Key Points
- Scientists captured the first molecular “movie” of the human enzyme hPNPase at work.
- The enzyme employs a unique “base-flipping” mechanism to cleave RNA with high precision.
- The research revealed an unexpected entry path for RNA into the enzyme, overturning old theories.
- Defects in this enzyme are known to cause severe inherited neurological and hearing disorders.
Scientists have created the first-ever detailed “movie” of a vital human enzyme in action. This protein, called hPNPase, acts as a guardian within cells, carefully degrading RNA to maintain genetic health. The new findings reveal exactly how it works and explain why defects in this enzyme lead to severe inherited diseases.
Using advanced microscopes, researchers at the Karolinska Institutet captured the enzyme at three stages of its catalytic cycle. They discovered a sophisticated two-step process. First, the enzyme grabs onto a strand of RNA. Then, in a surprising move, it flips the end of the RNA strand around by 180 degrees.
One of the lead authors, Ole Unseld, explained that “base flipping” is a control mechanism that ensures the enzyme cleaves the RNA at the precise site, preventing accidental damage to the genetic code.
The research also overturned a long-held belief about how RNA enters the enzyme. Scientists previously thought it traversed a central channel, but the new images show that this path is blocked in humans. Instead, the RNA enters from the bottom of the enzyme, a process previously unobserved. The lead researcher, Martin Hällberg, called this discovery “completely unexpected” and a key adaptation in human cells.
This fundamental research has direct implications for human health. Mutations in the gene that creates hPNPase are known to cause devastating conditions like Leigh syndrome and hereditary hearing loss.
By creating a detailed map of the enzyme, scientists can now better predict which mutations are harmful. This allows physicians to use the new models to determine whether a patient’s mutation disrupts the enzyme’s function, helping families obtain clearer diagnoses.
Source: Nucleic Acids Research (2025)
