Mapping epoxyquinoid biosynthesis: Enzyme functions across bacteria and fungi

Epoxyquinoids are a unique class of natural products featuring an epoxide embedded within a quinone/quinol scaffold, typically as an epoxycyclohexenone (ECH). Their striking stereochemical diversity arises from multiple permutations of epoxide and hydroxyl configurations across the epoxyquinol and epoxyhydroquinone families. These highly oxygenated cores contain contiguous stereocenters and reactive functionalities, and their structural diversity correlates with broad bioactivity spanning antibacterial, antifungal, antiparasitic, anti-inflammatory, and antiproliferative effects. A shared epoxide-quinone (or keto-epoxide) pharmacophore acts as an electrophilic warhead that covalently engages protein nucleophiles via Michael addition and epoxide opening, underpinning diverse modes of action. Recent biosynthetic advances have uncovered tailoring enzymes with unusual catalytic strategies that forge the epoxide, install additional functionality, and tune oxidation states through redox chemistry. This review highlights current knowledge of experimentally characterized pathways and enzyme functions across Actinobacteria, Ascomycota, and Basidiomycota, illuminating common logic and organism-specific innovations in epoxyquinoid assembly.