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Contents

1 Overview 2 History/Origin 3 Function 4 Structure 5 Mechanism 6 Health & Disease in Humans 7 3D Structure

Overview

Mevacor Lovastatin (1cqp) (9) is a potent anticholesteremic agent, a common drug used to lower LDL (low-density lipoprotein) and triglyceride levels of patients susceptible to heart attacks, strokes, and chest pain due to clogged arteries. (6)

History/Origin

Lovastatin was discovered by Alfred Alberts and his team at Merck in 1978 after screening only 18 compounds over 2 weeks. The agent, also known as mevinolin, was isolated from the fungi Aspergillus terreus. Research on this compound was suddenly shut down in 1980 and the drug was not approved until 1987. Interesting, Akira Endo at Sankyo Co. (Japan) patented lovastatin isolated from Monascus ruber four months before Merck. Lovastatin was found to be 2 times more potent than its predecessor, mevastatin, the first discovered statin. (1)

Function

Lovastatin is hydrolyzed to the ß-hydroxyacid form after ingestion. It is a principal metabolite and inhibitor of HMG-CoA, an enzyme that metabolizes the conversion of HMG-CoA to mevalonate. Mevalonate is an early rate limited step in the biosynthesis of cholesterol. (2) Both lovastatin and its ß-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. (2) It works to reduce the amount of cholesterol in the blood by blocking an enzyme that is needed by the body to make cholesterol. (4) Lovastatin is a member of the cholesterol lowering drugs class called HMG-CoA reductase inhibitors, or, more commonly called statins. Statins reduce cholesterol by inhibiting an enzyme HMG-CoA reductase, abundant in the liver. This enzyme is necessary in the pathway for the production of cholesterol. Statins also increase high density lipoprotein (HDL) cholesterol (or "good" cholesterol) (3)

Structure

The molecular formula of Lovastatin is C24H36O5 (1) and the molecular weight is 404.55 (1) Lovastatin contains two domains of Integrin alpha-L. Image:Pic 1

Image:Pic2

Image:Pic3

The image (top) shows two copies of Integrin alpha-L, and 2 non-polymeric entities including: two copies of magnesium ion (middle) and two copies of lovastatin (bottom). (9) Integrin alpha-L contains an alpha and beta chain, length is 182 amino acids, weighs 20.82 KDa. (9) Since lovastatin inhibits HMG-CoA reductase, it is reasonable to hypothesize that the two molecules, HMG-CoA and lovastatin, share some common structural features. Images were captured using X-ray diffraction. (9)

Image:Pic4

An image of beta-hydroxyacid form of lovastatin.

Mechanism

NAD(H) by the small domain of the symmetry-related monomer.

Image:Pic5

Lovastatin is structurally similar to hydroxymethylglutarate (HMG), a substituent of HMG-Coenzyme A (HMG-CoA), a substrate of the cholesterol biosynthesis pathway via the mevalonic acid pathway. Lovastatin is a competitive inhibitor of HMG-CoA reductase with a binding affinity 20, 000 times greater than HMG-CoA. Lovastatin is activated by in vivo hydrolysis of the lactone ring. (1) To begin the mechanism, a water molecule performs a nucleophilic attack on the carbonyl carbon on lovastatin, resulting in the opening of the ring which produces the ß-hydroxyacid form of the drug. This hydrolyzed molecule results in a terminal carboxylic acid group. This group is similar to the thioester group found on HMG-COA (3-hydroxyl-3-methylgutarylcoenzyme A) which is then reduced to an alcohol by HMG-CoA reductase through a NADPH-dependent reduction to form mevalonate in the isopentenyl pyrophosphate formation process. It is thought that HMG-CoA reduces the ß-hydroxyacid on Lovastatin at its carboxylic acid end in a similar manner. There are two binding domains on HMG-CoA reductase as it works synchronously with NADH. NADH binds to the smaller domain within the dimer as the substrate, HMG-CoA, binds to the larger domain of the dimer. Through competitive inhibition, Lovastatin binds to the larger domain in this manner with the carboxylic acid end facing the NADH. This reduces the probability of HMG-CoA reductase binding to HMG-CoA which then prevents the production of mevalonate which is essential to producing cholesterol. (7)

Health & Disease in Humans

Cells require cholesterol because it aids in the structure of cell membranes by restricting the membrane from being too fluid (10). Low-density lipoproteins (LDL) and high-density lipoproteins (HDL) carry cholesterol to and from cells. Also, cholesterol is also not able to dissolve in blood and require these lipoproteins for transportation. These lipoproteins and an individual's triglyceride level is what makes up their total cholesterol count. LDL is termed as “bad” cholesterol because of its relationship with plaque, a thick and hard build of cholesterol that can block arteries. HDL aids in the removal of LDL from the arteries and carries it back to the liver where it can be broken down and expelled from the body (12). A total cholesterol level less than 200 mg/dL is recommended by healthcare providers (11). Elevated levels of cholesterol in the arteries can directly influence the risk of heart attacks, strokes, atherosclerosis and other heart diseases (12). Mevacor Lovastatin can treat high levels of LDL cholesterol and triglyceride through the interruption of the cholesterol biosynthesis pathway. It also reduces the risk of heart attacks, angina, coronary revascularization procedures in individuals without symptomatic cardiovascular disease. Also used for individuals suffering from coronary heart disease (12). Severe medical side effects when using Lovastatin include: constipation, memory loss or forgetfulness, confusion. Other side effects include: headache, nausea, vomiting, diarrhea, abdominal pain, and muscle pain (3). In rare cases, taking Lovastatin can result in Rhabdomyolysis, a condition that results in the breakdown of skeletal muscle tissue and can lead to tissue failure (3).

Structural highlights

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