De novo biosynthesis of the hops bioactive flavonoid xanthohumol in yeast

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作者
Shan Yang
Ruibing Chen
Xuan Cao
Guodong Wang
Yongjin J. Zhou
机构
[1] Chinese Academy of Sciences,Division of Biotechnology, Dalian Institute of Chemical Physics
[2] University of Chinese Academy of Sciences,State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, The Innovative Academy of Seed Design
[3] Chinese Academy of Sciences,CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics
[4] Chinese Academy of Sciences,Dalian Key Laboratory of Energy Biotechnology, Dalian Institute of Chemical Physics
[5] Chinese Academy of Sciences,undefined
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Nature Communications | / 15卷
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摘要
The flavonoid xanthohumol is an important flavor substance in the brewing industry that has a wide variety of bioactivities. However, its unstable structure results in its low content in beer. Microbial biosynthesis is considered a sustainable and economically viable alternative. Here, we harness the yeast Saccharomyces cerevisiae for the de novo biosynthesis of xanthohumol from glucose by balancing the three parallel biosynthetic pathways, prenyltransferase engineering, enhancing precursor supply, constructing enzyme fusion, and peroxisomal engineering. These strategies improve the production of the key xanthohumol precursor demethylxanthohumol (DMX) by 83-fold and achieve the de novo biosynthesis of xanthohumol in yeast. We also reveal that prenylation is the key limiting step in DMX biosynthesis and develop tailored metabolic regulation strategies to enhance the DMAPP availability and prenylation efficiency. Our work provides feasible approaches for systematically engineering yeast cell factories for the de novo biosynthesis of complex natural products.
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