A few examples to illustrate some of the contributors of rate enhancement.

Acid-Base Catalysis: The reaction catalyzed by triose phosphate isomerase is the second fastest listed in the graph on the first page.

• In part, this is because it is nothing but a series of proton transfers, which are the fastest of uncatalyzed reactions

In aqueous solutions, bimolecular proton transfers occur at diffusion controlled rates - that is, as rapidly as the molecules involved can collide with each other, about 10⁹ to 10¹⁰ per second.

The enzyme catalyzes the proton transfers using a glutamate residue as a base, and a histidine as the acid:

Net, we pull a proton off carbon, as above, put one onto the oxygen, pull one off the other oxygen, and put the original one back onto the other carbon.

The whole transformation is a proton relay.

Proponents argue that the proton transfers can occur at greater than diffusion controlled rates since the enzyme maintains proper orientation (controls the entropy factor) for all the reacting species.

TIM with 2-Phosphoglycolate (a substrate mimic) Bound	Closeup of Catalytic Site

The orientation of the catalytic residues and the substrate for proton relay is evident.

Nucleophilic Catalysis: A subgroup of a larger mechanism type that might be called "covalent catalysis".

• The enzyme forms a covalent bond to the substrate at some point during reaction

• An example is the activity of acetoacetate decarboxylase:

The amino side chain of a lysine in the active site forms a Schiff base with the acetoacetate

• The positive charge of the Schiff base then facilitates decarboxylation

• (You should be able to write a complete mechanism for this reaction as it occurs in vitro)