• A couple of kinases use ATP to convert mevalonate to its pyrophosphate.

• The pyrophosphate then is decarboxylated by mevalonate pyrophosphate decarboxylase to get to the 5-carbon basic unit of the terpenes.

The crystal structure of the decarboxylase as present in yeast has been determined and is shown below. Many decarboxylases require thiamine (B₁) pyrophosphate as a cofactor; this one apparently does not.

The other structure is the isomerase from E. coli; it has a manganese (red) at the active site, and a cysteine (yellow), without which all activity is lost [Proc. Nat. Acad. Sci., 2001, 98, 12896; this paper is noteworthy for its extensive use of homology modeling.].

Mevalonate Decarboxylase	Isopentenyl Pyrophosphate Isomerase

A straightforward organic chemistry "curly arrow" mechanism can be written for the decarboxylation. [Write it yourself; think about what kinds of groups on the enzyme might be involved.]

The isomerization of the double bond uses an enzyme, of course, but we could do it easily in the laboratory. [Again, can you write an organic chemistry mechanism?]

The isopentenyl and dimethylallyl pyrophosphates are in equilibrium

• The next step couples the two by an S_N1 reaction

• The product of this reaction then is coupled by another S_N1 to a second isopentenyl pyrophosphate

The enzymes accomplishing the couplings are called prenyl transferases. Most organisms have one enzyme for each step; however, the avian enzyme does both steps.

• The enzyme must have at the active site a group that can remove the allylic H from isopentenyl pyrophosphate.

• It also requires groups that can stabilize a carbocation

• The rest of the binding cavity should be lilpophilic, to interact with the hydrocarbon chain

Farnesyl Synthase (1ubx) with Farnesyl Diphosphate Bound	Farnesyl Synthase (1uby) with DimethylAllyl Phosphate Bound
Closeup of Farnesyl Synthase Binding Pocket

Two structure features are important:

• The binding cavity is lined with non-polar, lipophilic residues (blue)

• At the end where the carbocation is formed, aspartate residues (yellow) sit on each side of the cavity; negative charges stabilizing the positive one electrostatically

• Mg ions (green) coordinate to the phosphate and to the aspartates, positioning the substrate

This is a strategy Mother Nature uses frequently.

Finally, note that like all enzymatic reactions this one is stereospecific:

• The pro-R hydrogen is abstracted

• The allyl cation adds to the si face of the double bond

Here is the stereochemistry required for the observed result: