Isomerization

Abstract

Isomerization reactions are important in metabolism to potentiate further transformations that would otherwise be chemically impossible. A familiar example from glycolysis is phosphohexose isomerase, which catalyzes the interconversion of D-glusose-6-P and D-fructose-6-P. The formation of fructose-6-P makes it chemically feasible at a later step of glycolysis to cleave the six-carbon sugar into two three-carbon sugars, glyceraldehyde-3-P, and dihydroxyacetone-P by aldolase. No such cleavage of glucose-6-P into two three-carbon sugars is possible. The dihydroxyacetone-3-P is converted into glyceraldehyde-3-P by another isomerase, triosephosphate isomerase. In this way, glucose-6-P can be transformed into two molecules of glyceraldehyde-3-P, which can then be metabolized through glycolysis to pyruvate. Both reactions of phosphohexose and triosephosphate isomerases involve aldose/ketose interconversions and proceed by similar chemical mechanisms. Other important isomerases include phosphomutases, epimerases, racemases, and carbon-skeleton mutases, all of which have their roles in metabolism. The chemical mechanisms vary with the classes of isomerases and include enolizations, hydride transfer, oxidation/reduction, phosphotransfer, and radical rearrangements. In this chapter, we consider the mechanisms by which enzymes catalyze isomerization reaction. The interconversions of glucose-6-P and fructose-6-P and of the triose phosphates can be formulated chemically. The transformation in is an internal oxidation-reduction, in which the aldehyde group of the aldose is reduced and the neighboring alcoholic group is oxidized. This reaction can take place by either of two chemical mechanisms: an initial enolization at C2 to produce an enediolate intermediate that can be protonated at C1 to produce the product or a direct hydride transfer from C2 to C1. These mechanisms are outlined in scheme 7-1. Loss of the proton C2(H) by enolization in the upper pathway leads to the enediolate intermediate, and return of the proton to C1 (black arrows in scheme 7-1) leads to the ketose product. The hydride transfer mechanism in the lower pathway begins with the dissociation of the alcoholic proton to form the alcoholate intermediate. The alcoholate provides the driving force for the 1,2-hydride transfer (colored arrows in scheme 7-1) accompanied by protonation of the oxygen at C1. The two mechanisms require different hydrogen transfer regimes.