Oxygen-transfer reactions by enzymatic flavin-N5 oxygen adducts—Oxidation is not a must

Flavoenzymes catalyze numerous redox reactions including the transfer of an O₂-derived oxygen atom to organic substrates, while the other one is reduced to water. Investigation of some of these monooxygenases led to a detailed understanding of their catalytic cycle, which involves the flavin-C_4α-(hydro)peroxide as hallmark oxygenating species, and newly discovered flavoprotein monooxygenases were generally assumed to operate similarly. However, discoveries in recent years revealed a broader mechanistic versatility, including enzymes that utilize flavin-N₅ oxygen adducts for catalysis in the form of the flavin-N₅-(hydro)peroxide and the flavin-N₅-oxide species. In this review, I will highlight recent developments in that area, including noncanonical flavoenzymes from natural product biosynthesis and sulfur metabolism that provide first insights into the chemical properties of these species. Remarkably, some enzymes may even combine the flavin-N₅-peroxide and the flavin-N₅-oxide species for consecutive oxygen-transfers to the same substrate and thereby in essence operate as dioxygenases.