重构异戊二烯焦磷酸代谢以促进萜类化合物的合成

Engineering ›› 2023, Vol. 28 ›› Issue (9) : 166 -178. DOI: 10.1016/j.eng.2023.03.019

研究论文

徐显皓 ^a^,^b ,
吕雪芹 ^a^,^b ,
崔世修 ^a^,^b ,
刘延峰 ^a^,^b ,
夏洪志 ^c ,
李江华 ^a^,^b ,
堵国成 ^a^,^b ,
李兆丰 ^d ,
陈坚 ^b^,^* ,
刘龙 ^a^,^b^,^*

作者信息 +

Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids Bioproduction

Xianhao Xu ^a^,^b ,
Xueqin Lv ^a^,^b ,
Shixiu Cui ^a^,^b ,
Yanfeng Liu ^a^,^b ,
Hongzhi Xia ^c ,
Jianghua Li ^a^,^b ,
Guocheng Du ^a^,^b ,
Zhaofeng Li ^d ,
Rodrigo Ledesma-Amaro ^e ,
Jian Chen ^b^,^* ,
Long Liu ^a^,^b^,^*

Author information +

文章历史 +

Received	Accepted	Published
2022-06-10	2023-03-21
Issue Date
2024-06-13

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Abstract

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.