The article discusses the challenges of methyltransferase efficiency in natural product diversification, focusing on ferulic acid biosynthesis. By engineering the substrate binding pocket of caffeic acid O-methyltransferase (AtCOMT) to enhance hydrogen bond interactions, a mutant with higher catalytic efficiency and substrate specificity was developed. This mutant exhibited a 5.79-fold increase in kcat/Km compared to the wild-type. Through fed-batch fermentation, a titer of 1.273 g/L ferulic acid was achieved, representing a remarkable 21.3-fold improvement over the wild-type. The study highlighted the potential of rational design involving hydrogen bond networks to enhance enzyme activity and specificity, paving the way for efficient biosynthesis of valuable compounds like ferulic acid in a sustainable and green manner.