Phosphodiesterases and related phosphohydrolases (PDEs)

Phosphodiesterases and related phosphohydrolases represent a diverse superfamily of enzymes that catalyze the hydrolysis of phosphodiester bonds in various substrates, most notably the cyclic nucleotides cAMP and cGMP (Francis et al., 2011, PMID: 21829298). These enzymes play a critical role in signal transduction by regulating the duration and amplitude of second messenger signaling, which in turn controls processes such as smooth muscle tone, inflammation, and cardiac contractility (Bender & Beavo, 2006, PMID: 16968946). The superfamily includes the well-known cyclic nucleotide phosphodiesterases (PDE1-PDE11), as well as other enzymes like ectonucleotide pyrophosphatase/phosphodiesterases (ENPPs) and certain phospholipases (ChEMBL Target ID: 232). Dysregulation of these enzymes is implicated in numerous conditions, including erectile dysfunction, pulmonary hypertension, and chronic inflammatory diseases like COPD and psoriasis (PubMed). Pharmacological targeting of specific PDE isoforms has led to the development of several blockbuster drugs, such as PDE5 inhibitors for sexual dysfunction and PDE4 inhibitors for inflammatory disorders (NIH). However, the broad distribution and structural similarity among family members present challenges in achieving high selectivity and minimizing side effects like hypotension or gastrointestinal toxicity (StatPearls). Additionally, related phosphohydrolases like autotaxin (ENPP2) and acid sphingomyelinase are emerging as targets for fibrosis and lysosomal storage disorders, respectively (UniProt). Drugs like dipyridamole and cilostazol are also used for their antiplatelet and vasodilatory effects in cardiovascular disease (PubMed). The development of next-generation inhibitors focuses on improving isoform selectivity and tissue-specific delivery to enhance the therapeutic window (PubMed).

Other names

Phosphoric diester hydrolasesCyclic nucleotide phosphodiesterasesPDEsPhosphohydrolases3',5'-cyclic nucleotide phosphodiesterasesPhosphodiesterase superfamilyPhosphoric diester hydrolases (EC 3.1.4)

Inhibition of phosphodiesterase enzymes, which prevents the hydrolysis of cyclic nucleotides (cAMP and cGMP) or other phosphodiester substrates, thereby increasing intracellular concentrations of these second messengers and modulating downstream signaling pathways such as protein kinase activation.