| Affiliation: | 1. Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan;2. Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, Chiba, Japan;3. National Institute of Health Sciences, Tokyo, Japan;4. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA;5. Department of Chemical and Biomolecular Engineering and, Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA;6. School of Biosciences, The University of Nottingham Malaysia Campus, Selangor, Malaysia |
| Abstract: | 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 . |
