Mechanism of 3‐Methylglutaconyl CoA Decarboxylase AibA/AibB: Pericyclic Reaction versus Direct Decarboxylation

Abstract The enzyme 3‐methylglutaconyl coenzyme A (CoA) decarboxylase (called AibA/AibB) catalyzes the decarboxylation of 3‐methylglutaconyl CoA to generate 3,3‐dimethylacrylyl‐CoA, representing an important step in the biosynthesis of isovaleryl‐coenzyme A in Myxococcus xanthus when the regular pathway is blocked. A novel mechanism involving a pericyclic transition state has previously been proposed for this enzyme, making AibA/AibB unique among decarboxylases. Herein, density functional calculations are used to examine the energetic feasibility of this mechanism. It is shown that the intramolecular pericyclic reaction is associated with a very high energy barrier that is similar to the barrier of the same reaction in the absence of the enzyme. Instead, the calculations show that a direct decarboxylation mechanism has feasible energy barriers that are in line with the experimental observations.