Nonribosomal biosynthesis of backbone-modified peptides

Niquille DL, Hansen DA, Mori T, Fercher D, Kries H, Hilvert D (2018) Nonribosomal biosynthesis of backbone-modified peptides Nat Chem 10(3), 282-287. PubMed PDF

Abstract

Biosynthetic modification of nonribosomal peptide backbones represents a potentially powerful strategy to modulate the structure and properties of an important class of therapeutics. Using a high-throughput assay for catalytic activity, we show here that an L-Phe-specific module of an archetypal nonribosomal peptide synthetase can be reprogrammed to accept and process the backbone-modified amino acid (S)-β-Phe with near-native specificity and efficiency. A co-crystal structure with a non-hydrolysable aminoacyl-AMP analogue reveals the origins of the 40,000-fold α/β-specificity switch, illuminating subtle but precise remodelling of the active site. When the engineered catalyst was paired with downstream module(s), (S)-β-Phe-containing peptides were produced at preparative scale in vitro (~1 mmol) and high titres in vivo (~100 mg l–1), highlighting the potential of biosynthetic pathway engineering for the construction of novel nonribosomal β-frameworks.

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doi: 10.1038/nchem.2891 PMID: 29461527