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

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

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.

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