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Phosphodiesterase

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cGMP
cAMP

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.

History

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

The potential for selective phosphodiesterase inhibitors to be used as therapeutic agents was predicted in the 1970s by Weiss and coworkers.[5] 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).

Nomenclature and classification

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,[7] 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.[8] 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 2',5'-phosphodiester bond linking adenosines of the 5'-triphosphorylated oligoadenylates.[9][10] PDE12 is not a member of the cyclic nucleotide phosphodiesterase superfamily that contains PDE1 through PDE11.

Clinical significance

Phosphodiesterase enzymes have been shown to be different in different types of cells, including normal and leukemic lymphocytes[11] and are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties.[12]

Inhibitors of PDE can prolong or enhance the effects of physiological processes mediated by cAMP or cGMP by inhibition of their degradation by PDE.[13]

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[14] and benign prostatic hyperplasia.[15]

Paraxanthine, the main metabolite of caffeine, is another cGMP-specific phosphodiesterase inhibitor which inhibits PDE9, a cGMP preferring phosphodiesterase.[16] PDE9 is expressed as high as PDE5 in the corpus cavernosum.[17]

Pharmacological effect of PDE inhibitors

PDE inhibitors have been identified as new potential therapeutics in areas such as pulmonary arterial hypertension, coronary heart disease, dementia, depression, asthma, COPD, protozoal infections (including malaria) and schizophrenia.[citation needed]

PDE also are important in seizure incidence. For example, PDE compromised the antiepileptic activity of adenosine. In addition, using of a PDE inhibitor (pentoxifylline) in pentylenetetrazole-induced seizure indicated the antiepileptic effect by increasing the time latency to seizure incidence and decreasing the seizure duration in vivo.[18]

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.[citation needed]

Dipyridamole inhibits PDE-3 and PDE-5. This leads to intraplatelet accumulation of cAMP and/or cGMP, inhibiting platelet aggregation.[19]

Zaprinast inhibits the growth of asexual blood-stage malaria parasites (P. falciparum) in vitro with an ED50 value of 35 μM, and inhibits PfPDE1, a P. falciparum cGMP-specific phosphodiesterase, with an IC50 value of 3.8 μM.[20]

Xanthines such as caffeine and theobromine are cAMP-phosphodiesterase inhibitors. However, the inhibitory effect of xanthines on phosphodiesterases are only seen at dosages higher than what people normally consume.[citation needed]

Sildenafil, Tadalafil and Vardenafil are PDE-5 inhibitors and are widely used in the treatment of erectile dysfunction.

