Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids Bioproduction
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 t...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Engineering |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2095809923002771 |
| _version_ | 1797388838461505536 |
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| author | Xianhao Xu Xueqin Lv Shixiu Cui Yanfeng Liu Hongzhi Xia Jianghua Li Guocheng Du Zhaofeng Li Rodrigo Ledesma-Amaro Jian Chen Long Liu |
| author_facet | Xianhao Xu Xueqin Lv Shixiu Cui Yanfeng Liu Hongzhi Xia Jianghua Li Guocheng Du Zhaofeng Li Rodrigo Ledesma-Amaro Jian Chen Long Liu |
| author_sort | Xianhao Xu |
| collection | DOAJ |
| description | 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-multi-output (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), and β-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. |
| first_indexed | 2024-03-08T22:47:07Z |
| format | Article |
| id | doaj.art-ca938e727558457f9f2a7d988c5bb549 |
| institution | Directory Open Access Journal |
| issn | 2095-8099 |
| language | English |
| last_indexed | 2024-03-08T22:47:07Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Engineering |
| spelling | doaj.art-ca938e727558457f9f2a7d988c5bb5492023-12-17T06:38:20ZengElsevierEngineering2095-80992023-09-0128166178Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids BioproductionXianhao Xu0Xueqin Lv1Shixiu Cui2Yanfeng Liu3Hongzhi Xia4Jianghua Li5Guocheng Du6Zhaofeng Li7Rodrigo Ledesma-Amaro8Jian Chen9Long Liu10Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China; Science Center for Future Foods, Ministry of Education, Jiangnan University, Wuxi 214122, ChinaKey Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China; Science Center for Future Foods, Ministry of Education, Jiangnan University, Wuxi 214122, ChinaKey Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China; Science Center for Future Foods, Ministry of Education, Jiangnan University, Wuxi 214122, ChinaKey Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China; Science Center for Future Foods, Ministry of Education, Jiangnan University, Wuxi 214122, ChinaRichen Bioengineering Co., Ltd., Nantong 226000, ChinaKey Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China; Science Center for Future Foods, Ministry of Education, Jiangnan University, Wuxi 214122, ChinaKey Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China; Science Center for Future Foods, Ministry of Education, Jiangnan University, Wuxi 214122, ChinaState Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, ChinaDepartment of Bioengineering and Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UKScience Center for Future Foods, Ministry of Education, Jiangnan University, Wuxi 214122, China; Corresponding authors.Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China; Science Center for Future Foods, Ministry of Education, Jiangnan University, Wuxi 214122, China; Corresponding authors.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-multi-output (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), and β-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.http://www.sciencedirect.com/science/article/pii/S2095809923002771TerpenoidsGenetic circuitsBacillus subtilisIsoprene pyrophosphate |
| spellingShingle | Xianhao Xu Xueqin Lv Shixiu Cui Yanfeng Liu Hongzhi Xia Jianghua Li Guocheng Du Zhaofeng Li Rodrigo Ledesma-Amaro Jian Chen Long Liu Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids Bioproduction Engineering Terpenoids Genetic circuits Bacillus subtilis Isoprene pyrophosphate |
| title | Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids Bioproduction |
| title_full | Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids Bioproduction |
| title_fullStr | Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids Bioproduction |
| title_full_unstemmed | Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids Bioproduction |
| title_short | Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids Bioproduction |
| title_sort | remodeling isoprene pyrophosphate metabolism for promoting terpenoids bioproduction |
| topic | Terpenoids Genetic circuits Bacillus subtilis Isoprene pyrophosphate |
| url | http://www.sciencedirect.com/science/article/pii/S2095809923002771 |
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