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.
Highlights
Acetyl-Coenzyme A (CoA) is a fundamental metabolite for all life on Earth, and is a key starting point for the biosynthesis of a variety of industrial chemicals and natural products
In order to build an artificial acetyl-CoA pathway from one carbon, we proposed the Synthetic Acetyl-CoA (SACA) pathway, where two molecules of formaldehyde would be transferred into one molecule of acetyl-CoA through only three steps (Fig. 1a)
We could realize the biosynthesis of acetyl-CoA from formaldehyde and even other one-carbon resources
Summary
Acetyl-CoA is a fundamental metabolite for all life on Earth, and is a key starting point for the biosynthesis of a variety of industrial chemicals and natural products. We design and construct a Synthetic Acetyl-CoA (SACA) pathway by repurposing glycolaldehyde synthase and acetyl-phosphate synthase. The SACA pathway was verified by cell growth using glycolaldehyde, formaldehyde and methanol as supplemental carbon source. Microbiology, Chinese Academy of Sciences, 100101 Beijing, China These authors contributed : Xiaoyun Lu, Yuwan Liu, Yiqun Yang, Shanshan Wang. These authors jointly supervised this work: Huifeng Jiang, Yin Li, Yongjun Liu. Correspondence and requests for materials should be addressed to Acetyl-CoA is a hub metabolite in central metabolic pathways for all living life, which harnesses the catabolism and anabolism of almost all fundamental nutrients, such as sugar[1], fat[2,3], and protein[4] in cells.
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