Three Rings to Rule Them All: How Versatile Flavoenzymes Orchestrate the Structural Diversification of Natural Products

[Image: see text] The structural diversification of natural products is instrumental to their versatile bioactivities. In this context, redox tailoring enzymes are commonly involved in the modification and functionalization of advanced pathway intermediates en route to the mature natural products. In recent years, flavoprotein monooxygenases have been shown to mediate numerous redox tailoring reactions that include not only (aromatic) hydroxylation, Baeyer–Villiger oxidation, or epoxidation reactions but also oxygenations that are coupled to extensive remodeling of the carbon backbone, which are often central to the installment of the respective pharmacophores. In this Perspective, we will highlight recent developments and discoveries in the field of flavoenzyme catalysis in bacterial natural product biosynthesis and illustrate how the flavin cofactor can be fine-tuned to enable chemo-, regio-, and stereospecific oxygenations via distinct flavin-C4a-peroxide and flavin-N5-(per)oxide species. Open questions remain, e.g., regarding the breadth of chemical reactions enabled particularly by the newly discovered flavin-N5-oxygen adducts and the role of the protein environment in steering such cascade-like reactions. Outstanding cases involving different flavin oxygenating species will be exemplified by the tailoring of bacterial aromatic polyketides, including enterocin, rubromycins, rishirilides, mithramycin, anthracyclins, chartreusin, jadomycin, and xantholipin. In addition, the biosynthesis of tropone natural products, including tropolone and tropodithietic acid, will be presented, which features a recently described prototypical flavoprotein dioxygenase that may combine flavin-N5-peroxide and flavin-N5-oxide chemistry. Finally, structural and mechanistic features of selected enzymes will be discussed as well as hurdles for their application in the formation of natural product derivatives via bioengineering.