Discovery and Biosynthesis of Nitrilobacillins by Post-Translational Introduction of C-Terminal Nitrile Groups.

Authors

Lide Cha, Chuyang Qian, Chandrashekhar Padhi, Lingyang Zhu, Wilfred A van der Donk

Published in

Journal of the American Chemical Society. Jun 23, 2026. Epub Jun 23, 2026.

Abstract

Nitrile-containing natural products are produced in all kingdoms of life. Despite the wide application of nitrile-containing peptide scaffolds in medicinal chemistry, the presence of the nitrile group is unprecedented in ribosomally synthesized and post-translationally modified peptides (RiPPs). In this work, we report the identification and characterization of a RiPP biosynthetic gene cluster (BGC), where an asparagine synthetase-like (AS-like) protein encoded in the BGC converts the C-terminal carboxylate of the precursor peptide to a nitrile. Furthermore, a multinuclear nonheme iron-dependent oxidative enzyme (MNIO) and an α-ketoglutarate-dependent HExxH motif-containing enzyme (αKG-HExxH) perform stereoselective β-hydroxylation of aspartate and proline residues, respectively. Structure prediction-guided mechanistic evaluation of the nitrile synthetase provided insights into the possible mechanism of catalysis. These findings extend our understanding of the structural diversity of RiPPs and demonstrate the catalytic versatility of AS-like enzymes in natural product biosynthesis.

PMID:
42335466
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.

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