Abstract
AbstractThe uridyl peptide antibiotics (UPAs), of which pacidamycin is a member, have a clinically unexploited mode of action and an unusual assembly. Perhaps the most striking feature of these molecules is the biosynthetically unique 3′‐deoxyuridine that they share. This moiety is generated by an unusual, small and monomeric dehydratase, Pac13, which catalyses the dehydration of uridine‐5′‐aldehyde. Here we report the structural characterisation of Pac13 with a series of ligands, and gain insight into the enzyme's mechanism demonstrating that H42 is critical to the enzyme's activity and that the reaction is likely to proceed via an E1cB mechanism. The resemblance of the 3′‐deoxy pacidamycin moiety with the synthetic anti‐retrovirals, presents a potential opportunity for the utilisation of Pac13 in the biocatalytic generation of antiviral compounds.
Highlights
The uridyl peptide antibiotics (UPAs), of which pacidamycin is a member, have a clinically unexploited mode of action and an unusual assembly
We report the structural characterisation of Pac13 with a series of ligands, and gain insight into the enzymes mechanism demonstrating that H42 is critical to the enzymes activity and that the reaction is likely to proceed via an E1cB mechanism
Nucleic acids play a central role in nature and modified nucleosides are present in a wide range of anti-viral, anticancer drugs and antibiotics.[1]
Summary
The uridyl peptide antibiotics (UPAs), of which pacidamycin is a member, have a clinically unexploited mode of action and an unusual assembly. This moiety is generated by an unusual, small and monomeric dehydratase, Pac13, which catalyses the dehydration of uridine-5’-aldehyde.
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