Molecular basis for two stereoselective Diels-Alderases that produce decalin skeletons

Abstract

Molecular chirality, discovered by Louis Pasteur in the middle of the 19th century1, is found 3 in most primary and secondary metabolites. Particularly, the so-called natural products are 4 rich in chiral centres2. The stereochemistry of natural products is strictly recognized in living 5 organisms, and is thus closely related to their biological functions. The Diels–Alder (DA) 6 reaction, which forms a six-membered ring with up to four chiral centres, is a fundamental 7 practical reaction for C–C bond formation in synthetic chemistry3. Nature has also adopted 8 this reaction to elaborate the complex structures of natural products using enzymes derived 9 from various progenitor proteins4-7. Although enzymes catalysing the DA reaction, Diels–10 Alderases (DAases), have attracted increasing attention, little is known about the molecular 11 mechanism by which they control the stereochemistry and perform catalysis. Here, we solved 12 the X-ray crystal structures of a pair of decalin synthases, Fsa2 and Phm7, that catalyse 13 intramolecular DA reactions to form enantiomeric decalin scaffolds during biosynthesis of the 14 HIV-1 integrase inhibitor equisetin and its stereochemical opposite, phomasetin8,9