Biosynthesis of Mycotoxin Fusaric Acid and Application of a PLP-Dependent Enzyme for Chemoenzymatic Synthesis of Substituted l-Pipecolic Acids

J Am Chem Soc. 2020 Nov 18;142(46):19668-19677. doi: 10.1021/jacs.0c09352. Epub 2020 Nov 6.

Abstract

Fusaric acid (FA) is a well-known mycotoxin that plays an important role in plant pathology. The biosynthetic gene cluster for FA has been identified, but the biosynthetic pathway remains unclarified. Here, we elucidated the biosynthesis of FA, which features a two-enzyme catalytic cascade, a pyridoxal 5'-phosphate (PLP)-dependent enzyme (Fub7), and a flavin mononucleotide (FMN)-dependent oxidase (Fub9) in synthesizing the picolinic acid scaffold. FA biosynthesis also involves an off-line collaboration between a highly reducing polyketide synthase (HRPKS, Fub1) and a nonribosomal peptide synthetase (NRPS)-like carboxylic acid reductase (Fub8) in making an aliphatic α,β-unsaturated aldehyde. By harnessing the stereoselective C-C bond-forming activity of Fub7, we established a chemoenzymatic route for stereoconvergent synthesis of a series of 5-alkyl-, 5,5-dialkyl-, and 5,5,6-trialkyl-l-pipecolic acids of high diastereomeric ratio.

Publication types

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

MeSH terms

  • Aldehydes / chemistry
  • Aspergillus nidulans / enzymology
  • Aspergillus nidulans / metabolism
  • Biosynthetic Pathways
  • Flavin Mononucleotide / chemistry
  • Fusaric Acid / biosynthesis*
  • Multigene Family
  • Mycotoxins / biosynthesis*
  • Oxidoreductases / metabolism*
  • Peptide Synthases / metabolism*
  • Picolinic Acids / chemistry
  • Pipecolic Acids / chemistry*
  • Polyketide Synthases / metabolism*
  • Stereoisomerism

Substances

  • Aldehydes
  • Mycotoxins
  • Picolinic Acids
  • Pipecolic Acids
  • Polyketide Synthases
  • Flavin Mononucleotide
  • Oxidoreductases
  • carboxylic acid reductase
  • Peptide Synthases
  • non-ribosomal peptide synthase
  • Fusaric Acid
  • picolinic acid