Combining metabolic engineering and biocompatible chemistry for efficient production of food ingredients

Biocompatible chemistry, that is non‐enzymatic chemical reactions compatible with living organisms, 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 can be used for synthesizing valuable food ingredients 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 managed to convert the homolactic bacterium 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 was extended to (S,S)‐2,3‐butanediol (S‐BDO) through efficiently linking two metabolic pathways via chemical catalysis. This resulted in 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 ever reported, demonstrating the promising combination of metabolic engineering and biocompatible chemistry as well as the great potential of L. lactis as a new production platform.