Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids Bioproduction  

作　　者：Xianhao Xu Xueqin Lv Shixiu Cui Yanfeng Liu Hongzhi Xia Jianghua Li Guocheng Du Zhaofeng Li Rodrigo Ledesma-Amaro Jian Chen Long Liu 

机构地区：[1]Key Laboratory of Carbohydrate Chemistry and Biotechnology,Ministry of Education,Jiangnan University,Wuxi 214122,China [2]Science Center for Future Foods,Ministry of Education,Jiangnan University,Wuxi 214122,China [3]Richen Bioengineering Co.,Ltd.,Nantong 226000,China [4]State Key Laboratory of Food Science and Technology,Jiangnan University,Wuxi 214122,China [5]Department of Bioengineering and Centre for Synthetic Biology,Imperial College London,London SW72AZ,UK

出　　处：《Engineering》2023年第9期166-178,共13页工程（英文）

基　　金：financially supported by the National Natural Science Foundation of China(32070085,32200050,31871784,and 32021005);the Natural Science Foundation of Jiangsu Province(BK20221079);National Postdoctoral Program for Innovative Talents(BX20220136);the Jiangsu Funding Program for Excellent Postdoctoral Talent(2022ZB498);the Fundamental Research Funds for the Central Universities(JUSRP52019A,JUSRP121010 and JUSRP221013);National Key Research and Development Program of China(2020YFA0908300);Postgraduate Research&Practice Innovation Program of Jiangsu Provence(KYCX18_1797)。

摘　　要：Terpenoids are the largest family of natural products.They are made from the building block isoprene pyrophosphate(IPP),and their bioproduction using engineered cell factories has received a great deal of attention.To date,the insufficient metabolic supply of IPP remains a great challenge for the efficient synthesis of terpenoids.In this work,we discover that the imbalanced metabolic flux distribution between the central metabolism and the IPP supply hinders IPP accumulation in Bacillus subtilis(B.subtilis).Therefore,we remodel the IPP metabolism using a series of genetically encoded two-input-multioutput(TIMO)circuits that are responsive to pyruvate or/and malonyl-CoA,resulting in an IPP pool that is significantly increased by up to four-fold.As a proof-of-concept validation,we design an IPP metabolism remodeling strategy to improve the production of three valuable terpenoids,including menaquinone-7(MK-7,4.1-fold),lycopene(9-fold),andβ-carotene(0.9-fold).In particular,the titer of MK-7 in a 50-L bioreactor reached 1549.6 mg·L^(-1),representing the highest titer reported so far.Thus,we propose a TIMO genetic circuits-assisted IPP metabolism remodeling framework that can be generally used for the synergistic fine-tuning of complicated metabolic modules to achieve the efficient bioproduction of terpenoids.

关 键 词：TERPENOIDS Genetic circuits Bacillus subtilis Isoprene pyrophosphate 

分 类 号：O629.61[理学—有机化学]