Fungal Dirigent Protein Controls the Stereoselectivity of Multicopper Oxidase-Catalyzed Phenol Coupling in Viriditoxin Biosynthesis

J Am Chem Soc. 2019 May 22;141(20):8068-8072. doi: 10.1021/jacs.9b03354. Epub 2019 May 8.


Paecilomyces variotii produces the antibacterial and cytotoxic ( M)-viriditoxin (1) together with a trace amount of its atropisomer ( P)-viriditoxin 1'. Elucidation of the biosynthesis by heterologous pathway reconstruction in Aspergillus nidulans identified the multicopper oxidase (MCO) VdtB responsible for the regioselective 6,6'-coupling of semiviriditoxin (10), which yielded 1 and 1' at a ratio of 1:2. We further uncovered that VdtD, an α/β hydrolase-like protein lacking the catalytic serine, directs the axial chirality of the products. Using recombinant VdtB and VdtD as cell-free extracts from A. nidulans, we demonstrated that VdtD acts like a dirigent protein to control the stereoselectivity of the coupling catalyzed by VdtB to yield 1 and 1' at a ratio of 20:1. Furthermore, we uncovered a unique Baeyer-Villiger monooxygenase (BVMO) VdtE that could transform the alkyl methylketone side chain to methyl ester against the migratory aptitude.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / biosynthesis*
  • Anti-Bacterial Agents / chemistry
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism*
  • Aspergillus nidulans / genetics
  • Biocatalysis
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / metabolism*
  • Naphthols / chemistry
  • Naphthols / metabolism
  • Oxidation-Reduction
  • Paecilomyces / metabolism
  • Stereoisomerism


  • Anti-Bacterial Agents
  • Antineoplastic Agents
  • Fungal Proteins
  • Naphthols
  • viriditoxin
  • Mixed Function Oxygenases