cGMP-specific phosphodiesterase type 5

Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme (EC 3.1.4.17) 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.

PDE5A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4OEX, 1RKP, 1T9R, 1T9S, 1TBF, 1UDT, 1UDU, 1UHO, 1XOZ, 1XP0, 2CHM, 2H40, 2H42, 2H44, 2XSS, 3B2R, 3BJC, 3HC8, 3HDZ, 3JWQ, 3JWR, 3LFV, 3MF0, 3SHY, 3SHZ, 3SIE, 3TGE, 3TGG, 4G2W, 4G2Y, 4I9Z, 4IA0, 4MD6, 4OEW
Identifiers
Aliases	PDE5A, CGB-PDE, CN5A, PDE5, phosphodiesterase 5A
External IDs	OMIM: 603310 MGI: 2651499 HomoloGene: 842 GeneCards: PDE5A
EC number	3.1.4.35
Gene location (Human) Chr. Chromosome 4 (human)^[1] Band 4q26 Start 119,494,397 bp^[1] End 119,628,804 bp^[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)^[2] Band 3|3 G1 Start 122,522,596 bp^[2] End 122,653,023 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon ascending aorta right coronary artery popliteal artery gastric mucosa caput epididymis rectum left coronary artery corpus epididymis visceral pleura Top expressed in left lung lobe left colon cervix ciliary body islet of Langerhans right lung ascending aorta ileum right lung lobe carotid body More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding 3',5'-cyclic-nucleotide phosphodiesterase activity cGMP binding metal ion binding cyclic-nucleotide phosphodiesterase activity catalytic activity phosphoric diester hydrolase activity hydrolase activity 3',5'-cyclic-GMP phosphodiesterase activity protein binding Cellular component cytosol cellular component Biological process positive regulation of MAP kinase activity cGMP metabolic process positive regulation of cardiac muscle hypertrophy cGMP catabolic process negative regulation of T cell proliferation positive regulation of oocyte development metabolism relaxation of cardiac muscle signal transduction negative regulation of cardiac muscle contraction regulation of nitric oxide mediated signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8654 242202 Ensembl ENSG00000138735 ENSMUSG00000053965 UniProt O76074 Q8CG03 RefSeq (mRNA) NM_033437 NM_001083 NM_033430 NM_153422 RefSeq (protein) NP_001074 NP_236914 NP_246273 NP_700471 Location (UCSC) Chr 4: 119.49 – 119.63 Mb Chr 3: 122.52 – 122.65 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

The phosphodiesterase (PDE) isozymes, found in several tissues including the rod and cone photoreceptor cells of the retina, belong to a large family of cyclic nucleotide PDEs that catalyze cAMP and cGMP hydrolysis.^[5][6]

The interest in PDEs as molecular targets of drug action has grown with the development of isozyme-selective PDE inhibitors that offer potent inhibition of selected isozymes without the side-effects attributed to nonselective inhibitors such as theophylline.^[7][8]

Sildenafil, vardenafil, tadalafil, and avanafil are PDE5 inhibitors that are significantly more potent and selective than zaprinast and other early PDE5 inhibitors.

Action of PDE5

PDE5 is an enzyme that accepts cGMP and breaks it down. Sildenafil, vardenafil and tadalafil are inhibitors of this enzyme, which bind to the catalytic site of PDE5. Both inhibitors bind with high affinity and specificity, and cGMP-binding to the allosteric sites stimulates binding of PDE5 inhibitors at the catalytic site. The kinetics of inhibitor binding and inhibition of catalysis imply the existence of two PDE5 conformers, and results of native gel electrophoresis reveal that PDE5 exists in two apparently distinct conformations, i.e., an extended conformer and a more compact conformer.

PDE5 activity is modulated by a rapidly reversible redox switch. Chemical reduction of PDE5 relieves autoinhibition of enzyme functions; allosteric cGMP-binding activity is increased 10-fold, and catalytic activity is increased ~3-fold. The redox effect on allosteric cGMP-binding occurs in the isolated regulatory domain. A change in the state of reduction of PDE5 or the isolated regulatory domain is associated with an apparent conformational change similar to that caused by phosphorylation.

Tissue distribution of PDE5

PDE5 is expressed in human colonic cells and in intestinal tissue and its activity is regulated by intracellular cGMP levels in these cells that increase on GCC activation. This presumably occurs through binding of cGMP to the GAF domains in the N-terminus of PDE5, resulting in allosteric activation of the enzyme.

