fosfodiesterase

Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze phosphodiester bonds in cyclic nucleotides, principally cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). By lowering intracellular levels of these second messengers, PDEs regulate signaling pathways that influence vascular tone, cardiac function, neurotransmission, and vision.

Most PDEs are metalloenzymes that require two divalent metal ions, commonly Mg2+ or Mn2+, in the catalytic site. These ions help activate a water molecule that attacks the phosphodiester bond, producing 5'-mononucleotides (AMP or GMP). Substrate preference and regulation vary among families, allowing tissue-specific control of cyclic nucleotide signaling.

The PDE superfamily includes several gene families (PDE1–PDE11), each with distinct tissue distribution and regulatory properties. Notable examples: PDE1 is activated by Ca2+/calmodulin; PDE3 degrades both cAMP and cGMP but is inhibited by cGMP; PDE4, PDE7, and PDE8 preferentially hydrolyze cAMP; PDE5 and PDE9 are selective for cGMP; PDE6 participates in retinal phototransduction. PDE10 and PDE11 have more complex specificities and broader distribution.

Pharmacology and clinical relevance are driven by PDE inhibitors, which modulate cyclic nucleotide signaling. PDE5 inhibitors (sildenafil, tadalafil, vardenafil) treat erectile dysfunction and pulmonary arterial hypertension. PDE3 inhibitors (milrinone) are used in acute heart failure management. PDE4 inhibitors (roflumilast) are used in COPD for anti-inflammatory effects. Non-selective inhibitors (e.g., IBMX) are primarily research tools.

Dysregulation of PDE activity is linked to cardiovascular, neurological, and inflammatory conditions. Because different PDEs regulate distinct cellular pools of cAMP and cGMP, they remain attractive targets for drugs aimed at finely tuning intracellular signaling.