Phosphodiesterase

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 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.

History

These multiple forms (isoforms or subtypes) of phosphodiesterase were isolated from rat brain using polyacrylamide gel electrophoresis in the early 1970s [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.] [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.] and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues. [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.]

The potential for selective phosphodiesterase inhibitors to be used as therapeutic agents was predicted as early as 1977 by Weiss and Hait. [Weiss, B. and Hait, W.N.: Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents. Ann. Rev. Pharmacol. Toxicol. 17:441-477, 1977.] 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 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.] . 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 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) [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.]

Clinical significance

PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. [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]

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, 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.

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