Enzymatic Cascade Reactions in Biosynthesis

Abstract

Enzyme-mediated cascade reactions are widespread in biosynthesis. To facilitate comparison with the mechanistic categorizations of cascade reactions by synthetic chemists and delineate the common underlying chemistry, we discuss four types of enzymatic cascade reactions: those involving nucleophilic, electrophilic, pericyclic, and radical reactions. Two subtypes of enzymes that generate radical cascades exist at opposite ends of the oxygen abundance spectrum. Iron-based enzymes use O ₂ to generate high valent iron-oxo species to homolyze unactivated C–H bonds in substrates to initiate skeletal rearrangements. At anaerobic end, enzymes reversibly cleave S-adenosylmethionine (SAM) to generate the 5’-deoxyadenosyl radical as a powerful oxidant to initiate C–H bond homolysis in bound substrates. The latter enzymes are termed radical SAM enzymes. We categorize the former as “thwarted oxygenases”.

Graphical Abstract

Fantastic four: Generally, enzymes are highly selective catalysts for single reactions. However, some enzymes instead control a series of reactions in a cascade-like fashion. This Review highlights four types of enzymatic cascade strategies, mediated by nucleophilic, electrophilic, pericyclic, and radical-based reactions, observed in the biosynthesis of complex natural products