2-Keto acids to branched-chain alcohols as biofuels: Application of reaction network analysis and high-level quantum chemical methods to understand thermodynamic landscapes

The discovery of biochemical reaction pathways consisting of both known and novel reactions to synthesize carbon-based compounds is of tremendous interest for the production of biofuels. One attractive target is energy-rich alcohols that can be produced via a series of enzymatic transformations. Computational tools for generating networks of reactions to produce alcohols have been demonstrated, yet the number of potential pathways was still too large to be explored experimentally. Here we present the results of high-level quantum chemical calculations to predict the thermodynamic feasibility of various reactions. The conversion of pyruvic acid to 1-butanol was used as an example system. The free energy landscapes generated using ab initio methods were compared against group contribution analysis for a reaction network of ABE fermentation of pyruvic acid. Secondly, detailed reaction energetics were calculated for Ehrlich’s pathway for the conversion of 2-keto acids to alcohols. Finally, the energetics for the conversion of non-native keto acids such as 2-keto-butanoic acid, 2-keto-valeric acid and 2-keto-isovaleric acid to their corresponding alcohols were evaluated, and the thermodynamic landscapes were compared to that of the native substrate, pyruvic acid.