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

Abstract

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.

Keywords

Aldehyde/alcohol dehydrogenase / Butanol / Carboxylic acid reductase / Clostridium / Cofactor regeneration / Metabolic engineering / Protein engineering

Author Contributions

C.D.M.: Conceptualization, Writing-original draft, Visualization; Q.W.: Writing-review & editing; G.W.: Writingreview & editing; S.-T.Y.: Conceptualization, Writing-review & editing, Visualization, Supervision, Project administration, Funding acquisition.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.

Funding

This work was supported by the Advanced Research Projects Agency-Energy (ARPA-E) (Grant number: DEAR0001512) and the US Department of Energy—Office of Energy Efficiency & Renewable Energy (DOE-EERE) (Grant number: EE0010300).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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