Fermentative Production of 2,4-Dihydroxybutyrate from Glucose via a Redox Balanced Route

2,4-Dihydroxybutanoic acid (DHB) is a hydroxy fatty acid originating from butyric acid characterized by hydroxyl groups at the second and fourth carbon positions. Besides being initially synthesized as a precursor for methionine to improve animal nutrition, DHB is also acknowledged as a sustainable platform chemical to produce biobased products in the chemical and pharmaceutical industries with broad market potential. In this study, we illustrated a redox-balanced pathway for the de novo biosynthesis of DHB utilizing the native metabolic route of the E. coli strain, which highlights the advantage of the l-homoserine derived pathway for DHB biosynthesis. Subsequent improvements were achieved through systematic metabolic engineering strategies, including deletion of competing pathways, reinforcement of the biosynthetic pathway, and increasing the availability of precursors. The engineered strain achieved a production titer of 22.0 g/L DHB in a fed-batch bioreactor, the highest ever recorded yield of fermentative DHB production from glucose. This study demonstrated an effective de novo biosynthetic route for the sustainable production of DHB from abundant biomass.