Biosynthesis of Sterols - II
The first part of the scheme, from acetate, in the form of acetyl CoA, to mevalonate:
Acetyl CoA is ubiquitous as an acetyl transfer agent:
- The name is short for acetyl Coenzyme A, sometimes referred to as "active acetate"
- It is derived from pantothenic acid, one of the B vitamins
- This is CoA itself; it is acetylated on the sulfur to form acetyl CoA.
Some blather about "energy rich" bonds often accompanies the "active acetate" designation in many textbooks.
- No such thing as an "energy rich" bond exists.
- Breaking any bond costs energy.
- Calling a bond "energy rich" is just a sloppy way of saying that reactions in which it is broken are exothermic - the whole reaction, not the breaking of the bond.
Acetyl CoA is an effective acetyl transfer agent because:
- Thiol esters are less delocalized than oxygen esters; hence nucleophilic attack on the carbonyl is easier
- Thiolate anions are better leaving groups than alkoxide ions because they are the conjugate bases of stronger acids
Herr Doktor Professor Claisen knew about the chemistry of the first step more than 100 years ago.
It's just a Claisen condensation.
The second step is an aldol condensation, followed by hydrolysis of the thiol ester. The product, 3-hydroxy-3-methyl glutarate is known as HMG.
The final step in this chart is an especially interesting one, which is carried out by an enzyme called HMG reductase.
|HMG CoA synthase (1tet), CoA Bound
||HMG Reductase (1dq8; tetramer) with Bound CoA
This enzyme is the enzyme inhibited by the "statin" pharmaceuticals mentioned on the first page.
- Cholesterol biosynthesis is inhibited pharmaceutically by blocking the catalytic activity of this enzyme, at only the third step of the cholesterol biosynthesis
- A common mutation (up to 40%) in the gene coding for this enzyme affects low density lipids (the bad guys) by only about ±3%
- In fact, Mother Nature inhibits the pathway at this stage also, by phosphorylating the enzyme.
This page last modified 1:35 PM on Tuesday April 15th, 2014.
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