Engineering sulfoxide synthases for efficient microbial production of ergothioneine: Mechanisms, strategies, and...

Ergothioneine (ERG), a natural antioxidant with significant physiological functions and commercial value, is increasingly produced via microbial synthesis. Sulfoxide synthases play a pivotal role in this process by catalyzing the CS bond formation between cysteine and histidine derivatives-A rate-limiting step determining ERG yield and economic viability. This review comprehensively summarizes recent advances in the molecular mechanisms, structural features, and substrate selectivity of these enzymes, with a focus on engineering strategies (e.g., enhancing expression, improving activity, and mining novel variants) to boost catalytic efficiency and increase ERG yield. Furthermore, future research directions for sulfoxide synthases and related engineering strategies in promoting ERG biosynthesis are discussed. The insights and engineering approaches presented here extend beyond ERG production, offering a generalizable framework for understanding sulfur biocatalysis and developing high-value sulfur-containing compounds, thus providing broad theoretical and industrial implications for synthetic biology and metabolic engineering.