Phosphodiesterase

Last updated
cGMP CGMP.svg
cGMP
cAMP CAMP.svg
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.

Contents

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. Pde families.png
PDE substrate specificities by enzyme family. Both means it hydrolyzes both cAMP and cGMP.

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 ( Plasmodium 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.

Related Research Articles

<span class="mw-page-title-main">Phosphodiesterase inhibitor</span> Drug

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

<span class="mw-page-title-main">Cyclic nucleotide</span> Cyclic nucleic acid

A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.

<span class="mw-page-title-main">Tadalafil</span> Medication used to treat erectile dysfunction

Tadalafil, sold under the brand name Cialis among others, is a medication used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension. It is taken by mouth. Onset is typically within half an hour and the duration is up to 36 hours.

<span class="mw-page-title-main">Cyclic guanosine monophosphate</span> Chemical compound

Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface. Through protein kinases activation, cGMP can relax smooth muscle. cGMP concentration in urine can be measured for kidney function and diabetes detection.

<span class="mw-page-title-main">PDE5 inhibitor</span> Vasodilating drug

A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.

cGMP-specific phosphodiesterase type 5 Mammalian protein found in Homo sapiens

Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

<span class="mw-page-title-main">Cyclic nucleotide phosphodiesterase</span> Class of enzymes

3′,5′-cyclic-nucleotide phosphodiesterases (EC 3.1.4.17) are a family of phosphodiesterases. Generally, these enzymes hydrolyze a nucleoside 3′,5′-cyclic phosphate to a nucleoside 5′-phosphate:

<span class="mw-page-title-main">Phosphodiesterase 3</span> Class of enzymes

PDE3 is a phosphodiesterase. The PDEs belong to at least eleven related gene families, which are different in their primary structure, substrate affinity, responses to effectors, and regulation mechanism. Most of the PDE families are composed of more than one gene. PDE3 is clinically significant because of its role in regulating heart muscle, vascular smooth muscle and platelet aggregation. PDE3 inhibitors have been developed as pharmaceuticals, but their use is limited by arrhythmic effects and they can increase mortality in some applications.

Phosphodiesterase 1, PDE1, EC 3.1.4.1, systematic name oligonucleotide 5′-nucleotidohydrolase) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). Phosphodiesterase 1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP.

<span class="mw-page-title-main">Phosphodiesterase 2</span> Class of enzymes

The PDE2 enzyme is one of 21 different phosphodiesterases (PDE) found in mammals. These different PDEs can be subdivided to 11 families. The different PDEs of the same family are functionally related despite the fact that their amino acid sequences show considerable divergence. The PDEs have different substrate specificities. Some are cAMP selective hydrolases, others are cGMP selective hydrolases and the rest can hydrolyse both cAMP and cGMP.

<span class="mw-page-title-main">IBMX</span> Chemical compound

IBMX (3-isobutyl-1-methylxanthine), like other methylated xanthine derivatives, is both a:

  1. competitive non-selective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNFα and leukotriene synthesis, and reduces inflammation and innate immunity, and
  2. nonselective adenosine receptor antagonist.
<span class="mw-page-title-main">Avanafil</span> Chemical compound

Avanafil is a PDE5 inhibitor approved for erectile dysfunction by the FDA on April 27, 2012 and by EMA on June 21, 2013. Avanafil is sold under the brand names Stendra and Spedra. It was invented at Mitsubishi Tanabe Pharma, formerly known as Tanabe Seiyaku Co., and licensed to Vivus Inc., which partnered with Menarini Group to commercialise Spedra in over forty European countries, Australia, and New Zealand. Metuchen Pharmaceuticals obtained exclusive rights within the United States.

<span class="mw-page-title-main">PDE4A</span> Protein-coding gene in the species Homo sapiens

cAMP-specific 3',5'-cyclic phosphodiesterase 4A is an enzyme that in humans is encoded by the PDE4A gene.

<span class="mw-page-title-main">PDE4B</span> Protein-coding gene in the species Homo sapiens

cAMP-specific 3',5'-cyclic phosphodiesterase 4B is an enzyme that in humans is encoded by the PDE4B gene.

<span class="mw-page-title-main">PDE11A</span> Protein-coding gene in the species Homo sapiens

Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A is an enzyme that in humans is encoded by the PDE11A gene.

<span class="mw-page-title-main">PDE10A</span> Enzyme and protein-coding gene in humans

cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A is an enzyme that in humans is encoded by the PDE10A gene.

<span class="mw-page-title-main">Piclamilast</span> Chemical compound

Piclamilast, is a selective PDE4 inhibitor. It is comparable to other PDE4 inhibitors for its anti-inflammatory effects. It has been investigated for its applications to the treatment of conditions such as chronic obstructive pulmonary disease, bronchopulmonary dysplasia and asthma. It is a second generation compound that exhibits structural functionalities of the PDE4 inhibitors cilomilast and roflumilast. The structure for piclamilast was first elucidated in a 1995 European patent application. The earliest mention of the name "piclamilast" was used in a 1997 publication.

<span class="mw-page-title-main">Zaprinast</span> Chemical compound

Zaprinast was an unsuccessful clinical drug candidate that was a precursor to the chemically related PDE5 inhibitors, such as sildenafil (Viagra), which successfully reached the market. It is a phosphodiesterase inhibitor, selective for the subtypes PDE5, PDE6, PDE9 and PDE11. IC50 values are 0.76, 0.15, 29.0, and 12.0 μM, respectively.

Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.

Benjamin Weiss is an American neuropharmacologist, Emeritus Professor of Pharmacology and Physiology at Drexel University College of Medicine. He is best known for his work with cyclic nucleotide phosphodiesterases. He was the first to propose, based on his experimental work, that selective inhibition of phosphodiesterases which are expressed differentially in all tissues, could be used as a target for drug development. His work is the basis for many marketed and developmental human drugs that selectively inhibit cyclic nucleotide phosphodiesterases.

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. ↑ 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.