Condensation of Macrocyclic Polyketides Produced by Penicillium sp. DRF2 with Mercaptopyruvate Represents a New Fungal Detoxification Pathway

  • J Nat Prod. 2016 Jun 24;79(6):1668-78. doi: 10.1021/acs.jnatprod.6b00295.
Marcos V de Castro  1 ,  Laura P Ióca  1 ,  David E Williams  2 ,  Bruna Z Costa  3 ,  Carolina M Mizuno  1  4 ,  Mario F C Santos  1 ,  Karen de Jesus  1 ,  Éverton L F Ferreira  1 ,  Mirna H R Seleghim  4 ,  Lara D Sette  5 ,  Edenir R Pereira Filho  6 ,  Antonio G Ferreira  6 ,  Natália S Gonçalves  7 ,  Raquel A Santos  7 ,  Brian O Patrick  8 ,  Raymond J Andersen  2 ,  Roberto G S Berlinck  1
Affiliations
  • 1. Instituto de Quimica de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.
  • 2. Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia , Vancouver, BC V6T 1Z1, Canada.
  • 3. Instituto de Quimica, Universidade Estadual de Campinas , Caixa Postal 6154, CEP 13083-970, Campinas, SP, Brazil.
  • 4. Departamento de Ecologia e Biologia Evolutiva, Universidade Federal de São Carlos , São Carlos, SP, Brazil.
  • 5. Departamento de Bioquímica e Microbiologia, Instituto de Biociências, Universidade Estadual Paulista "Júlio de Mesquita Filho" , Campus Rio Claro, Avenida 24-A, 1515, Rio Claro, SP, Brazil.
  • 6. Departamento de Química, Universidade Federal de São Carlos , CEP 13565-905, São Carlos, SP, Brazil.
  • 7. Laboratório de Genética e Biologia Molecular, Universidade de Franca , Avenida Dr. Armando Salles Oliveira, 201. Pq. Universitário, Franca, SP, Brazil.
  • 8. Department of Chemistry, University of British Columbia , Vancouver, BC V6T 1Z1, Canada.
PMID: 27227682 DOI: 10.1021/acs.jnatprod.6b00295
Abstract

Application of a refined procedure of experimental design and chemometric analysis to improve the production of curvularin-related polyketides by a marine-derived Penicillium sp. DRF2 resulted in the isolation and identification of cyclothiocurvularins 6-8 and cyclosulfoxicurvularins 10 and 11, novel curvularins condensed with a mercaptolactate residue. Two additional new curvularins, 3 and 4, are also reported. The structures of the sulfur-bearing curvularins were unambiguously established by analysis of spectroscopic data and by X-ray diffraction analysis. Analysis of stable isotope feeding experiments with [U-(13)C3(15)N]-l-cysteine confirmed the presence of the 2-hydroxy-3-mercaptopropanoic acid residue in 6-8 and the oxidized sulfoxide in 10 and 11. Cyclothiocurvularins A (6) and B (7) are formed by spontaneous reaction between 10,11-dehydrocurvularin (2) and mercaptopyruvate (12) obtained by transamination of cysteine. High ratios of [U-(13)C3(15)N]-l-cysteine incorporation into cyclothiocurvularin B (7), the isolation of two diastereomers of cyclothiocurvularins, the lack of cytotoxicity of cyclothiocurvularin B (7) and its methyl ester (8), and the spontaneous formation of cyclothiocurvularins from 10,11-dehydrocurvularin and mercaptopyruvate provide evidence that the formation of cyclothiocurvularins may well correspond to a 10,11-dehydrocurvularin detoxification process by Penicillium sp. DRF2.