Biosynthesis and recruitment of reactive amino acids in nonribosomal peptide assembly lines.

Reactive amino acid side chains play important roles in the binding of peptides to specific targets. In addition, their reactivity enables selective peptide conjugation and functionalization for pharmaceutical purposes. Diverse reactive amino acids are incorporated into nonribosomal peptides, which serve as a source for drug candidates. Notable examples include (poly)unsaturated (enamine, alkyne, and furyl) and halogenated residues, strained carbacycles (cyclopropyl and cyclopropanol), small heterocycles (oxirane and aziridine), and reactive N-N functionalities (hydrazones, diazo compounds, and diazeniumdiolates). Their biosynthesis requires diverse biocatalysts for sophisticated reaction mechanisms. Several avenues have been identified for their incorporation into peptides, the recruitment by adenylation domains or ligases, on-line modifications, and enzymatic tailoring reactions. Combined with protein engineering approaches, this knowledge provides new opportunities in synthetic biology and bioorthogonal chemistry. Copyright © 2024 Elsevier Ltd. All rights reserved.

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Friedrich Johannes Ehinger, Christian Hertweck. Biosynthesis and recruitment of reactive amino acids in nonribosomal peptide assembly lines. Current opinion in chemical biology. 2024 Aug;81:102494

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PMID: 38936328

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