QM/MM studies of the type II isopentenyl diphosphate–dimethylallyl diphosphate isomerase demonstrate a novel role for the flavin coenzyme

Abstract

The type II isopentenyl diphosphate:dimethylallyl diphosphate isomerase (IDI-2) catalyzes the reversible isomerization of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). Although a growing body of experiments have suggested that the flavin coenzyme of IDI-2 serves a novel function as an acid–base catalyst, the detailed reaction mechanism of IDI-2 is still unknown. In this paper, a combined quantum-mechanical/molecular-mechanical (QM/MM) approach has been applied to investigate the detailed reaction mechanism of IDI-2. The one-base mechanism in which the N-5 nitrogen of the zwitterionic form of reduced FMN acts as the acid–base catalyst has been supported by our computational results, and a IPP-FMN adduct is also proposed for the first time. The mechanistic details including the fundamental reaction pathways, the complete energy profiles of the whole catalytic cycle, and the specific role of the coenzyme and key residues are all obtained. It is proved that IDI-2 employs novel flavin chemistry with the coenzyme acting as a general acid–base catalyst.