Metal Ions as Lewis Acids

Reactions catalyzed by metal ions that do not change their oxidation states during the reaction are usually group transfer reactions, in which a group such as the phosphoryl group (−PO₃²⁻) is transferred. These enzymes usually use metal ions such as Zn²⁺, Mg²⁺, and Mn²⁺, and they range from true metalloenzymes, in which the metal ion is tightly bound, to metal-activated enzymes, which require the addition of metal ions for activity. Because tight binding is usually the result of specific metal–ligand interactions, metalloenzymes tend to be rather specific for a particular metal ion. In contrast, the binding of metal ions to metal-activated enzymes is largely electrostatic in nature; consequently, several different metal ions with similar charges and sizes can often be used to give an active enzyme.

Metalloenzymes generally contain a specific metal ion, whereas metal-activated enzymes can use any of several metal ions of similar size and charge.

A metal ion that acts as a Lewis acid can catalyze a group transfer reaction in many different ways, but we will focus on only one of these, using a zinc enzyme as an example. Carbonic anhydrase is found in red blood cells and catalyzes the reaction of CO₂ with water to give carbonic acid.

Although this reaction occurs spontaneously in the absence of a catalyst, it is too slow to absorb all the CO₂ generated during respiration. Without a catalyst, tissues would explode due to the buildup of excess CO₂ pressure. Carbonic anhydrase contains a single Zn²⁺ ion per molecule, which is coordinated by three histidine imidazole ligands and a molecule of water. Because Zn²⁺ is a Lewis acid, the pK_a of the Zn²⁺–OH₂ unit is about 8 versus 14 for pure water. Thus at pH 7–8, a significant fraction of the enzyme molecules contain the Zn²⁺–OH⁻ group, which is much more reactive than bulk water. When carbon dioxide binds in a nonpolar site next to the Zn²⁺–OH⁻ unit, it reacts rapidly to give a coordinated bicarbonate ion that dissociates from the enzyme:

Thus the function of zinc in carbonic anhydrase is to generate the hydroxide ion at pH 7.0, far less than the pH required in the absence of the metal ion.