Mechanistic Insights Into Post‐translational α‐Keto‐β‐Amino Acid Formation by a Radical S‐Adenosyl Methionine Peptide Splicease - Institut Pasteur
Article Dans Une Revue Angewandte Chemie International Edition Année : 2024

Mechanistic Insights Into Post‐translational α‐Keto‐β‐Amino Acid Formation by a Radical S‐Adenosyl Methionine Peptide Splicease

Résumé

Radical S-adenosyl methionine enzymes catalyze a diverse repertoire of post-translational modifications in protein and peptide substrates. Among these, an exceptional and mechanistically obscure example is the installation of α-keto-β-amino acid residues by formal excision of a tyrosinederived tyramine unit. The responsible spliceases are key maturases in a widespread family of natural products termed spliceotides that comprise potent protease inhibitors, with the installed β-residues being crucial for bioactivity. Here, we established the in vitro activity of the model splicease PcpXY to interrogate the mechanism of non-canonical protein splicing. Identification of shunt and coproducts, deuterium labeling studies, and density functional theory energy calculations of hypothesized intermediates support a mechanism involving hydrogen abstraction at tyrosine Cα as the initial site of peptide radical formation and release of 4-hydroxybenzaldehyde as the tyrosine-derived coproduct. The data illuminate key features of this unprecedented radical-mediated biotransformation yielding ketoamide pharmacophores that are also present in peptidomimetic therapeutics.
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pasteur-04849093 , version 1 (19-12-2024)

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Anna Lisa Vagstad, Edgars Lakis, Katja-Sophia Csizi, William Walls, Daniel Richter, et al.. Mechanistic Insights Into Post‐translational α‐Keto‐β‐Amino Acid Formation by a Radical S‐Adenosyl Methionine Peptide Splicease. Angewandte Chemie International Edition, 2024, pp.e202418054. ⟨10.1002/anie.202418054⟩. ⟨pasteur-04849093⟩

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