High-titer heterologous production in E. coli of lyngbyatoxin, a protein kinase C activator from an uncultured marine cyanobacterium

ACS Chem Biol. 2013 Sep 20;8(9):1888-93. doi: 10.1021/cb400189j. Epub 2013 Jun 17.

Abstract

Many chemically complex cyanobacterial polyketides and nonribosomal peptides are of great pharmaceutical interest, but the levels required for exploitation are difficult to achieve from native sources. Here we develop a framework for the expression of these multifunctional cyanobacterial assembly lines in Escherichia coli using the lyngbyatoxin biosynthetic pathway, derived from a marine microbial assemblage dominated by the cyanobacterium Moorea producens. Heterologous expression of this pathway afforded high titers of both lyngbyatoxin A (25.6 mg L(-1)) and its precursor indolactam-V (150 mg L(-1)). Production, isolation, and identification of all expected chemical intermediates of lyngbyatoxin biosynthesis in E. coli also confirmed the previously proposed biosynthetic route, setting a solid chemical foundation for future pathway engineering. The successful production of the nonribosomal peptide lyngbyatoxin A in E. coli also opens the possibility for future heterologous expression, characterization, and exploitation of other cyanobacterial natural product pathways.

Publication types

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

MeSH terms

  • Biosynthetic Pathways*
  • Cyanobacteria / genetics
  • Cyanobacteria / metabolism*
  • Escherichia coli / genetics
  • Escherichia coli / metabolism*
  • Gene Expression
  • Genes, Bacterial
  • Industrial Microbiology / methods
  • Lyngbya Toxins / genetics
  • Lyngbya Toxins / metabolism*
  • Marine Toxins / genetics
  • Marine Toxins / metabolism*
  • Protein Kinase C / metabolism

Substances

  • Lyngbya Toxins
  • Marine Toxins
  • Protein Kinase C
  • lyngbyatoxin A