Recent Advances and Challenges in Engineering Metabolic Pathways and Cofactor Regeneration for Enhanced n-Butanol Biosynthesis

The biological production of n-butanol has seen renewed interest due to the need for the production of sustainable aviation fuel, for which n-butanol serves as a direct precursor. However, biological production of this alcohol is still limited by the fermentation’s low titers and low yields. Many approaches have been taken to increase n-butanol production, such as using alternative host organisms, utilizing heterologous enzymes for acid reduction and cofactor regeneration, and protein engineering of critical enzymes in the n-butanol production metabolic pathway. This review highlights key achievements made in each of these areas and shows the potential for these approaches in increasing n-butanol production. The review closes by pinpointing the challenges and limitations in these approaches and recommends that the ultimate approach to n-butanol production should inevitably utilize noncanonical redox cofactors to drive metabolic flux for butanol biosynthesis from glucose.