Fosfodiesterave

Fosfodiesterave, known in English as phosphodiesterases (PDEs), are enzymes that catalyze the hydrolysis of phosphodiester bonds. In signaling biology, the most studied PDEs hydrolyze 3',5'-cyclic nucleotides, such as cyclic AMP (cAMP) and cyclic GMP (cGMP), converting them to their inactive 5'-monophosphate forms and thereby regulating intracellular signaling pathways. This activity is distinct from the nucleases that cleave phosphodiester bonds within DNA or RNA.

In humans, PDEs are organized into multiple gene families (PDE1 through PDE11), with numerous isoforms arising from alternative splicing. They differ in substrate preference: some are cAMP-specific (for example, PDE4), some are cGMP-specific (such as PDE5 and PDE9), while others can hydrolyze both cAMP and cGMP (like PDE1, PDE2, PDE3, PDE10, and PDE11). Tissue distribution also varies widely; PDE5 is abundant in smooth muscle of the penis and pulmonary vasculature, PDE4 is prominent in inflammatory cells and the CNS, PDE3 is found in heart and platelets, among others. Regulation occurs through regulatory domains, phosphorylation, and in some families via calcium/calmodulin.

Mechanistically, PDEs bind divalent metal ions and possess catalytic domains that cleave the 3',5'-phosphodiester bond of cyclic nucleotides, producing 5'-monophosphates. Structural diversity includes regulatory regions such as GAF domains and others that modulate activity and localization.

Pharmacologically, PDE inhibitors are important drugs and research tools. Examples include sildenafil and tadalafil (PDE5 inhibitors for erectile dysfunction and pulmonary hypertension), roflumilast (PDE4 inhibitor for COPD), and milrinone (PDE3 inhibitor used in heart failure). Inhibition is often tissue- and isoform-selective, aiming to modulate specific signaling pathways with targeted therapeutic effects.