Constructing a synthetic pathway for acetyl-coenzyme A from one-carbon through enzyme design

Xiaoyun Lu, Yuwan Liu, Yiqun Yang, Shanshan Wang, Qian Wang, Xiya Wang, Zhihui Yan, Jian Cheng, Cui Liu, Xue Yang, Hao Luo, Sheng Yang, Junran Gou, Luzhen Ye, Lina Lu, Zhidan Zhang, Yu Guo, Yan Nie, Jianping Lin, Sheng Li, Chaoguang Tian, Tao Cai, Bingzhao Zhuo, Hongwu Ma, Wen Wang, Yanhe Ma, Yongjun Liu (), Yin Li () and Huifeng Jiang ()
Additional contact information
Xiaoyun Lu: Chinese Academy of Sciences
Yuwan Liu: Chinese Academy of Sciences
Yiqun Yang: Chinese Academy of Sciences
Shanshan Wang: ShanghaiTech University
Qian Wang: Chinese Academy of Sciences
Xiya Wang: Shandong University
Zhihui Yan: Chinese Academy of Sciences
Jian Cheng: Chinese Academy of Sciences
Cui Liu: Chinese Academy of Sciences
Xue Yang: Chinese Academy of Sciences
Hao Luo: Chinese Academy of Sciences
Sheng Yang: Chinese Academy of Sciences
Junran Gou: Chinese Academy of Sciences
Luzhen Ye: Chinese Academy of Sciences
Lina Lu: Chinese Academy of Sciences
Zhidan Zhang: Chinese Academy of Sciences
Yu Guo: University of Chinese Academy of Sciences
Yan Nie: ShanghaiTech University
Jianping Lin: Chinese Academy of Sciences
Sheng Li: ShanghaiTech University
Chaoguang Tian: Chinese Academy of Sciences
Tao Cai: Chinese Academy of Sciences
Bingzhao Zhuo: Northwestern Polytechnical University
Hongwu Ma: Chinese Academy of Sciences
Wen Wang: Northwestern Polytechnical University
Yanhe Ma: Chinese Academy of Sciences
Yongjun Liu: Shandong University
Yin Li: Chinese Academy of Sciences
Huifeng Jiang: Chinese Academy of Sciences

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

Abstract: Abstract Acetyl-CoA is a fundamental metabolite for all life on Earth, and is also a key starting point for the biosynthesis of a variety of industrial chemicals and natural products. Here we design and construct a Synthetic Acetyl-CoA (SACA) pathway by repurposing glycolaldehyde synthase and acetyl-phosphate synthase. First, we design and engineer glycolaldehyde synthase to improve catalytic activity more than 70-fold, to condense two molecules of formaldehyde into one glycolaldehyde. Second, we repurpose a phosphoketolase to convert glycolaldehyde into acetyl-phosphate. We demonstrated the feasibility of the SACA pathway in vitro, achieving a carbon yield ~50%, and confirmed the SACA pathway by 13C-labeled metabolites. Finally, the SACA pathway was verified by cell growth using glycolaldehyde, formaldehyde and methanol as supplemental carbon source. The SACA pathway is proved to be the shortest, ATP-independent, carbon-conserving and oxygen-insensitive pathway for acetyl-CoA biosynthesis, opening possibilities for producing acetyl-CoA-derived chemicals from one-carbon resources in the future.

Date: 2019
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DOI: 10.1038/s41467-019-09095-z

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