Structural Biochemistry/Enzyme/Catalytic Principles

General Information Enzymes commonly employ one or more strategies to catalyze specific reactions. These strategies are designed to increase the binding energy which in turn establishes substrate specificity and increases catalytic efficiency.

Acid-Base Catalysis
Acid-base catalysis facilitates a reaction by stabilizing the charges in the transition state through the use of an acid or base, which donates protons or accepts them, respectively. Nucleophilic and electrophilic groups are activated as a result of the proton addition or removal and causes the reaction to proceed. Many acid-base catalysis reactions involve histidine because it has a pH close to 7, allowing it to act as both an acid and a base. An example of acid-base catalysis is peptide hydrolysis by chymotrypsin. Chymotrypsin uses a histidine residue as a base catalyst to increase the nucleophilicity of serine. Chymotrypsin uses a histindine residue as a base catalyst to help to strengthen the neucleophillic property of serine, whereas a histindine residue in carbonic anhydrase helps the removal of hydrogen ion from zinc bound water molecule to generate OH-.



In the picture, serine acts as a nucleophile and attacks the carbonyl group of the substrate, while histidine accepts the proton from serine and the tetrahedral intermediate is formed. The collapse of the tetrahedral intermediate forms the acyl enzyme. Water loses a proton to histidine and attacks the acyl enzyme and the oxyanion hole is formed. The reaction ends with the release of a carboxylic acid. The cycle then continues with a new substrate.

Another example of acid-base catalysis is the reaction with carbonic anhydrase. His residues in carbonic anhydrase facilitates the removal of a hydrogen ion from zinc-bound water to generate a hydroxide ion.

Covalent Catalysis
In covalent catalysis, the active site of an enzyme contains a reactive group, usually a powerful nucleophile, the be comes covalently attached to a part of the substrate in the course of catalysis. The covalent bonded intermediate reduces the energy of the transition state, lowering the activation energy. However, the covalent bond must be broken to regenerate the enzyme. This mechanism is found in enzymes such as proteases like chymotrypsin and trypsin, where an acyl-enzyme intermediate is formed.

Some enzymes utilize non-amino acid cofactors to form covalent intermediates with reactant molecules. These intermediates also lower the activation energy, but the capabilities of cofactors allow enzymes to carryout reactions that amino acid side residues alone could not.

Catalysis by Approximation
In reactions that include two distinct substrates, the reaction rate may be enhanced by bringing the two substrates together along a single binding surface on an enzyme.

Metal Ion Catalysis
Metal ions can function catalytically by forming nucleophiles by direct coordination, by serving as electrophiles to stabilize a negative charge on a reactive intermediate, and by serving as a bridge between enzyme and substrate which increases the binding energy.

Reference
Berg, Jeremy M. John L. Tymoczko. Lubert Stryer. Biochemistry Sixth Edition. New York: W.H. Freeman, and Company 2007.