Structural Biochemistry/Catalytic Strategies/General Acid-Base Catalysis

General acid-base catalysis involves a molecule besides water that acts as a proton donor or acceptor during the enzymatic reaction. In order to avoid having an unstable charged intermediates in the reaction, an enzyme has appropriately located functional groups readily to donate a proton or accept a proton to stabilize the transition state. When a functional group accepts a proton, it will release or donate a proton by the end of the catalytic cycle, and vice versa. Functional groups that participate in reaction are His imidazole, alpha-amino group, alpha-carboxyl group, thiol of Cys, R group of carboxyls of Glu and Asp, aromatic OH of Tyr, and guanidino group of ARG. The protonation of these functional groups are dependent on the pH, therefore the enzymatic catalytic activity is sensitive to the pH level.

General acid-base catalysis is involved in a majority of enzymatic reactions, wherein the side chains of various amino acids act as general acids or general basis. General acid–base catalysis needs to be distinguished from specific acid–base catalysis.

• Specific acid–base catalysis means specifically, –OH or H+ accelerates the reaction. The reaction rate is dependent on pH only (which of course is a function of –OH and H+ concentrations), and not on buffer concentration.

• In General acid–base catalysis, the buffer aids in stabilizing the transition state via donation or removal of a proton. Therefore, the rate of the reaction is dependent on the buffer concentration, as well as the appropriate protonation state.

Example
The pKa of Histidine is close to neutral thus making it the most effective candidate for general acid or base because it can either donate or accept protons. His 119 plays the role of a general acid that donates a proton to 5'-hydroxyl of nucleoside. On the other hand, His 12 acts as a general base which accepting a proton from the 2'-hydroxyl of 3'-nucleotide. As a result, a 2’-3’ cyclic phosphate intermediate is formed. When water replaces the nucleoside, the roles of His 119 and His 12 are reversed. In the end, the original Histidine protonation states are restored.

His 119 is the acid and His 12 is the base. A 2'-3' cyclic phosphate intermediate is formed. Reversely, His 119 is the base and His 12 is the acid. His 119 and His 12 return to their initial states.