Question

1. Statin drugs, like Mevacor (lovastatin) and Lipitor (atorvastatin), act as competitive inhibitors of HMG-CoA reductase by mimicking the structure of mevalonate. However, it is not this inhibition that directly lowers cholesterol levels in the blood.  
   1. What enzymatic reaction does HMG CoA-reductase catalyze? What is important about this step of cholesterol synthesis?
2. 2. How can statins mechanistically cause a decrease in LDL cholesterol in the blood if it is not a direct effect of decreased cellular cholesterol synthesis?

Answer 1

a. HMG CoA-reductase is the rate-controlling enzyme of the metabolic pathway that produces cholesterol and other isoprenoids. HMG CoA-reductase catalyses the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. The mevalonate pathway is an important step for the production of cholesterol. Isoprenoids, heme, vitamin K etc. It is best pathway as the target of statins, a class of cholesterol lowering drugs.

b. Statins act by competitively inhibiting HMG-CoA reductase enzyme, which is the rate-limiting enzyme of the mevalonate pathway. Statins have almost similar as the structure of HMG-CoA on a molecular level, they fit into the enzyme's active site and compete with the native substrate (HMG-CoA). This competitive action reduces the rate by which HMG-CoA reductase is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol.