Condensation of macrocyclic polyketides produced by Penicillium sp. DRF2 with mercaptopyruvate represents a new fungal detoxification pathway

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-(C3N)-C-13-N-15]-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-(C3N)-C-13-N-15]-L-cysteine incorporation into cyclothiocurvularin B (7), the isolation of two diastereomers of cyclothiocurvularin, 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 cyclothiocurvularin may well correspond to a 10,11-dehydrocurvularin detoxification process by Penicillium sp. DRF279616681678CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informaçãosem informação2012/50026-3; 2005/60175-2; 2010/50190-2; 2013/50228-

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

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-(C3N)-C-13-N-15]-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-(C3N)-C-13-N-15]-L-cysteine incorporation into cyclothiocurvularin B (7), the isolation of two diastereomers of cyclothiocurvularin, 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 cyclothiocurvularin may well correspond to a 10,11-dehydrocurvularin detoxification process by Penicillium sp. DRF2.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)NSERCCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Sao Paulo, Inst Quim Sao Carlos, CP 780, BR-13560970 Sao Carlos, SP, BrazilUniv British Columbia, Dept Chem, Vancouver, BC V6T 1Z1, CanadaUniv British Columbia, Dept Earth Ocean & Atmospher Sci, Vancouver, BC V6T 1Z1, CanadaUniv Estadual Campinas, Inst Quim, Caixa Postal 6154, BR-13083970 Campinas, SP, BrazilUniv Fed Sao Carlos, Dept Ecol & Biol Evolut, Sao Carlos, SP, BrazilUniv Estadual Paulista, Inst Biociencias, Dept Bioquim & Microbiol, Campus Rio Claro,Ave 24-A, BR-1515 Rio Claro, SP, BrazilUniv Fed Sao Carlos, Dept Quim, BR-13565905 Sao Carlos, SP, BrazilUniv Franca, Lab Genet & Biol Mol, Ave Dr Armando Salles Oliveira,201 Pq Univ, Franca, SP, BrazilInst Pasteur, Dept Microbiol, Unit Mol Biol Gene Extremophiles, F-75015 Paris, FranceUniv Estadual Paulista, Inst Biociencias, Dept Bioquim & Microbiol, Campus Rio Claro,Ave 24-A, BR-1515 Rio Claro, SP, BrazilFAPESP: 2005/60175-2FAPESP: 2010/50190-2FAPESP: 2013/50228-8FAPESP: 2012/50026-