Recent advances in understanding the enzymatic reactions of [4+2] cycloaddition and spiroketalization.

Diels-Alder-like [4+2] cycloaddition and ketalization of dihydroxy ketones are cyclization reactions with different mechanisms that produce characteristic cyclohexene and spiroketal units, respectively. Here, we review newly identified, naturally occurring '[4+2] cycloadditionases' and 'spiroketalases' and reveal several similarities between the two types of enzymes. During catalysis, these enzymes control product stereochemistry or/and enhance the transformation rate. They exhibit convergent evolution of [4+2] cycloaddition or spiroketalization activity, which is likely dependent on interactions of variable protein folds with specialized chemical structures. An understanding of these similarities is expected to allow for establishment of the underlying principles for the application and catalyst design of associated enzymatic reactions in organic chemistry and synthetic biology.