Figure 1.

Overall strategies of systems metabolic engineering for the bio‐based production of chemicals from FA and CO₂. Synthetic formatotrophs are developed by constructing synthetic FA assimilation pathways, introducing Fdhs to supply ATP and reducing powers from FA, and employing ALE and/or rational metabolic engineering strategies, such as redistribution of carbon flux, optimization of gene expression, enhancement of ATP conversion, and optimization of culture condition. Then, fermentation processes are developed to facilitate enhanced formatotrophic growth. Finally, the synthetic formatotrophs are metabolically engineered for fermentative production of chemicals. Abbreviations are: Ac‐CoA, acetyl‐CoA; Cyd, cytochrome bd‐I ubiquinol oxidase; Cyo, cytochrome bo3 ubiquinol oxidase; F6P, fructose 6‐phosphate; FA, formic acid; G6P, glucose 6‐phosphate; GAP, glyceraldehyde 3‐phosphate; Glu, glucose; GOI, gene of interest; LPS, lipopolysaccharide; PEP, phosphoenolpyruvate; PYR, pyruvate; R5P, ribose 5‐phosphate; SA, succinic acid; LA, lactate; Fdh, formate dehydrogenase.