Discovery and Evolution of [4 + 2] Cyclases

[4 + 2] Cyclases are potent biocatalysts that have been bestowed upon microorganisms and plants by nature, equipping them with the powerful tools to utilize and implement the [4 + 2] cycloaddition reaction for constructing the cyclohexene core in synthesizing valuable molecules. Over the past two years, eleven new enzymes have joined this pericyclase club and undergone extensive investigation. In this review, we present a comprehensive overview of recent advancements in characterizing [4 + 2] cyclases with regard to their catalytic mechanism and stereoselectivity. We particularly focus on insights gained from enzyme co-crystal structures, cofactors, as well as the effects of glycosylation. Advancements in understanding the mechanisms of natural [4 + 2] cyclases offer the potential to mimic evolutionary processes and engineer artificial enzymes for the development of valuable and practical biocatalysts.