title: Condensation of Macrocyclic Polyketides Produced by Penicillium sp. DRF2 with Mercaptopyruvate Represents a New Fungal Detoxification Pathway.
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.
authors.affiliation: Instituto de Quimica de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.
authors.forename: Marcos V
authors.initials: MV
authors.lastname: de Castro
authors.affiliation: Instituto de Quimica de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.
authors.forename: Laura P
authors.initials: LP
authors.lastname: Ióca
authors.affiliation: Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia , Vancouver, BC V6T 1Z1, Canada.
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.affiliation: Instituto de Quimica, Universidade Estadual de Campinas , Caixa Postal 6154, CEP 13083-970, Campinas, SP, Brazil.
authors.forename: Bruna Z
authors.initials: BZ
authors.lastname: Costa
authors.affiliation: Instituto de Quimica de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.|Departamento de Ecologia e Biologia Evolutiva, Universidade Federal de São Carlos , São Carlos, SP, Brazil.
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Mizuno
authors.affiliation: Instituto de Quimica de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.
authors.forename: Mario F C
authors.initials: MF
authors.lastname: Santos
authors.affiliation: Instituto de Quimica de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.
authors.forename: Karen
authors.initials: K
authors.lastname: de Jesus
authors.affiliation: Instituto de Quimica de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.
authors.forename: Éverton L F
authors.initials: ÉL
authors.lastname: Ferreira
authors.affiliation: Departamento de Ecologia e Biologia Evolutiva, Universidade Federal de São Carlos , São Carlos, SP, Brazil.
authors.forename: Mirna H R
authors.initials: MH
authors.lastname: Seleghim
authors.affiliation: 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.
authors.forename: Lara D
authors.initials: LD
authors.lastname: Sette
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos , CEP 13565-905, São Carlos, SP, Brazil.
authors.forename: Edenir R
authors.initials: ER
authors.lastname: Pereira Filho
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos , CEP 13565-905, São Carlos, SP, Brazil.
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Ferreira
authors.affiliation: Laboratório de Genética e Biologia Molecular, Universidade de Franca , Avenida Dr. Armando Salles Oliveira, 201. Pq. Universitário, Franca, SP, Brazil.
authors.forename: Natália S
authors.initials: NS
authors.lastname: Gonçalves
authors.affiliation: Laboratório de Genética e Biologia Molecular, Universidade de Franca , Avenida Dr. Armando Salles Oliveira, 201. Pq. Universitário, Franca, SP, Brazil.
authors.forename: Raquel A
authors.initials: RA
authors.lastname: Santos
authors.affiliation: Department of Chemistry, University of British Columbia , Vancouver, BC V6T 1Z1, Canada.
authors.forename: Brian O
authors.initials: BO
authors.lastname: Patrick
authors.affiliation: Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia , Vancouver, BC V6T 1Z1, Canada.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.affiliation: Instituto de Quimica de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.
authors.forename: Roberto G S
authors.initials: RG
authors.lastname: Berlinck
mesh_terms: D018360:Crystallography, X-Ray; D003545:Cysteine; D004354:Drug Screening Assays, Antitumor; D008386:Marine Biology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010407:Penicillium / Q000737:chemistry*; D061065:Polyketides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013237:Stereoisomerism; D015025:Zearalenone / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D061065:Polyketides; D015025:Zearalenone; D003545:Cysteine; C013455:curvularin