Use of a scaffold peptide in the biosynthesis of amino acid-derived natural products

Chi P. Ting, Michael A. Funk, Steve L. Halaby, Zhengan Zhang, Tamir Gonen, Wilfred A. Van Der Donk

Research output: Contribution to journalArticlepeer-review

Abstract

Genome sequencing of environmental bacteria allows identification of biosynthetic gene clusters encoding unusual combinations of enzymes that produce unknown natural products. We identified a pathway in which a ribosomally synthesized small peptide serves as a scaffold for nonribosomal peptide extension and chemical modification. Amino acids are transferred to the carboxyl terminus of the peptide through adenosine triphosphate and amino acyl-tRNA-dependent chemistry that is independent of the ribosome. Oxidative rearrangement, carboxymethylation, and proteolysis of a terminal cysteine yields an amino acid-derived small molecule. Microcrystal electron diffraction demonstrates that the resulting product is isosteric to glutamate. We show that a similar peptide extension is used during the biosynthesis of the ammosamides, which are cytotoxic pyrroloquinoline alkaloids. These results suggest an alternative paradigm for biosynthesis of amino acid-derived natural products.

Original languageEnglish (US)
Pages (from-to)280-284
Number of pages5
JournalScience
Volume365
Issue number6450
DOIs
StatePublished - Jul 19 2019

ASJC Scopus subject areas

  • General

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