The mechanism of action of E4021 on both the nonactivated and activated forms of rod PDE6 because both states are relevant to understanding how PDE5-selective inhibitors may alter signal transduction pathways in photoreceptor cells. PDE5-selective inhibitors may show good discrimination of PDE5 from most other PDE isoforms.

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.

Immunohistology has shown that PDE5 localizes in heart cells at the sarcomere z-disk, but can also be found in diffuse amounts in the cytosol.^[9] Increased expression of PDE5 has also been measured in hypertrophic disease and has been linked to oxidative stress, and PDE5 inhibition has shown beneficial effects in the failing heart.^[10] In an experiment, PDE5 overexpression was found to contribute to worsened pathological remodeling after mouse cardiomyocytes experienced myocardial infarction.^[11] The role of PDE5 in heart failure and cardiac treatment involving PDE5 inhibitors have been major areas of focus for both lab and clinical studies.^[12]

PDE5-inhibiting drugs

The most commonly available PDE5 inhibitors are sildenafil (Viagra)^[13], vardenafil (Levitra)^[14], tadalafil (Cialis)^[15], and avanafil (Stendra)^[16].

PDE5 inhibitors are not routinely prescribed as first line treatment for erectile dysfunction. This is as they cause unwanted side effects like hair loss, headache, and nausea (among others). Often, erectile dysfunction can instead be treated non-pharmacologically, by identifying and addressing a psychogenic cause of the disease^[17].

Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction for patients receiving protease inhibitors, like Atazanavir, which are used to treat HIV. Coadministration of a protease inhibitor with a PDE5 inhibitor is expected to substantially increase the PDE5 inhibitor concentration and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism.^{[citation needed]}

PDE5 inhibitor drugs are effective in men regardless of why they have erectile dysfunction — including vascular disease, nerve problems, and even psychological causes.^{[citation needed]} PDE5-inhibiting drugs can cause a number of side-effects, including headache, lightheadedness, dizziness, flushing, nasal congestion, and changes in vision.^{[citation needed]} In 2011, the Food and Drug Administration (FDA) issued additional guidance on regulations related to cGMP manufacture and packaging.^[18]

Sildenafil

Main article: Sildenafil

 

Bulk bag of counterfeit Viagra

Sildenafil (marketed as Viagra) was the first PDE5 inhibitor on the market. Originally created as a treatment for high blood pressure in 1989, it was found to have a secondary use as an effective PDE5 inhibitor, enabling men who use it to gain stronger erections after arousal. The FDA approved Viagra on March 27, 1998.^[19] Discovered by Pfizer, sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum in the penis. This means that, when sildenafil is present in the organism, normal sexual stimulation leads to increased levels of cGMP in the corpus cavernosum, which leads to better erections. Without sexual stimulation and no activation of the NO/cGMP system, sildenafil should not cause an erection.

Studies in vitro have shown that sildenafil is selective for PDE5.^[20] Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina that is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels.^[21]

Vardenafil

Main article: Vardenafil

Vardenafil (marketed as Levitra, Staxyn and Vivanza) was the second oral PDE-5 inhibitor for erectile dysfunction to be FDA approved in August 2003.^{[citation needed]}

Tadalafil

Main article: Tadalafil

Tadalafil (marketed as Cialis) is a PDE5 inhibitor used to treat erectile dysfunction^[22] and pulmonary arterial hypertension.^[23] It has a longer half life than sildenafil of 17.5 hours, allowing it to be taken once a day.^[23] Tadalafil "daily" (5 mg) is also used for treatment of benign prostate hyperplasia.^[24]

In patients with pulmonary arterial hypertension, tadalafil improves symptoms and also slows down the progressive deterioration in breathlessness seen in this condition.^[23] Studies have shown that tadalafil is more selective for PDE5 over PDE6 than sildenafil or vardenafil.^[25]

