Formaldehyde metabolism in the biocatalytic upgrading of lignin

Formaldehyde is a toxic metabolite generated in the bacterial catabolism of lignin-derived aromatic compounds (LDACs) through the oxidative O-demethylation of methoxylated aromatics. Microbial cell factories designed to convert LDACs to commodity chemicals should ideally utilize formaldehyde to improve carbon efficiency and strain fitness. Methylotrophs and natural degraders of LDACs have evolved various strategies for utilizing formaldehyde. These range from cofactor-dependent detoxification systems that extract reducing equivalents to cyclical pathways that synthesize building blocks. In addition, recent engineering efforts, driven in part by interest in C1 feedstocks, have yielded useful synthetic formaldehyde metabolic pathways. In this review, we outline several of these routes, highlighting gaps and metabolic engineering opportunities, with a particular focus on improving LDAC biocatalysts.