Differential Substrate Sensing in Terpene Synthases from Plants and Microorganisms: Insight from Structural, Bioinformatic, and EnzyDock Analyses

Abstract

Terpene synthases (TPS) catalyze the first step in the formation of terpenoids, which comprise the largest class of natural products in nature. TPS employ a family of universal natural substrates, composed of isoprenoid units bound to a diphosphate moiety. The intricate structures generated by TPS are the result of substrate binding and folding in the active site, enzyme‐controlled carbocation reaction cascades, and final reaction quenching. A key unaddressed question in class I TPS is the asymmetric nature of the diphosphate‐(Mg2+)3 cluster, which forms a critical part of the active site. In this asymmetric ion‐cluster, two diphosphate oxygens protrude into the active site pocket. The substrate hydrocarbon tail, which is eventually molded into terpenes, can bind to either of these oxygens, yet to which is unknown. Here, we employ structural, bioinformatics, and EnzyDock docking tools to address this enigma. We bring initial data suggesting that this difference is rooted in evolutionary differences between TPS. We hypothesize that this alteration in binding, and subsequent chemistry, is due to TPS originating from plants or microorganisms. We further suggest that this difference can cast light on the frequent observation that the chiral products or intermediates of plant and bacterial terpene synthases represent opposite enantiomers.