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

Science. 2019 Jul 19;365(6450):280-284. doi: 10.1126/science.aau6232.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Amino Acids / metabolism
  • Biological Products / chemistry
  • Biological Products / metabolism*
  • Escherichia coli
  • Multigene Family
  • Peptide Biosynthesis*
  • Peptides / chemistry
  • Peptides / metabolism
  • Pseudomonas syringae / genetics
  • Pseudomonas syringae / metabolism
  • Pyrroles / chemistry
  • Quinolines / chemistry

Substances

  • Amino Acids
  • Biological Products
  • Peptides
  • Pyrroles
  • Quinolines
  • pyrroloquinoline