Combining Metabolic Engineering and Biocompatible Chemistry for High-Yield Production of Homo-Diacetyl and Homo-(S,S)-2,3-Butanediol

Biocompatible chemistry is gaining increasing attention because of its potential within biotechnology for expanding the repertoire of biological transformations carried out by enzymes. Here we demonstrate how biocompatible chemistry is used for synthesizing important value-added compounds as well as for linking metabolic pathways to achieve redox balance and rescued growth. By comprehensive rerouting of metabolism, activation of respiration, and finally metal ion catalysis, we successfully manage to convert the homolactic Lactococcus lactis into a homo-diacetyl producer with high titer (95 mM or 8.2 g/L) and high yield (87% of the theoretical maximum). Subsequently, the pathway is extended to (S,S)-2,3-butanediol (S-BDO) through efficiently linking two metabolic pathways by chemical catalysis. The outcome is efficient homo-S-BDO production with a titer of 74 mM (6.7 g/L) S-BDO and a yield of 82%. The diacetyl and S-BDO production rates and yields obtained are the highest reported, demonstrating the promising combination of metabolic engineering and biocompatible chemistry and the great potential of L. lactis as a new production platform.