Biocatalytic and synthetic biology strategies for S-type lignin valorization

Lignin, as one of the most abundant natural aromatic polymers, holds significant potential for valorization into high-value products. However, its complex and heterogeneous structure presents a major challenge for bioconversion. This review focuses on the bioconversion of lignin-derived syringyl monomers, which are characterized by 3,5-dimethoxy-substituted aromatic rings that create metabolic bottlenecks during microbial O-demethylation and ring cleavage. Recent advances are summarized in lignin depolymerization, biological funneling, and synthetic biology-driven pathway design for converting syringyl monomers into value-added products. Special attention is given to critical enzymes, including Rieske non-heme iron monooxygenases, tetrahydrofolate-dependent O-demethylase systems, and cytochrome P450 peroxygenases, which are pivotal for demethylation. Furthermore, metabolic engineering strategies are discussed to enhance the efficiency of lignin conversion and address challenges such as cofactor imbalance and intermediate toxicity. Finally, this review discusses future research priorities, including broad-substrate-range O-demethylase engineering, host tolerance improvement, validation using realistic lignin-derived streams, and industrial translation. Advancing the bioconversion of lignin syringyl monomers could enable sustainable production of renewable products and supports a circular bioeconomy.