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

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-phosphat...

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Published in:	Nature communications Vol. 10; no. 1; p. 1378
Main Authors:	Lu, Xiaoyun, Liu, Yuwan, Yang, Yiqun, Wang, Shanshan, Wang, Qian, Wang, Xiya, Yan, Zhihui, Cheng, Jian, Liu, Cui, Yang, Xue, Luo, Hao, Yang, Sheng, Gou, Junran, Ye, Luzhen, Lu, Lina, Zhang, Zhidan, Guo, Yu, Nie, Yan, Lin, Jianping, Li, Sheng, Tian, Chaoguang, Cai, Tao, Zhuo, Bingzhao, Ma, Hongwu, Wang, Wen, Ma, Yanhe, Liu, Yongjun, Li, Yin, Jiang, Huifeng
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 26-03-2019 Nature Publishing Group Nature Portfolio
Subjects:	631/553/552 631/61/318 Acetaldehyde - analogs & derivatives Acetaldehyde - metabolism Acetyl Coenzyme A - biosynthesis Aldehyde-Lyases - genetics Aldehyde-Lyases - metabolism Biosynthesis Carbon Carbon - metabolism Carbon sources Catalysis Catalytic activity Cell growth Chemicals Coenzyme A Design Design engineering Escherichia coli - genetics Escherichia coli - metabolism Feasibility studies Formaldehyde Formaldehyde - metabolism Glycolaldehyde Humanities and Social Sciences Metabolic Engineering Metabolites multidisciplinary Natural products Organic chemistry Organophosphates - metabolism Phosphates Phosphoketolase Plasmids Science Science (multidisciplinary)
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Summary:	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 13 C-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. The microbial synthesis of carbon-containing compounds from single carbon precursors is desirable, yet designed pathways to achieve this goal overlap with host metabolism. Here the authors design a de novo metabolic pathway to assimilate formaldehyde into acetyl-CoA that does not overlap with known metabolic networks.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-09095-z