Promiscuous enzymatic activity-aided multiple-pathway network design for metabolic flux rearrangement in hydroxytyrosol biosynthesis

Wei Chen, Jun Yao, Jie Meng, Wenjing Han, Yong Tao, Yihua Chen, Yixin Guo, Guizhi Shi, Yang He (), Jian-Ming Jin () and Shuang-Yan Tang ()
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Wei Chen: Institute of Microbiology, Chinese Academy of Sciences
Jun Yao: Institute of Microbiology, Chinese Academy of Sciences
Jie Meng: Institute of Microbiology, Chinese Academy of Sciences
Wenjing Han: Beijing Technology and Business University
Yong Tao: Institute of Microbiology, Chinese Academy of Sciences
Yihua Chen: Institute of Microbiology, Chinese Academy of Sciences
Yixin Guo: Yunnan Provincial Academy of Science and Technology
Guizhi Shi: University of Chinese Academy of Sciences
Yang He: Zhejiang University
Jian-Ming Jin: Beijing Technology and Business University
Shuang-Yan Tang: Institute of Microbiology, Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Genetic diversity is a result of evolution, enabling multiple ways for one particular physiological activity. Here, we introduce this strategy into bioengineering. We design two hydroxytyrosol biosynthetic pathways using tyrosine as substrate. We show that the synthetic capacity is significantly improved when two pathways work simultaneously comparing to each individual pathway. Next, we engineer flavin-dependent monooxygenase HpaBC for tyrosol hydroxylase, tyramine hydroxylase, and promiscuous hydroxylase active on both tyrosol and tyramine using directed divergent evolution strategy. Then, the mutant HpaBCs are employed to catalyze two missing steps in the hydroxytyrosol biosynthetic pathways designed above. Our results demonstrate that the promiscuous tyrosol/tyramine hydroxylase can minimize the cell metabolic burden induced by protein overexpression and allow the biosynthetic carbon flow to be divided between two pathways. Thus, the efficiency of the hydroxytyrosol biosynthesis is significantly improved by rearranging the metabolic flux among multiple pathways.

Date: 2019
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DOI: 10.1038/s41467-019-08781-2

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