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Adipic acid has extensive industrial applications in various fields. The direct production of adipic acid by the bioreduction of glucose-derived cis,cis-muconic acid constitutes a remarkably promising pathway. While the enoate reductase from Heyndrickxia coagulanspossesses weak catalytic activity in the conversion of cis,cis-muconic acid to adipic acid, its low activity makes it challenging to meet the demands of industrial production. In this study, we devised an effective multiscale computational strategy to design variants with enhanced activity. A focused library comprising only 15 variants was generated. Experimental validation confirmed that the in vivoactivity of the optimal variant M8(G27M/I374S) was enhanced by 14.2-fold compared to the wild-type enzyme. Adipic acid production reached 0.9 g/L under 10 mM substrate concentration, achieving a yield of 61%, which is about 19 times higher than the wild type (3.2%). Further engineering of metabolic pathways offers promising prospects for achieving industrial biosynthesis of adipic acid.