Phosphodiesterase (PDE) enzymes
cAMP cGMPPhosphodiester bonds chemically means Phosphorus atom attached by two ester bonds, and this exactly is what we can find in molecules like cAMP and cGMP which has a closed ring in its structure because of these two ester bonds which were formed by the reaction of two of the hydroxyl groups in phosphoric acid with hydroxyl groups on the other molecules like AMP and GMP. Scientists always consider the Phosphodiester bonds the central to all lifes on Earth, due to its forming of the main backbone of the strands of nucleic acid. In RNA and DNA, the phosphodiester bond is the bridge between the 5′ carbon atom of one sugar molecule and the 3′ carbon atom of another, HYPERLINK “https://en.wikipedia.org/wiki/Deoxyribose” o “Deoxyribose”deoxyribose in DNA and ribose in RNA. Strong irreversible covalent bonds forms between the phosphate group and two 5-carbon ring carbohydrates (pentoses) forming two HYPERLINK “https://en.wikipedia.org/wiki/Ester” o “Ester”esterbonds and forming the linkage between the two different sugar molecules.
These two ester bonds in the phosphodiester bond which considered the central of our lives can be broken by type of enzymes called phosphodiesterase (PDE) isoenzymes. This type of enzymes can break down the HYPERLINK “https://en.wikipedia.org/wiki/Phosphodiester_bond” o “Phosphodiester bond”phosphodiester bonds by adding water molecule (hydrolysis). The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the HYPERLINK “https://en.wikipedia.org/wiki/Phosphodiester_bond” o “Phosphodiester bond”phosphodiester bond in the second messenger molecules HYPERLINK “https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate” o “Cyclic adenosine monophosphate”cAMP and HYPERLINK “https://en.wikipedia.org/wiki/Cyclic_guanosine_monophosphate” o “Cyclic guanosine monophosphate”cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. The phosphodiesterase (PDE) isoenzymes exists in many different types of families, including HYPERLINK “https://en.wikipedia.org/wiki/Autotaxin” o “Autotaxin”autotaxin, phospholipases C and D, restriction endonucleases, DNases, HYPERLINK “https://en.wikipedia.org/wiki/RNase” o “RNase”RNases, sphingomyelin and phosphodiesterase which all are responsible of breaking the phosphodiester backbone bonds of DNA or RNA.
So, Phosphodiestrase isoenzymes are very important regulators for the signal transduction mediateation by these second messenger molecules.
The phosphodiesterase enzyme hydrolyze (break it down by adding water) to work as a catalyst of breaking down the of phosphodiester bonds. Exactly as the bonds in the molecule of cyclic AMP and cyclic GMP. So, scientists consider the phosphodiesterase enzyme that plays very important role in the repairing procedures of DNA damage.
There are very significant results of the phosphodiestrases work. For example: The disintegration of cAMP and c GMP (which is a naturally occurring by the second messenger that helps to maintain the immune homeostasis), this disintegration occurs by one type of PDEs types which activates the immune cells to release pro inflammatory mediators such as TNF-?, IL-17. And also indirectly PDE4 decreases the production of anti-inflammatory mediators such as IL-10. So, inhibiting that type of PDEs is clearly an attractive strategy to treat the inflammatory diseases, which means that we need to stop those phosphodiestrase enzymes by some inhibitors.
Nomenclature of Phosphodiestrases:
The nomenclature of phosphodiesrases means identifying the PDEs families. Scientists identifying them by the following:
A numeral, then a capital letter denotes the gene in that family of the numeral, and a second and final numeral to indicate the stacking variant derived from a single gene.
For example: PDE6C2 means that: family 6, gene C, attached variant 2.
Classification of Phosphodiestrases:
The scientists classify the big family of PDE enzymes into 12 families, named from PDE1 to PDE12.
PDE4, PDE7 & PDE8 all are catalyzing the breaking down of cyclic adenosine monophosphate (cAMP).
PDE5, PDE6 & PDE9 all are catalyzing the breaking down of cyclic guanosine monophosphate (cGMP).
PDE1, PDE2, PDE3, PDE10, PDE11 all are catalysing the breakingdown of both cAMP and cGMP.
The inhibitors of phosphodiesterase enzymes are drugs that prevents by competition of one or more of the different types of the enzyme HYPERLINK “https://en.wikipedia.org/wiki/Phosphodiesterase” o “Phosphodiesterase”phosphodiesterase (PDE), so that the inhibitors blocks the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE different types and keep it active. The everywhere presence of these inhibitors means that they are non-specific and they have a wide range of actions. For example: some of the first found a therapeutic use were the actions in the heart, and lungs.AAs another example, the mammalian phosphodiesterases hydrolyze cAMP. So they are very essential for the regulation of this intracellular second messenger. And we can say that Different inhibitors are preventing each one of the similar enzymes because these enzymes shares structural and biochemical similarities, but each one of them can be differentiated by its sensitivity to isoenzyme-specificity and the substrate competitive inhibitors.
We can add more details about the PDEs inhibitors as the follwoing: PDE11 isoenzyme for example has actions on the Skeletal muscle, prostate, kidney, liver, pituitary, salivary glands and testis, and its actions can be prevented by the inhibitors Zaprinast, dipyridamole. PDE10 isoenzyme for example has actions on the skeletal muscle, prostate, kidney, liver, pituitary, salivary glands and testis, and its actions can be prevented by the inhibitors Zaprinast, dipyridamole. PDE9 isoenzyme for example has actions on the Spleen, small intestine, and the brain, and its actions can be prevented by the inhibitors zaprinast; dipyridamole. PDE8 isoenzyme has been divided into two subtypes 8a and 8b. 8a for example has actions on the testis, ovary, ileum, colon, heart, brain, kidney, pancreas, airways,and monocyte. While 8b has actions on the thyroid. Both subtypes of PDE8 (8a and 8b) can be prevented by the inhibitor Dipyridamole. PDE7 isoenzyme for example has actions on the skeletal muscle, heart, kidney, airways, T-lymphocyte, B lymphocyte, monocyte and eosinophil, its actions can be prevented by the inhibitor Dipyridamole. PDE6 isoenzyme for example has actions only on the Retina, its actions can be prevented by the inhibitors sildenafil; zaprinast and dipyridamole.
Chemical combination and Phosphodiestrase docking:
When we are going to design drug in the molecular designing field, we always use a very important method, we call it molecular docking; which predicts the best stereo directions and rotations of one molecule which we call legand when attach to a second molecule which we call substrate to form a stable complex. Characterizing the binding behavior plays very important role in the differentiating of the rational design for the drugs as well as to explain the fundamental biochemical processes. We use our knowledge about the best stereo directions and rotations, and by this way we can predict how much strength have the bonds or how much binding affinity we have between the two used molecules. Because of its ability to predict the binding conformation of small molecule called ligand to the appropriate target binding site, molecular docking is one of the most methods we are using frequently in the drug design, discovery & development (DDD).