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

• DOI: 10.1021/acs.biochem.1c00763
• Publication Date: 2021-12-28T19:55:58Z
• Authors: Marina Toplak; Robin Teufel
• Keywords: 570; Biological Products; 0303 health sciences; 03 medical and health sciences; Bacteria; Bacterial Proteins; Flavoproteins; Flavins; Polyketides; Oxidation-Reduction; Biosynthetic Pathways; Substrate Specificity

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