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Lovastatin (Mevacor)
Lovastatin is a cholesterol-lowering agent under the group of drugs characterized as statin. It is isolated from a strain of Aspergillus Terreus. Lovastatin is an inactive lactone which is hydrolyzed to the corresponding beta-hydroxyacid form. Lovastatin serves as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA is a catalyst for the conversion of HMG-CoA to mevanolate, an important rate-limiting process for the cholesterol biosynthesis.
The empirical formula of lovastatin is C24H36O5.
Lovastatin's molecular weight is 404.55 gram/mol.
Lovastatin reduces both normal and elevated LDL cholesterol concentrations. This includes the reduction of serum cholesterol. Lovastatin may, not only reduces the production of LDL cholesterol, but also induces the LDL receptors. This LDL receptors induction effect undoubtedly benefits the FH patient, who suffers from the genetic disease which results in disfunctional LDL receptors. Evidence also has shown that Lovastatin does not only cause the reduction of cholesterol, but also reduces the circulating LDL particles. Lovastatin can also increase HDL levels and reduces VLDL cholesterol and plasma triglycerides.
After and oral dose of lovastatin, it readily hydrolyzed to the corresponding beta-hydroxyacid. Lovastatin and its beta-hydroxyacid are highly bound to human plasma proteins. The plasma concentrations of the drug peak after two hours and declined to about 10% of peak in 24 hours. Lovastatin has high selectivity for the liver, its primary site of action.
Lovastatin has been shown to be highly effective in reducing total cholesterol and LDL cholesterol in heterozygous familial hypercholesterolemia patients. It is interesting to note that the dosage given in the evening is more effective than the dosage given in the morning. This might be because cholesterol is synthesized mainly at night. It is even more interesting to note that patients treated with lovastatin had shown side effects of shorter sleeping hours.
Lovastatin also shows signigicant effect on coronary atherosclerosis.
Lovastatin and its interaction
Since lovastatin inhibits HMG-CoA reductase, which is a catalyst to HMG-CoA in cholesterol biosynthesis, it is reasonable to hypothesize that the two molecules, HMG-CoA and lovastatin, share some common structural features.
Here is a picture of Lovastatin
This is the site where the terminal carboxylic acid group of the hydrolyzed beta-hydroxyacid will form. Following an oral dosage, a water molecule does a nuclephilic attack on the carbonyl carbon of the drug and opens the ring, resulting in the beta-hydroxyacid form of lovastatin.
Here
is a picture of the beta-hydroxyacid form of lovastatin.
The lactone group seen in the lovastatin picture on the left is hydrolyzed and opened to form the terminal carboxylic acid group on the beta-hydroxyacid.
The CoA thioester group of HMG-CoA is reduced to an alcohol
by HMG-CoA reductase in an NADPH-dependent reduction to form mevalonate
in the isopentenyl pyrophosphate
formation process. The group that is similar in property to the thioester
group on HMG-CoA is the newly formed terminal carboxylic acid group. Since
lovastatin is inactive in its lactone form, it is reasonable to suggest
that the HMG-CoA reductase will reduce the beta-hydroxyacid at its carboxylic
acid end in a similar fashion to the thioester reduction. Research has
suggested that the HMG-CoA group binds to the active site of its reductase,
HMG-CoA reductase, with NAD(H) as the other cofactor. HMG-CoA is bound
predominantly by the large domain of one monomer and NAD(H) by the small
domain of the symmetry-related monomer.
The picture on the left is one of the monomers (blue) of HMG-CoA reductase. The arrows point at the active sites at the junction of the top and the stem of the T shaped monomer. These active sites are the large and small domains on the dimer. The HMG-CoA is bound by the large domain in an extended form that stretches across the active site cavity. The NAD(H) is bound to the small domain of the symmetry-related monomer of HMG-CoA reductase. In these binding configurations, the nicotinamide ring of the NAD(H) is positioned within 3.5 Angstrom adjacent to the scissile bond of HMG-CoA. Thus, dimerization is a prerequisite for the active sites in HMG-CoA reductase. This reaction is analogous to the two successive reactions of an aldehyde dehydrogenase and an alcohol dehydrogenase, but both are done by HMG-CoA reductase.
A competitive inhibitor acts by reducing the concentration of free enzyme available for substrate binding and reduces the amount of product. In this particular case, lovastatin (in its beta-hydroxyacid form) acts as a competitive inhibitor and reduces the binding of HMG-CoA to HMG-CoA reductase, thus reduces the amount of cholesterol product. The suggested hypothesis is that the structure of lovastatin has the ability to bind to HMG-CoA reductase's large domain in a way similar to that of HMG-CoA. Also, instead of the thioester group of HMG-CoA binding next to the NAD(H), it is the terminal carboxylic acid group on the beta-hydroxyacid that will interact with the NAD(H) in its competitive inhibiting process.
Here is the proposed competitive inhibition.
Lovastatin does have some side effects. This includes elevation in serum levels of liver enzymes, myopathy, and shortened sleep period (up to three hours).
any
comments or suggestions?? thamrong@panther.middlebury.edu
