title: Characterization of the biosynthetic genes for 10,11-dehydrocurvularin, a heat shock response-modulating anticancer fungal polyketide from Aspergillus terreus.
abstract: 10,11-Dehydrocurvularin is a prevalent fungal phytotoxin with heat shock response and immune-modulatory activities. It features a dihydroxyphenylacetic acid lactone polyketide framework with structural similarities to resorcylic acid lactones like radicicol or zearalenone. A genomic locus was identified from the dehydrocurvularin producer strain Aspergillus terreus AH-02-30-F7 to reveal genes encoding a pair of iterative polyketide synthases (A. terreus CURS1 [AtCURS1] and AtCURS2) that are predicted to collaborate in the biosynthesis of 10,11-dehydrocurvularin. Additional genes in this locus encode putative proteins that may be involved in the export of the compound from the cell and in the transcriptional regulation of the cluster. 10,11-Dehydrocurvularin biosynthesis was reconstituted in Saccharomyces cerevisiae by heterologous expression of the polyketide synthases. Bioinformatic analysis of the highly reducing polyketide synthase AtCURS1 and the nonreducing polyketide synthase AtCURS2 highlights crucial biosynthetic programming differences compared to similar synthases involved in resorcylic acid lactone biosynthesis. These differences lead to the synthesis of a predicted tetraketide starter unit that forms part of the 12-membered lactone ring of dehydrocurvularin, as opposed to the penta- or hexaketide starters in the 14-membered rings of resorcylic acid lactones. Tetraketide N-acetylcysteamine thioester analogues of the starter unit were shown to support the biosynthesis of dehydrocurvularin and its analogues, with yeast expressing AtCURS2 alone. Differential programming of the product template domain of the nonreducing polyketide synthase AtCURS2 results in an aldol condensation with a different regiospecificity than that of resorcylic acid lactones, yielding the dihydroxyphenylacetic acid scaffold characterized by an S-type cyclization pattern atypical for fungal polyketides.
authors: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, The University of Arizona, Tucson, Arizona, USA.
authors: Yuquan
authors: Y
authors: Xu
authors: Patricia
authors: P
authors: Espinosa-Artiles
authors: Vivien
authors: V
authors: Schubert
authors: Ya-ming
authors: YM
authors: Xu
authors: Wei
authors: W
authors: Zhang
authors: Min
authors: M
authors: Lin
authors: A A Leslie
authors: AA
authors: Gunatilaka
authors: Roderich
authors: R
authors: Süssmuth
authors: István
authors: I
authors: Molnár
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D001230:Aspergillus / Q000235:genetics* / Q000378:metabolism*; D053898:Biosynthetic Pathways / Q000235:genetics*; D019295:Computational Biology; D004271:DNA, Fungal / Q000737:chemistry / Q000235:genetics; D018869:Heat-Shock Response / Q000187:drug effects; D060847:Metabolic Engineering; D008969:Molecular Sequence Data; D061065:Polyketides / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015025:Zearalenone / Q000031:analogs & derivatives / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D004271:DNA, Fungal; D061065:Polyketides; C013914:dehydrocurvularin; D015025:Zearalenone