Pseudouridine synthase (PUS)

Pseudouridine synthases (PUS) are a diverse family of enzymes that catalyze the site-specific isomerization of uridine to pseudouridine (Ψ), the most abundant post-transcriptional modification in RNA (UniProt Consortium, 2023). This modification, often called the fifth nucleotide, enhances RNA base-stacking and thermal stability, which is critical for the proper folding and function of tRNA, rRNA, and snRNA (Karijolich et al., 2010). In humans, PUS enzymes like PUS1, PUS7, and DKC1 (dyskerin) play vital roles in regulating gene expression and translational efficiency (Guzzi et al., 2018). Dysregulation of these enzymes is strongly associated with human diseases; for instance, mutations in PUS1 cause the mitochondrial disorder Myopathy, Lactic Acidosis, and Sideroblastic Anemia (MLASA) (Bykhovskaya et al., 2004). Overexpression of PUS7 is linked to increased aggressiveness in several cancers, such as glioblastoma and leukemia, by promoting the translation of oncogenic proteins (Guzzi et al., 2018). Consequently, PUS enzymes have emerged as promising therapeutic targets, particularly in oncology, where small-molecule inhibitors are being investigated to disrupt the survival and proliferative capacity of malignant cells (Cui et al., 2021). 5-Fluorouracil is known to act as a suicide inhibitor of these enzymes by forming a covalent adduct at the active site, which contributes to its cytotoxic profile (Hoang and Ferré-D'Amaré, 2001). Beyond cancer, PUS enzymes are being studied for their roles in viral infections and intellectual disabilities, highlighting their broad biological significance (Ruzicka et al., 2017).

Other names

RNA pseudouridylate synthasetRNA pseudouridine synthaseΨ synthaseRNA-independent pseudouridine synthaseUridine-to-pseudouridine isomerase

Suicide inhibition of the enzyme by forming a covalent adduct with the active site uracil-binding pocket, preventing the isomerization of uridine to pseudouridine.