Structure‐Guided Engineering of a Promiscuous O ‐Methyltransferase for a SAM Regeneration Biocatalysis Platform of Methylated Pharmaceuticals

, is designed. This fusion enzyme outperforms the free-enzyme cascade system and facilitates the gram-scale synthesis of a series of methylated compounds with enhanced anti-inflammatory activity. This work provides a versatile methylating biocatalyst and establishes an efficient SAM regeneration methylation platform, overcoming limitations in enzymatic methylation and enabling the sustainable production of high-value pharmaceuticals.