Recent insights into the biosynthesis and biological activities of the peptide-derived redox cofactor mycofactocin

Covering: 2011 to 2025The importance of redox cofactors like nicotinamide adenine dinucleotide or flavin adenine dinucleotide as cofactors for enzymatic reactions in living organisms is widely known. However, many microbial species also employ unusual redox cofactors such as the coenzyme F₄₂₀ or the peptide-derived pyrroloquinoline quinone (PQQ). In this review, we introduce the reader to the recently discovered bacterial redox cofactor mycofactocin (MFT), a valine-tyrosine-derived small molecule of the class of ribosomally synthesized and post-translationally modified peptides (RiPPs) with remarkable biosynthetic and functional similarities to PQQ. The cofactor plays an important role in the reoxidation of non-exchangeable nicotinamide redox cofactors of specialized oxidoreductases in mycobacteria and related actinobacteria. We highlight the bioinformatic discovery of the mycofactocin gene cluster and its auxiliary genes, present strategies for the chemical synthesis of the cofactor, and take a detailed look at the biosynthesis of the glycosylated molecule. Subsequently, the diverse mycofactocin-inducing conditions and associated oxidoreductase families are reviewed, and a potential electron transfer route from high-energy alcohols via mycofactocin to oxygen as a final electron acceptor is presented. The review concludes with a comparison of the physiological roles of PQQ and MFT, and an outlook for future research questions and potential biotechnological applications of mycofactocin.