Phosphodiesterase

Source: Wikipedia, the free encyclopedia.
cGMP
cAMP

A phosphodiesterase (PDE) is an

restriction endonucleases (which all break the phosphodiester backbone of DNA or RNA
), as well as numerous less-well-characterized small-molecule phosphodiesterases.

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

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

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.

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

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]

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]

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. PMID 4342220
    .
  2. S2CID 46018589
    .
  3. PMID 165666
    .
  4. PMID 183099
    .
  5. PMID 17360
    .
  6. PMID 10976911
    .
  7. PMID 17376027
    .
  8. PMID 15938621
    .
  9. 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. S2CID 9806864
    .
  13. ISBN 978-0-7020-5362-7
    .
  14. PMID 18474859
    .
  15. S2CID 205840859
    .
  16. PMID 23261866
    .
  17. PMID 23034509
    .
  18. PMID 21946102
    .
  19. PMID 21649691
    .
  20. PMID 16038615
    .

External links
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