These multiple forms (isoforms or subtypes) of phosphodiesterase were isolated from rat brain using polyacrylamide gel electrophoresis in the early 1970s byWeiss and coworkers,[1][2] and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues, also byWeiss and coworkers.[3][4]
The PDE nomenclature signifies thePDE family with an Arabic numeral, then a capital letter denotes thegene in that family, and a second and final Arabic numeral then indicates thesplice 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, namelyPDE1-PDE11,[7] inmammals. The classification is based on:
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 and8); others are cGMP-selective (PDE5,6, and9). Others can hydrolyse both cAMP and cGMP (PDE1,2,3,10, and11).PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase. AlthoughPDE2 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.
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 bycAMP orcGMP by inhibition of their degradation by PDE.[13]
Paraxanthine, the main metabolite ofcaffeine, 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]
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]
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-stagemalaria parasites (Plasmodium falciparum)in vitro with anED50 value of 35 μM, and inhibits PfPDE1, aP. falciparum cGMP-specific phosphodiesterase, with an IC50 value of 3.8 μM.[20]
Xanthines such ascaffeine andtheobromine arecAMP-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 andVardenafil are PDE-5 inhibitors and are widely used in the treatment of erectile dysfunction.
Recently a PDE was found to break down and release human body grime found on laundry. With the help of this newly discovered nuclease, the yellow stains and odors, that normally remain on clothes with classical detergents, can easily be removed.[21]
^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.PMID4342220.
^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.PMID4375704.S2CID46018589.
^Weiss B (1975). "Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase".Advances in Cyclic Nucleotide Research.5:195–211.PMID165666.
^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.PMID17376027.
^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.PMID15938621.
^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.PMID21946102.