References

  1. ^ Uzunov P, Weiss B (September 1972). "Separation of multiple molecular forms of cyclic adenosine-3',5'-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis". Biochimica et Biophysica Acta. 284 (1): 220–6. doi:10.1016/0005-2744(72)90060-5. PMID 4342220.
  2. ^ Strada SJ, Uzunov P, Weiss B (December 1974). "Ontogenetic development of a phosphodiesterase activator and the multiple forms of cyclic AMP phosphodiesterase of rat brain". Journal of Neurochemistry. 23 (6): 1097–103. doi:10.1111/j.1471-4159.1974.tb12204.x. PMID 4375704. S2CID 46018589.
  3. ^ Weiss B (1975). "Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase". Advances in Cyclic Nucleotide Research. 5: 195–211. PMID 165666.
  4. ^ Fertel R, Weiss B (July 1976). "Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung". Molecular Pharmacology. 12 (4): 678–87. PMID 183099.
  5. ^ Weiss B, Hait WN (1977). "Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents". Annual Review of Pharmacology and Toxicology. 17: 441–77. doi:10.1146/annurev.pa.17.040177.002301. PMID 17360.
  6. ^ Conti M (September 2000). "Phosphodiesterases and cyclic nucleotide signaling in endocrine cells". Molecular Endocrinology. 14 (9): 1317–27. doi:10.1210/mend.14.9.0534. PMID 10976911.
  7. ^ Conti, M.; Beavo, J. (2007). "Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling". Annual Review of Biochemistry. 76: 481–511. doi:10.1146/annurev.biochem.76.060305.150444. PMID 17376027.
  8. ^ Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T (June 2005). "Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system". Biochemistry. 44 (23): 8312–25. doi:10.1021/bi047313h. PMID 15938621.
  9. ^ Wood ER, Bledsoe R, Chai J, Daka P, Deng H, Ding Y, Harris-Gurley S, Kryn LH, Nartey E, Nichols J, Nolte RT, Prabhu N, Rise C, Sheahan T, Shotwell JB, Smith D, Tai V, Taylor JD, Tomberlin G, Wang L, Wisely B, You S, Xia B, Dickson H (August 2015). "The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors". The Journal of Biological Chemistry. 290 (32): 19681–96. doi:10.1074/jbc.M115.653113. PMC 4528132. PMID 26055709.
  10. ^ [1] phosphosite.org[full citation needed]
  11. ^ Weiss,B. and Winchurch, R.A.: Analyses of cyclic nucleotide phosphodiesterases in lymphocytes from normal and aged leukemic mice. Cancer Res. 38:1274-1280, 1978 http://cancerres.aacrjournals.org/content/canres/38/5/1274.full.pdf
  12. ^ Jeon YH, Heo YS, Kim CM, Hyun YL, Lee TG, Ro S, Cho JM (June 2005). "Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development". Cellular and Molecular Life Sciences. 62 (11): 1198–220. doi:10.1007/s00018-005-4533-5. PMID 15798894. S2CID 9806864.
  13. ^ Rang, HP; Ritter, JM; Flower, RJ; Henderson, G (2016). Rang & Dale's Pharmacology (8th ed.). Churchill Livingstone. p. 349. ISBN 978-0-7020-5362-7.
  14. ^ Khairallah M, Khairallah RJ, Young ME, Allen BG, Gillis MA, Danialou G, Deschepper CF, Petrof BJ, Des Rosiers C (May 2008). "Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency". Proceedings of the National Academy of Sciences of the United States of America. 105 (19): 7028–33. Bibcode:2008PNAS..105.7028K. doi:10.1073/pnas.0710595105. PMC 2383977. PMID 18474859.
  15. ^ Wang C (January 2010). "Phosphodiesterase-5 inhibitors and benign prostatic hyperplasia". Current Opinion in Urology. 20 (1): 49–54. doi:10.1097/MOU.0b013e328333ac68. PMID 19887943. S2CID 205840859.
  16. ^ Orrú, Marco; Guitart, Xavier; Karcz-Kubicha, Marzena; Solinas, Marcello; Justinova, Zuzana; Barodia, Sandeep Kumar; Zanoveli, Janaina; Cortes, Antoni; Lluis, Carme; Casado, Vicent; Moeller, F. Gerard (April 2013). "Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans". Neuropharmacology. 67C: 476–484. doi:10.1016/j.neuropharm.2012.11.029. ISSN 0028-3908. PMC 3562388. PMID 23261866.
  17. ^ da Silva, F H; Pereira, M N; Franco-Penteado, C F; De Nucci, G; Antunes, E; Claudino, M A (March 2013). "Phosphodiesterase-9 (PDE9) inhibition with BAY 73-6691 increases corpus cavernosum relaxations mediated by nitric oxide–cyclic GMP pathway in mice". International Journal of Impotence Research. 25 (2): 69–73. doi:10.1038/ijir.2012.35. ISSN 0955-9930. PMID 23034509.
  18. ^ Hosseini-Zare MS, Salehi F, Seyedi SY, Azami K, Ghadiri T, Mobasseri M, Gholizadeh S, Beyer C, Sharifzadeh M (November 2011). "Effects of pentoxifylline and H-89 on epileptogenic activity of bucladesine in pentylenetetrazol-treated mice". European Journal of Pharmacology. 670 (2–3): 464–70. doi:10.1016/j.ejphar.2011.09.026. PMID 21946102.
  19. ^ Gresele P, Momi S, Falcinelli E (October 2011). "Anti-platelet therapy: phosphodiesterase inhibitors". British Journal of Clinical Pharmacology. 72 (4): 634–46. doi:10.1111/j.1365-2125.2011.04034.x. PMC 3195739. PMID 21649691.
  20. ^ Yuasa K, Mi-Ichi F, Kobayashi T, Yamanouchi M, Kotera J, Kita K, Omori K (November 2005). "PfPDE1, a novel cGMP-specific phosphodiesterase from the human malaria parasite Plasmodium falciparum". The Biochemical Journal. 392 (Pt 1): 221–9. doi:10.1042/BJ20050425. PMC 1317681. PMID 16038615.
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