Chorismate Mutase (B. subtilis; 1dbf)	Chorismate Mutase (T. thermophilus; 1ode)

Prokaryotic versions of this enzyme are highly sequence and structure conserved; Swiss PDB gives an rms of 0.82 for a backbone alignment of the enzymes from B. subtilis and T. thermophilus:

The sequences align with 42% identity and 60% similarity of residues:

Eukaryotic enzymes, such as that from yeast are substantially different.

Yeast Chorismate Mutase (1r53)

• Sequence identity with either of the above enzymes is only about 1%

• In B. subtilis: two Arg, two Glu, a Thr, and a Lys

• In yeast: Two Arg, two Glu, a Thr, a Lys, and an Asn

Active Site of Yeast Chorismate Mutase

More about this active site later.

Recall that the reaction catalyzed by chorismate mutase is a [3,3]-sigmatropic (Cope) rearrangement, converting chorismate to prephenate:

The stereochemical course of [3,3]-sigmatropics commonly can be rationalized by placing the starting diene in a chair-like conformation:

In the case above, not only is the major product formed almost enantiomerically pure when an optically pure starting material is used, but it also is formed from the conformer with the large phenyl equatorial.

A boat-like transition state would lead to the other enantiomer of the product, which is not observed:

Estimates of the energy difference between the chair-like and boat-like transition states range from 6 to 12 kcal/mol, corresponding to rate differences of the order of 10³ - 10⁴.

Application of the chair-like transition state idea to chorismate leads to the following:

This picture leads to several interesting issues to discuss:

• Does the enzyme require the chair-like transition state for chorismate rearrangement?

• The conformation required for a chair-like transition state (TS) is not the preferred conformation

• How does the enzyme actually catalyze a reaction that is not subject to catalysis in solution?

• If indeed the TS is chair-like, can we design transition state inhibitors like that shown?