Stereoelectronic effects are simply the chemical and kinetic consequences of orbital overlap as, for example, in the enolization of norcamphor. The rate of the exo reaction is faster due to the developing p orbital having better overlap with the p system and therefore the transition state is stabilized relative to the transition state for the removal of the endo proton. Since stereoelectronic effects were first proposed in the 1950's, they have been demonstrated in many organic systems and their magnitude determined both experimentally and computationally.
Since stereoelectronic effects play an important role in many reactions in organic chemistry, it seems reasonable that enzymes, which have evolved to catalyze their reactions in the most efficient manner possible, would also employ them. There are a handful of cases where enzymes have been demonstrated to employ stereoelectronic effects, however, their magnitude has not been determined experimentally in any enzymatic system.
Nonenzymatic model studies have shown that pyridoxal phosphate (PLP) is able to catalyze transamination, racemization and decarboxylation reactions. PLP-dependent enzymes can catalyze all these reactions and more. However, a single PLP-dependent enzyme is quite specific, catalyzing only a single type of reaction. This raises the question of how PLP-dependent enzymes maintain their reaction specificity when using a cofactor that can catalyze multiple reactions. In answer to this question, Dunathan proposed in 1966 that PLP-dependent enzymes employ stereoelectronic effects to control their reaction specificity.
Dunathan's hypothesis held that enzymes place the bond to be broken parallel to the p system. In this way the developing p orbital is aligned for maximal overlap with the extended p system, lowering the energy of the transition state and increasing the rate of reaction. Although Dunathan's proposal is accepted, there is little experimental evidence to support it. One of our main goals is to study stereoelectronic effects in PLP-dependent enzymes in a quantitative manner.
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