DFT study on the mechanism of 1,3-hydrogen disposition in Isopentenyl pyrophosphate catalyzed by Isopentenyl pyrophosphate: Dimethylallyl pyrophosphate isomerase

Abstract

Biosynthesis of polyterpenoid and related molecules are largely accomplished via mevalonate pathway. One of the vital steps in this pathway is the inter-conversion of two intermediates isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) catalyzed by IPP:DMAPP isomerase (IDI). The crystal structure of the enzyme, bound to the substrate analogues and inhibitors, revealed possible mechanism of this inter-conversion; however, none of them could affirm the true nature of the transition state through which the process is taking place. Our DFT study on the pathway of this isomerization reaction at the active site of the enzyme suggests a favorable concerted mechanism that occurs through a single transition structure without generating any carbocation intermediate. In this mechanism, the Cys-67 residue acts as proton donor whereas Glu-116 acts as proton acceptor. The mechanism also reveals the active involvement of other two components present at the active site. A crystallographic water molecule (Wat508) and Glu-87 assist to reprotonate the conjugate base of cysteine residue through a proton shuttle mechanism while forming the transition structure of the isomerization reaction.