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Understanding thioamitide biosynthesis using pathway engineering and untargeted metabolomics

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Abstract

Thiostreptamide S4 is a thioamitide, a family of promising antitumour ribosomally synthesised and post-translationally modified peptides (RiPPs). The thioamitides are one of the most structurally complex RiPP families, yet very few thioamitide biosynthetic steps have been elucidated, even though the biosynthetic gene clusters (BGCs) of multiple thioamitides have been identified. We hypothesised that engineering the thiostreptamide S4 BGC in a heterologous host could provide insights into its biosynthesis when coupled with untargeted metabolomics and targeted mutations of the precursor peptide. Modified BGCs were constructed, and in-depth metabolomics enabled a detailed understanding of the biosynthetic pathway to thiostreptamide S4, including the identification of a protein critical for amino acid dehydration that has homology to HopA1, an effector protein used by a plant pathogen to aid infection. We use this biosynthetic understanding to bioinformatically identify diverse RiPP-like BGCs, paving the way for future RiPP discovery and engineering.

Graphical abstract: Understanding thioamitide biosynthesis using pathway engineering and untargeted metabolomics

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Article information


Submitted
14 Dec 2020
Accepted
19 Apr 2021
First published
19 Apr 2021

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2021, Advance Article
Article type
Edge Article

Understanding thioamitide biosynthesis using pathway engineering and untargeted metabolomics

T. H. Eyles, N. M. Vior, R. Lacret and A. W. Truman, Chem. Sci., 2021, Advance Article , DOI: 10.1039/D0SC06835G

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