Raising the production of phloretin by alleviation of by-product of chalcone synthase in the engineered yeast
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ising the production of phloretin by alleviation of by-product of chalcone synthase in the engineered yeast 1†
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Chunmei Jiang , Xiaonan Liu , Xianqing Chen , Yi Cai , Yibin Zhuang , Tian Liu , 2,3 2 2 2* 4* Xiaoxi Zhu , Hui Wang , Yuwan Liu , Huifeng Jiang & Wen Wang 1
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Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an
710072, China; Key Laboratory of Systems Microbial Biotechnology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China; University of Chinese Academy of Sciences, Beijing 100049, China; 4 Center for Ecology and Environmental Sciences, Northwestern Polytechnical University, Xi’an 710072, China; 5 Jiaxing Synbiolab Biotechnology Co., Ltd., Jiaxing 314006, China 3
Received November 19, 2019; accepted January 17, 2020; published online April 27, 2020
Phloretin is an important skin-lightening and depigmenting agent from the peel of apples. Although de novo production of phloretin has been realized in microbes using the natural pathway from plants, the efficiency of phloretin production is still not enough for industrial application. Here, we established an artificial pathway in the yeast to produce phloretin via assembling two genes of p-coumaroyl-CoA ligase (4CL) and chalcone synthase (CHS). CHS is a key enzyme which conventionally condenses a CoA-tethered starter with three molecules of malonyl-CoA to form the backbone of flavonoids. However, there was 33% of byproduct generated via CHS by condensing two molecules of malonyl-CoA during the fermentation process. Hence, we introduced a more efficient CHS and improved the supply of malonyl-CoA through two pathways; the by-product ratio was –1 decreased from 33% to 17% and the production of phloretin was improved from 48 to 83.2 mg L . Finally, a fed-batch –1 fermentation process was optimized and the production of phloretin reached 619.5 mg L , which was 14-fold higher than that of the previous studies. Our work established a platform for the biosynthesis of phloretin from the low-cost raw material 3-(4hydroxyphenyl) propanoic acid and also illustrated the potential for industrial scale bio-manufacturing of phloretin. phloretin, Saccharomyces cerevisiae, metabolic engineering, microbial cell factories, fed-batch fermentation Citation:
Jiang, C., Liu, X., Chen, X., Cai, Y., Zhuang, Y., Liu, T., Zhu, X., Wang, H., Liu, Y., Jiang, H., et al. (2020). Raising the production of phloretin by alleviation of by-product of chalcone synthase in the engineered yeast. Sci China Life Sci 63, https://doi.org/10.1007/s11427-019-1634-8
INTRODUCTION Phloretin, a dihydrochalcone, was firstly identified in the peel and bark of apples (Petersen, 1835; Gosch et al., 2009; Rana and Bhushan, 2016). In recent years, phloretin has been used in medical and cosmetic industries for its skin-light-
†Contributed equally to this work *Corresponding authors (Wen Wang, email: [email protected]; Huifeng Jiang, email: [email protected])
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