| Structural highlights
Publication Abstract from PubMed
D-Amino acid residues, found in countless peptides and natural products including ribosomally synthesized and post-translationally modified peptides (RiPPs), are critical for the bioactivity of several antibiotics and toxins. Recently, radical S-adenosyl-L-methionine (SAM) enzymes have emerged as the only biocatalysts capable of installing direct and irreversible epimerization in RiPPs. However, the mechanism underpinning this biochemical process is ill-understood and the structural basis for this post-translational modification remains unknown. Here we report an atomic-resolution crystal structure of a RiPP-modifying radical SAM enzyme in complex with its substrate properly positioned in the active site. Crystallographic snapshots, size-exclusion chromatography-small-angle x-ray scattering, electron paramagnetic resonance spectroscopy and biochemical analyses reveal how epimerizations are installed in RiPPs and support an unprecedented enzyme mechanism for peptide epimerization. Collectively, our study brings unique perspectives on how radical SAM enzymes interact with RiPPs and catalyze post-translational modifications in natural products.
Structural and mechanistic basis for RiPP epimerization by a radical SAM enzyme.,Kubiak X, Polsinelli I, Chavas LMG, Fyfe CD, Guillot A, Fradale L, Brewee C, Grimaldi S, Gerbaud G, Thureau A, Legrand P, Berteau O, Benjdia A Nat Chem Biol. 2024 Mar;20(3):382-391. doi: 10.1038/s41589-023-01493-1. Epub 2023 , Dec 29. PMID:38158457[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kubiak X, Polsinelli I, Chavas LMG, Fyfe CD, Guillot A, Fradale L, Brewee C, Grimaldi S, Gerbaud G, Thureau A, Legrand P, Berteau O, Benjdia A. Structural and mechanistic basis for RiPP epimerization by a radical SAM enzyme. Nat Chem Biol. 2024 Mar;20(3):382-391. PMID:38158457 doi:10.1038/s41589-023-01493-1
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