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 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.