Biochemistry - The Chemical Reactions of Living Cells, Volume 2 - D. Metzler 1980

Enzymes: Protein Catalysts of Cells
Enzyme Specificity
Prochiral Centers

Most Enzymes are capable of flawlessly distinguishing between the right and left sides of an organic substrate molecule, even when the latter possesses strict bilateral Symmetry. Before discussing this fact further, we must become familiar with the system for designating two identical groups attached to a carbon atom along with two other non-identical groups [44]. Let us consider the carbon atom of malic acid around which two hydrogen atoms and two other groups are located

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The priority of the groups attached to this carbon atom is determined in accordance with the RS-system (see Sec. A.5). Let us now ask the question: what will the configuration of the molecule be (R or S) if the priority of one of the two identical groups becomes higher, for example, As a result of replacing one of the hydrogen atoms with deuterium in the pro-S or pro-R position? From the scheme given above, it is easy to see (looking along the bond vector towards the group of lower priority and applying the standard rule for determining configuration) that if the hydrogen atom in the pro-R position (H_R) is replaced by deuterium, the molecule will have the R-configuration. Conversely, replacement of the H_S atom by deuterium leads to the S-configuration.

It is remarkable that when malic acid is dehydrated by the action of fumarase (Ch. 7, Sec. 3.6), only the hydrogen atom residing in the pro-R position is eliminated, while the atom in the pro-S position remains unaffected. This can be proven through elegant experiments by carrying out the Hydration of the dehydration product, fumarate, to yield malate in the presence of ²H₂O

The resulting malate contains deuterium in the pro-R position. Incubation of this malate with the enzyme in H₂O leads to the complete removal of deuterium. The dehydration product, fumarate, contains no deuterium; this would not be observed if the stereospecificity of the enzyme's action were not absolute.

Let us consider another striking example—the dehydrogenation (oxidation) of ethanol catalyzed by Alcohol dehydrogenase:

During the reaction, the hydrogen atom located in the pro-R position is abstracted. If the reverse reaction is carried out in such a way that deuterium from the reduced form of the coenzyme is incorporated into ethanol, optically active R-2-deuteroethanol is formed.

The ability of an enzyme to recognize one of a pair of hydrogen atoms belonging to a CH₂ group initially greatly astonished biochemists. However, it is now entirely clear that this feature of enzyme action is the rule rather than the exception, and is no more surprising than the fact that a right shoe fits only the right FOOT. Enzyme stereospecificity is a natural consequence of the complementarity between the enzyme and substrate surfaces.