Synthetic Formatotrophs for One-Carbon Biorefinery

The use of CO₂ as a carbon source in biorefinery is of great interest, but the low solubility of CO₂ in water and the lack of efficient CO₂ assimilation pathways are challenges to overcome. Formic acid (FA), which can be easily produced from CO₂ and more conveniently stored and transported than CO₂, is an attractive CO₂-equivalent carbon source as it can be assimilated more efficiently than CO₂ by microorganisms and also provides reducing power. Although there are native formatotrophs, they grow slowly and are difficult to metabolically engineer due to the lack of genetic manipulation tools. Thus, much effort is exerted to develop efficient FA assimilation pathways and synthetic microorganisms capable of growing solely on FA (and CO₂). Several innovative strategies are suggested to develop synthetic formatotrophs through rational metabolic engineering involving new enzymes and reconstructed FA assimilation pathways, and/or adaptive laboratory evolution (ALE). In this paper, recent advances in development of synthetic formatotrophs are reviewed, focusing on biological FA and CO₂ utilization pathways, enzymes involved and newly developed, and metabolic engineering and ALE strategies employed. Also, future challenges in cultivating formatotrophs to higher cell densities and producing chemicals from FA and CO₂ are discussed.