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Multienzyme Cascade Catalyzed Skeleton Rearrangement in a Caged Polyketide Biosynthesis
Jia-Liang Zhou1, Qiu-Yue Nie1, Xian-Feng Hou1
1State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences (CAS), CAS, Shanghai 200032, China.
Organic Letters
|December 31, 2024
Summary
Skeletal rearrangement is key for type II polyketide diversity. This study reveals how five oxidoreductases transform a planar intermediate into complex caged lactones, uncovering a multifunctional short-chain dehydrogenase.
Area of Science:
- Natural Product Biosynthesis
- Enzymology
- Organic Chemistry
Background:
- Type II polyketides exhibit significant structural complexity and diversity.
- Skeletal rearrangements are critical for generating this structural diversity.
Purpose of the Study:
- To investigate the enzymatic rearrangement of a planar tetracyclic intermediate to caged lactones in type II polyketide biosynthesis.
- To elucidate the mechanism of this skeletal rearrangement and identify key enzymes involved.
Main Methods:
- Chemical synthesis of the proposed linear tetracyclic substrate.
- In vivo and in vitro experiments to validate the transformation process.
- Isotope labeling studies to elucidate the enzyme-catalyzed mechanism.
Main Results:
- Demonstrated the transformation of a planar tetracyclic intermediate to caged lactones.
- Identified a cascade of five oxidoreductases responsible for the skeletal rearrangement.
- Discovered that the short-chain dehydrogenase TjhD5 possesses multifunctional activity, catalyzing multiple steps in the reaction sequence.
Conclusions:
- The skeletal rearrangement of type II polyketides involves a complex enzymatic cascade.
- TjhD5 is a key enzyme with a multifunctional role in this process, highlighting enzyme adaptability in natural product biosynthesis.
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