See also

• PDE5 drug design
• PDE5 inhibitor
• Phosphodiesterase
• Icariin

References

1. GRCh38: Ensembl release 89: ENSG00000138735 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000053965 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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 (BBA) - Enzymology. 284 (1): 220–6. doi:10.1016/0005-2744(72)90060-5. PMID 4342220.
6. 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.
7. Fertel R, Weiss B (July 1976). "Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung" (abstract). Molecular Pharmacology. 12 (4): 678–87. PMID 183099.
8. 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.
9. Nagayama T, Zhang M, Hsu S, Takimoto E, Kass DA (August 2008). "Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil". The Journal of Pharmacology and Experimental Therapeutics. 326 (2): 380–7. doi:10.1124/jpet.108.137422. PMID 18456872. S2CID 10202683.
10. Lu Z, Xu X, Hu X, Lee S, Traverse JH, Zhu G, Fassett J, Tao Y, Zhang P, dos Remedios C, Pritzker M, Hall JL, Garry DJ, Chen Y (April 2010). "Oxidative stress regulates left ventricular PDE5 expression in the failing heart". Circulation. 121 (13): 1474–83. doi:10.1161/CIRCULATIONAHA.109.906818. PMC 3110701. PMID 20308615.
11. Pokreisz P, Vandenwijngaert S, Bito V, Van den Bergh A, Lenaerts I, Busch C, Marsboom G, Gheysens O, Vermeersch P, Biesmans L, Liu X, Gillijns H, Pellens M, Van Lommel A, Buys E, Schoonjans L, Vanhaecke J, Verbeken E, Sipido K, Herijgers P, Bloch KD, Janssens SP (January 2009). "Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice". Circulation. 119 (3): 408–16. doi:10.1161/CIRCULATIONAHA.108.822072. PMC 3791110. PMID 19139381.
12. Hutchings DC, Anderson SG, Caldwell JL, Trafford AW (March 2018). "Phosphodiesterase-5 inhibitors and the heart: compound cardioprotection?". Heart. 104 (15): 1244–1250. doi:10.1136/heartjnl-2017-312865. PMC 6204975. PMID 29519873.
13. "Sildenafil". National Institute for Health and Care Excellence. 2018-08-07. Retrieved 2024-05-18.
14. "Vardenafil". National Institute for Health and Care Excellence. 2011-10-15. Retrieved 2024-05-18.
15. "Tadalafil". National Institute for Health and Care Excellence. 2012-07-15. Retrieved 2024-05-18.
16. "Avanafil". National Institute for Health and Care Excellence. 2017-08-24. Retrieved 2024-05-18.
17. "Erectile dysfunction: Phosphodiesterase-5 (PDE-5) inhibitors". National Institute for Health and Care Excellence. 2023-04-04. Retrieved 2024-05-18.
18. "FDA Issues Guidance on Dietary Supplement cGMP Regulations". The National Law Review. Duane Morris LLP. 2011-02-07. Retrieved 2012-01-19.
19. "Viagra". Drug Approval Package. United States Food and Drug Administration. March 27, 1998.
20. "Sildenafil 50 mg film-coated tablets". Medicines.org.uk. Retrieved November 4, 2015.
21. "Viagra -sildenafil citrate tablet". Daily Med- U.S National Library of Medicine. Retrieved November 5, 2015.
22. Khera M, Goldstein I (June 2011). "Erectile dysfunction". BMJ Clinical Evidence. 2011. PMC 3217797. PMID 21711956.
23. Henrie AM, Nawarskas JJ, Anderson JR (2015). "Clinical utility of tadalafil in the treatment of pulmonary arterial hypertension: an evidence-based review". Core Evidence. 10: 99–109. doi:10.2147/CE.S58457. PMC 4636095. PMID 26587013.
24. Hatzimouratidis K (August 2014). "A review of the use of tadalafil in the treatment of benign prostatic hyperplasia in men with and without erectile dysfunction". Therapeutic Advances in Urology. 6 (4): 135–47. doi:10.1177/1756287214531639. PMC 4054509. PMID 25083163.
25. Bischoff E (June 2004). "Potency, selectivity, and consequences of nonselectivity of PDE inhibition". International Journal of Impotence Research. 16 (Suppl 1): S11-4. doi:10.1038/sj.ijir.3901208. PMID 15224129. S2CID 22178197.

External links

• The cGMP Specific Phosphodiesterase Type 5 Enzyme
• Pfizer Pharmaceutical
• New Scientist article on Viagra and the female 'G spot' 2008-10-06 at the Wayback Machine
• Human PDE5A genome location and PDE5A gene details page in the UCSC Genome Browser.