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Phosphodiesterase

February 27, 2023

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.

External links

February 27, 2023
phosphodiesterase, phosphodiesterase, enzyme, that, breaks, phosphodiester, bond, usually, phosphodiesterase, refers, cyclic, nucleotide, phosphodiesterases, which, have, great, clinical, significance, described, below, however, there, many, other, families, p. 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 cGMP cAMP 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 Contents 1 History 2 Nomenclature and classification 3 Clinical significance 3 1 Pharmacological effect of PDE inhibitors 4 References 5 External linksHistory EditThese 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 EditThe 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 distributionDifferent 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 EditPhosphodiesterase 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 Edit 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 mM and inhibits PfPDE1 a P falciparum cGMP specific phosphodiesterase with an IC50 value of 3 8 mM 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 Edit 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 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 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 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 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 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 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 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 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 1 phosphosite org full citation needed 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 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 Rang HP Ritter JM Flower RJ Henderson G 2016 Rang amp Dale s Pharmacology 8th ed Churchill Livingstone p 349 ISBN 978 0 7020 5362 7 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 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 Orru 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 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 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 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 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 External links EditPhosphoric Diester Hydrolases at the US National Library of Medicine Medical Subject Headings MeSH Portal Biology Retrieved from https en wikipedia org w index php title Phosphodiesterase amp oldid 1104214145, wikipedia, wiki, book, books, library,

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