Why is HMG-CoA reductase a target in attempts to lower plasma cholesterol levels and explain how...

Why is HMG-CoA reductase a target in attempts to lower plasma cholesterol levels and explain how lovastatin and cholestyramine work to lower blood cholesterol levels?

Expert Solution

HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) is a key regulatory enzyme of the mevalonate pathway (this is involved in the synthesis of cholesterol and isoprenoids). In this pathway, it catalyzes the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonic acid.

In mammalian cells, the degradation of low-density lipoproteins in LDL receptors and oxidization of cholesterol species suppress the activity of HMG-CoA reductase and lowers the plasma concentration of cholesterol. So, the inhibition of HMG-CoA reductase is dependent on the activation of LDL receptors. The synthesis of cholesterol is extremely dependent on the concentration of HMG CoA and thus it acts as a rate-limiting step in the mevalonate pathway. These features make HMG-CoA as the prime target in attempts to lower plasma cholesterol levels.

Some inhibitors induce the expression of LDL receptors and cause degradation of LDL thereby inhibiting the activity of HMG-CoA. These inhibitors are collectively called as statins.

Mode of action of lovastatin: It acts as a competitive inhibitor for HMG-CoA. It is a prodrug with a gamma-lactone closed ring structure. After consumption, it gets hydrolyzed to beta-hydroxy acid form which as an active region of this compound. This binds to HMG-CoA and inhibits its activity. This inhibition, in turn, reduces the blood cholesterol level.

Mode of action of cholestyramine: This drug acts as a sequestering agent of bile acids. It specifically binds to the bile in the gastrointestinal tract and blocks its reabsorption in the intestine. This results in lowering of blood cholesterol levels.

gladiator answered 2 years ago

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