Involvement of Lipocalin-like CghA in Decalin-Forming Stereoselective Intramolecular [4+2] Cycloaddition

Understanding enzymatic Diels–Alder (DA) reactions that can form complex natural product scaffolds is of considerable interest. Sch 210972 1, a potential anti‐HIV fungal natural product, contains a decalin core that is proposed to form through a DA reaction. We identified the gene cluster responsibl...

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Veröffentlicht in:Chembiochem : a European journal of chemical biology 2015-11, Vol.16 (16), p.2294-2298
Hauptverfasser: Sato, Michio, Yagishita, Fumitoshi, Mino, Takashi, Uchiyama, Nahoko, Patel, Ashay, Chooi, Yit-Heng, Goda, Yukihiro, Xu, Wei, Noguchi, Hiroshi, Yamamoto, Tsuyoshi, Hotta, Kinya, Houk, Kendall N., Tang, Yi, Watanabe, Kenji
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Sprache:eng
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Zusammenfassung:Understanding enzymatic Diels–Alder (DA) reactions that can form complex natural product scaffolds is of considerable interest. Sch 210972 1, a potential anti‐HIV fungal natural product, contains a decalin core that is proposed to form through a DA reaction. We identified the gene cluster responsible for the biosynthesis of 1 and heterologously reconstituted the biosynthetic pathway in Aspergillus nidulans to characterize the enzymes involved. Most notably, deletion of cghA resulted in a loss of stereoselective decalin core formation, yielding both an endo (1) and a diastereomeric exo adduct of the proposed DA reaction. Complementation with cghA restored the sole formation of 1. Density functional theory computation of the proposed DA reaction provided a plausible explanation of the observed pattern of product formation. Based on our study, we propose that lipocalin‐like CghA is responsible for the stereoselective intramolecular [4+2] cycloaddition that forms the decalin core of 1. Decalin decadence: The C. globosum gene cluster responsible for the biosynthesis of Sch 210972, a potential anti‐HIV fungal polyketide–nonribosomal peptide hybrid natural product, has been identified. Genetic, biochemical and computational studies revealed the function of four enzymes involved. Most notably, lipocalin‐like CghA facilitates a stereoselective intramolecular [4+2] cycloaddition to form the decalin core.
ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.201500386