Cofactor F(420): an expanded view of its distribution, biosynthesis and roles in bacteria and archaea

Many bacteria and archaea produce the redox cofactor F(420). F(420) is structurally similar to the cofactors FAD and FMN but is catalytically more similar to NAD and NADP. These properties allow F(420) to catalyze challenging redox reactions, including key steps in methanogenesis, antibiotic biosynthesis and xenobiotic biodegradation. In the last 5 years, there has been much progress in understanding its distribution, biosynthesis, role and applications. Whereas F(420) was previously thought to be confined to Actinobacteria and Euryarchaeota, new evidence indicates it is synthesized across the bacterial and archaeal domains, as a result of extensive horizontal and vertical biosynthetic gene transfer. F(420) was thought to be synthesized through one biosynthetic pathway; however, recent advances have revealed variants of this pathway and have resolved their key biosynthetic steps. In parallel, new F(420)-dependent biosynthetic and metabolic processes have been discovered. These advances have enabled the heterologous production of F(420) and identified enantioselective F(420)H(2)-dependent reductases for biocatalysis. New research has also helped resolve how microorganisms use F(420) to influence human and environmental health, providing opportunities for tuberculosis treatment and methane mitigation. A total of 50 years since its discovery, multiple paradigms associated with F(420) have shifted, and new F(420)-dependent organisms and processes continue to be discovered.