Multienzyme\nCascade Catalyzed Skeleton Rearrangement\nin a Caged Polyketide Biosynthesis

Rearrangement\nof the skeleton is crucial for improving the structural\ncomplexity and diversity of type II polyketide natural products. In\nthis study, we investigated the rearrangement process from a planar\naromatic tetracyclic intermediate to the caged lactones, which is\nmanaged by five oxidoreductases. We chemically synthesized the proposed\nlinear tetracyclic substrate, validated the transformation process\nthrough <i>in vivo</i> and <i>in vitro</i> experiments,\nand elucidated the enzyme-catalyzed mechanism using isotope labeling.\nSignificantly, a short-chain dehydrogenase TjhD5 was discovered to\nplay a multifunctional role for multistep reactions.