Phosphodiesterase 12 (PDE12)

Phosphodiesterase 12 (PDE12) is a mitochondrial enzyme classified as an exoribonuclease belonging to the EEP (exonuclease/endonuclease/phosphatase) family[2]. Its principal known roles are twofold: 1) as the primary cellular enzyme that degrades 2',5'-oligoadenylate (2-5A), thereby acting as a negative regulator of the interferon-induced OAS/RNase-L antiviral pathway; and 2) as a mitochondrial deadenylase that removes poly(A) tails from mitochondrial mRNAs, controlling their stability and translation[1][2]. Inhibition of PDE12 causes 2-5A accumulation, augmenting RNase-L activity and antiviral responses, and has been explored as a therapeutic strategy for viral infections[1][3]. PDE12 is also essential for proper mitochondrial gene expression; its dysregulation can lead to broad effects on mitochondrial protein synthesis and respiratory function, and has been implicated in human neurodegenerative disease when mitochondrial mRNA polyadenylation is perturbed[2]. The enzyme is characterized by a two-domain structure with a positively charged catalytic cleft binding magnesium, and its inhibition is competitive, with inhibitors occupying the 2-5A substrate site[1]. There are no widely used drugs targeting PDE12, but potent experimental inhibitors are under investigation as antivirals[1][3].

Other names

2',5'-phosphodiesterase 122'-PDEmitochondrial deadenylase2'-phosphodiesteraseARF4-AS1DKFZp667B12183635

Competitive inhibition at the active site, blocking the degradation of 2-5A and/or deadenylation of mitochondrial mRNA, thereby enhancing antiviral pathways[1] Some inhibitors increase OAS/RNase-L pathway signaling by preventing degradation of 2-5A