Another example of transition state stabilization is chorismate mutase:

Yeast Chorismate Mutase (1r53)

which catalyzes the sigmatropic rearrangement:

The molecule must adopt a chair-like conformation for the reaction to occur:

The transition state mimic is very tightly bound:

Anti-entropic Effects: The entropy we are interested in here comes in two flavors: translational and rotational.

• An enzyme or enzyme substrate moving in three dimensions has three degrees of freedom; when the two combine into a complex one set of translational entropies is lost.
  • For a small molecule at 1 M concentration, this corresponds to about 120 J/deg/mol, or 35 kJ/mol (9 kcal/mol) at 25^o

• When the substrate binds, it may also lose some internal rotations around single bonds, which correspond to additional degrees of freedom, one for each single bond about which rotation is restricted
  • Such internal rotations have entropies of the order of 13 - 21 J/deg/mol.

• Thus, binding of substrate to enzyme is disfavored entropically (but, of course, so is the collision between two independent reactants)

• This unfavorable contribution to the binding free energy must be overcome by a favorable binding enthalpy. This is the first anti-entropic contribution of the enzyme.

Once binding has been accomplished, we no longer need to restrict reagent degrees of freedom to carry out a reaction. The absence of this further restriction constitutes a major contribution to enzyme rate enhancements. Here is an example:

The second reaction removes the translational entropy issue by building both functional groups required for reaction into the same molecule.

• It attempts to remove the rotational entropy problem by locking the functional groups in the right orientation by the interaction between the gem-dimethyl and the methyl ortho- to it

• The result is a molecule that lactonizes almost instantly.

The interlocking of the methyl groups is evident in the pictures above.

A final example: an acyl transfer reaction, which has less conformational restriction of the reactant, and thus a lower rate enhancement.