Fosfodiesteraz

Fosfodiesteraz, commonly known as phosphodiesterases (PDEs), are a family of enzymes that hydrolyze phosphodiester bonds in nucleotides. In humans and other organisms, the most studied substrates are cyclic nucleotides, particularly cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). By breaking these second messengers to their inactive 5'-monophosphate forms, PDEs regulate signaling pathways that control processes such as energy metabolism, muscle relaxation, neurotransmission, and cardiovascular function.

In mammals, phosphodiesterases are encoded by eleven gene families, PDE1 through PDE11, with multiple isoforms. Substrate specificity varies among families: PDE1, PDE2, PDE3, PDE10 and PDE11 hydrolyze both cAMP and cGMP with differing affinities; PDE4, PDE7 and PDE8 are predominantly cAMP-specific; PDE5, PDE9 and PDE6 preferentially hydrolyze cGMP. Many PDEs are regulated by calcium/calmodulin, phosphorylation, or allosteric factors, and several contain distinct regulatory domains that tailor their activity to tissue context.

Physiological roles of PDEs are diverse. By shaping intracellular levels of cAMP and cGMP, they modulate signaling cascades such as protein kinase A (PKA) and protein kinase G (PKG) pathways, influencing vascular tone, cardiac contractility, neuronal signaling, and inflammatory responses. In medicine, PDE inhibitors are widely used: PDE5 inhibitors (sildenafil, tadalafil) treat erectile dysfunction and pulmonary hypertension; PDE4 inhibitors (roflumilast, apremilast) have anti-inflammatory effects; PDE3 inhibitors (milrinone, cilostazol) aid in heart failure or claudication, though with notable side effects.

Beyond humans, bacterial PDEs regulate second messenger systems such as c-di-GMP and c-di-AMP, impacting biofilm formation and virulence.