9WAM

Plant O-Methyltransferase SmOMT

Summary for 9WAM

• Entry DOI: 10.2210/pdb9wam/pdb
• Descriptor: Caffeic acid O-methyltransferase, S-ADENOSYL-L-HOMOCYSTEINE (3 entities in total)
• Functional Keywords: an o-methyltransferase, smomt, was identified from the medicinal plant selaginella moellendorffii, transferase
• Biological source: Selaginella moellendorffii
• Total number of polymer chains: 2
• Total formula weight: 78022.19

Authors

Wei, H. (deposition date: 2025-08-12, release date: 2026-08-26)

Primary citation

Xiong, X.,Song, J.,Li, S.,Jin, L.,He, Q.,Zhang, B.,Cao, Y.,Yi, S.,Yang, Y.,Li, X.,Li, J.,Huang, W.
Structure-Guided Engineering of a Promiscuous O-Methyltransferase for a SAM Regeneration Biocatalysis Platform of Methylated Pharmaceuticals.
Adv Sci, 13:e17794-e17794, 2026

PubMed Abstract: O-Methylation catalyzed by plant O-methyltransferase plays a crucial role in both drug design and biosynthesis of natural products. However, their practical applications are often restricted by strict substrate specificity and a strong dependence on the expensive methyl donor S-adenosyl-L-methionine (SAM). Herein, an O-methyltransferase, SmOMT, is identified from the medicinal plant Selaginella moellendorffii, exhibiting substrate promiscuity and regioselectivity. SmOMT catalyzed the methylation of 25 structurally diverse substrates and demonstrated detectable N-methylation activity. Combined ternary complex structure and molecular dynamics studies of SmOMT elucidate its catalytic and regioselectivity mechanisms. A double mutant, SmOMT, with enhanced catalytic activity is obtained based on structural analysis. To overcome SAM dependence, a cascade system for SAM regeneration is successfully constructed by coupling SmOMT with a mutant halide methyltransferase, AtHMT. Employing the iMARS platform, a highly active fusion enzyme, AtHMT-L-SmOMT, 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.

PubMed: 41417579
DOI: 10.1002/advs.202517794

Experimental method

X-RAY DIFFRACTION (2.23 Å)