Phosphodiesterase

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A phosphodiesterase (PDE) 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, 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.

History[edit]

These multiple forms (isoforms or subtypes) of phosphodiesterase were isolated from rat brain using polyacrylamide gel electrophoresis in the early 1970s[1][2] and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues.[3][4]

The potential for selective phosphodiesterase inhibitors to be used as therapeutic agents was predicted as early as 1977 by Weiss and Hait.[5] This prediction has now come to pass in a variety of fields (e.g. Viagra as a PDE5 inhibitor and Rolipram as a PDE4 inhibitor ).

Nomenclature and classification[edit]

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)[6]

The superfamily of PDE enzymes is classified into 11 families, namely PDE1-PDE11, in mammals. The classification is based on:

PDE substrate specificities by enzyme family. Both means it hydrolyzes both cAMP and cGMP.
  • 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.[7] 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.

Clinical significance[edit]

Phosphodiesterase enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties.[8]

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. Sildenafil is also currently being investigated for its myo- and cardioprotective effects, with particular interest being given to the compound's therapeutic value in the treatment of Duchenne muscular dystrophy [9] and benign prostatic hyperplasia.[10]

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.

Xanthines such as caffeine and theobromine as well as thyroid hormone are phosphodiesterase inhibitors (enhance lipolysis as inhibition of phosphodiesterase enzyme, thereby preserving cAMP, also activating kinase enzyme, which phosphorylates hormone-sensitive lipase and activates lipolysis). However, the inhibitory effect of xanthines on phosphodiesterase are only seen at dosages higher than what people normally consume. Moderate chocolate intake decreases heart disease and diabetes, but consuming 1 oz of chocolate more than 2-4 times a week will increase these. [11] [12]

References[edit]

  1. ^ 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.
  2. ^ 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.
  3. ^ Weiss, B.: Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase. Adv. Cycl. Nucl. Res. 5:195-211, 1975.
  4. ^ Fertel, R. and Weiss, B.: Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung. Mol. Pharmacol. 12:678-687, 1976.
  5. ^ Weiss, B. and Hait, W.N.: Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents. Ann. Rev. Pharmacol. Toxicol. 17:441-477, 1977.
  6. ^ Conti M. (2000) Phosphodiesterases and Cyclic Nucleotide Signaling in Endocrine Cells Molecular Endocrinology 14 (9): 1317-1327.
  7. ^ Iffland, A et al. (2005). "Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system". Biochemistry. 44(23): p. 8312-25. 
  8. ^ 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. doi:10.1007/s00018-005-4533-5. PMID 15798894. 
  9. ^ Khairallah M, Khairallah RJ, Young ME, et al. (2008). "Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency". Proc. Nat. Acad. Sci. U.S.A. 105 (19): 7028–33. doi:10.1073/pnas.0710595105. PMC 2383977. PMID 18474859. 
  10. ^ Wang C. (2010). "Phosphodiesterase-5 inhibitors and benign prostatic hyperplasia". Current Opinion in Urology 20 (1): 49–54. doi:10.1097/MOU.0b013e328333ac68. PMID 19887943. 
  11. ^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052999/
  12. ^ http://www.clinicalnutritionjournal.com/article/S0261-5614%2814%2900050-8/abstract

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