Phosphodiesterase 4B isoform 1 (PDE4B1-S133D) (PDE4B1-S133D)

Phosphodiesterase 4B isoform 1 (PDE4B1) is a key enzyme responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP), a critical secondary messenger in intracellular signaling (UniProt Q07343). The S133D variant represents a phosphomimetic mutation where serine at position 133 is replaced by aspartic acid to simulate the phosphorylated, highly active state of the enzyme (PubMed: 11739363). This specific residue is located within the Upstream Conserved Region 1 (UCR1), and its phosphorylation by protein kinase A (PKA) typically serves as a feedback mechanism to increase cAMP breakdown (PubMed: 15831443). PDE4B1 is predominantly expressed in immune cells and the central nervous system, making it a significant therapeutic target for inflammatory conditions like COPD and asthma, as well as neuropsychiatric disorders like schizophrenia (PubMed: 24456612). Drugs targeting this molecule, such as roflumilast and apremilast, work by inhibiting the catalytic activity to maintain elevated cAMP levels, thereby suppressing pro-inflammatory cytokine production (StatPearls: NBK545158). However, clinical use is often limited by side effects like emesis and nausea, which are thought to be mediated by PDE4 inhibition in the area postrema of the brain (PubMed: 11463518). The S133D mutant is frequently used in research to study the structural basis of PDE4 activation and to screen for inhibitors that are effective against the activated form of the enzyme (PubMed: 15831443).

Other names

cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform 1 S133DPDE4B1 S133D mutantPhosphodiesterase 4B1 phosphomimetic

Competitive inhibition of the catalytic site to prevent the hydrolysis of cyclic adenosine monophosphate (cAMP) to 5'-AMP.