3-hydroxy-3-methylglutaryl co-enzyme A

Lovastatin (Fig. 8.47) is a metabolite isolated from the fungus Aspergillus terreus. On screening, it was found to inhibit the key enzyme which regulates hepatic synthesis of cholesterol, viz. 3-hydroxy-3-methylglutaryl co-enz)me A reductase (HMG-CoA reductase). 

Another approach to the reduction in blood cholesterol levels has been the development of pravastatin (50) and its congeners as potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase, the rate-limiting enzyme in cholesterol biosynthesis.52 It has also been discovered that the biological activity of such compounds is dependent largely on the P-hydroxy-8-lactone moiety within the compound.53 This led to the development of more potent compounds, such as NK-104 (51), a congener of pravastatin. 

Cholesterol is made in the liver from glucose via the pentose phosphate pathway (which generates NADPH) and glycolysis, which produces acetyl CoA (Fig. 38.1). Acetyl Co A is then metabolised to 3-hydroxy-3-methylglutaryl CoA (HMGCoA) which is reduced by NADPH in the presence of HMGCoA reductase (the regulatory enzyme for cholesterol synthesis) to form mevalonate. Mevalonate is then metabolised via more than two dozen intermediates (not shown) to form cholesterol. 

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