Sustainable metabolic engineering requires a perfect trifecta

The versatility of cellular metabolism in converting various substrates to products inspires sustainable alternatives to conventional chemical processes. Metabolism can be engineered to maximize the yield, rate, and titer of product generation. However, the numerous combinations of substrate, product, and organism make metabolic engineering projects difficult to navigate. A perfect trifecta of substrate, product, and organism is prerequisite for an environmentally and economically sustainable metabolic engineering endeavor. As a step toward this endeavor, we propose a reverse engineering strategy that starts with product selection, followed by substrate and organism pairing. While a large bioproduct space has been explored, the top-ten compounds have been synthesized mainly using glucose and model organisms. Unconventional feedstocks (e.g. hemicellulosic sugars and CO₂) and non-model organisms are increasingly gaining traction for advanced bioproduct synthesis due to their specialized metabolic modes. Judicious selection of the substrate-organism-product combination will illuminate the untapped territory of sustainable metabolic engineering.