP inhibited phosphodiesterase.
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)
PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural and functional properties. 
- 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.
- Weiss, B.: Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase. Adv. Cycl. Nucl. Res. 5:195-211, 1975.
- Fertel, R. and Weiss, B.: Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung. Mol. Pharmacol. 12:678-687, 1976.
- Weiss, B. and Hait, W.N.: Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents. Ann. Rev. Pharmacol. Toxicol. 17:441-477, 1977.
- Conti M. (2000) Phosphodiesterases and Cyclic Nucleotide Signaling in Endocrine Cells Molecular Endocrinology 14 (9): 1317-1327.
- Jeon Y, Heo Y, Kim C, Hyun Y, Lee T, Ro S, Cho J (2005). Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development. Cell Mol Life Sci 62 (11): 1198-220.
Hydrolase: esterases (EC 3.1)
|3.1.1: Carboxylic ester hydrolases||
Cholinesterase - Pectinesterase - 6-phosphogluconolactonase - PAF acetylhydrolase
Lipase (Gastric/Lingual, Pancreatic, Lysosomal, Hormone-sensitive, Endothelial, Hepatic, Lipoprotein, Monoacylglycerol, Diacylglycerol)
Phospholipase (A1, A2, B)
Palmitoyl thioesterase - Ubiquitin carboxy-terminal hydrolase L1
Alkaline phosphatase - Acid phosphatase (Prostatic)/Tartrate resistant acid phosphatase/Purple acid phosphatases - Nucleotidase - Glucose 6-phosphatase - Fructose 1,6-bisphosphatase -
Calcineurin - Phosphoprotein phosphatase (PP2A) - OCRL - Pyruvate dehydrogenase phosphatase - Fructose 2,6-bisphosphatase - Protein tyrosine phosphatase - PTEN
Autotaxin - Phospholipase (C, D) - Sphingomyelin phosphodiesterase - PDE1 - PDE2 - PDE3 - PDE5
Arylsulfatase B - Steroid sulfatase - Galactosamine-6 sulfatase - Arylsulfatase A - Iduronate-2-sulfatase - N-acetylglucosamine-6-sulfatase
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