Lovastatin Lowers Serum Cholesterol Levels

Chemists and biochemists have long sought a means of reducing serum cholesterol levels to reduce the risk of heart attack and cardiovascular disease. Because HMG-CoA reductase is the rate-limiting step in cholesterol biosynthesis, this enzyme is a likely drug target. Mevinolin, also known as lovastatin (see figure), was isolated from a strain of Aspergillus terreus and developed at Merck, Sharpe and Dohme for this purpose. It is now a widely prescribed cholesterol-lowering drug. Dramatic reductions of serum cholesterol are observed at doses of 20 to 80 mg per day.

Lovastatin is administered as an inactive lactone. After oral ingestion, it is hydrolyzed to the active mevinolinic acid, a competitive inhibitor of the reductase with a KI of 0.6 nM. Mevinolinic acid is thought to behave as a transition-state analog (Chapter 16) of the tetrahedral intermediate formed in the HMG-CoA reduc-tase reaction (see figure).

Derivatives of lovastatin have been found to be even more potent in cholesterol-lowering trials. Synvinolin lowers serum cholesterol levels at much lower doses than lovastatin.

Conversion of Lanosterol to Cholesterol Requires 20 Additional Steps

Although lanosterol may appear similar to cholesterol in structure, another 20 steps are required to convert lanosterol to cholesterol (Figure 25.35). The enzymes responsible for this are all associated with the endoplasmic reticulum. The primary pathway involves 7-dehydrocholesterol as the penultimate intermediate. An alternative pathway, also composed of many steps, produces the intermediate desmosterol. Reduction of the double bond at C-24 yields cholesterol. Cholesterol esters—a principal form of circulating cholesterol—are synthesized by acyl-CoA:cholesterol acyltransferases (ACAT) on the cytoplasmic face of the endoplasmic reticulum.

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