Current developments and challenges in the search for a naturally selected Diels-Alderase

Only a very few examples of enzymes known to catalyze pericyclic reactions have been reported, and presently no enzyme has been demonstrated unequivocally to catalyze a Diels-Alder reaction. Nevertheless, research into secondary metabolism has led to the discovery of numerous natural products exhibiting the structural hallmarks of [4 + 2] cycloadditions, prompting efforts to characterize the responsible enzymatic processes. These efforts have resulted in a growing collection of enzymes believed to catalyze pericyclic [4 + 2] cycloaddition reactions; however, in each case the complexity of the substrates and catalytic properties of these enzymes poses significant challenges in substantiating these hypotheses. Herein we consider the principles motivating these efforts and the enzymological systems currently under investigation.

► No enzyme has presently been identified unequivocally as a bona fide Diels-Alderase. ► Structural features of many natural products imply the existence of such an enzyme. ► Interest in these enzymes stems from uncertainty in how catalysis might be achieved. ► Several enzymes are currently under investigation as putative Diels-Alderases. ► Complexity of the substrates and reactions involved has made their study challenging.