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OverviewOverview

Mevacor (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/OriginHistory/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]

FunctionFunction

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]

StructureStructure

The molecular formula of is C24H36O5 [1] and the molecular weight is 404.55 [1] Lovastatin contains two domains of Integrin alpha-L. Integrin alpha-L contains an alpha and beta chain, length is 182 amino acids, weighs 20.82 KDa. The image below shows the two domains of in lovastatin.

The image (top) shows two copies of Integrin alpha-L bound to lovastatin. (9)(9) Since lovastatin inhibits , 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]

An image of beta-hydroxyacid form of lovastatin.

MechanismMechanism

Lovastatin is meant to interrupt the rate limiting step in the biosynthesis of cholesterol via the mevalonic acid pathway. Lovastatin is similar to hydroxymethyglutarate (HMG), which is a substituent of HMG-Coenzyme A (HMG-CoA). HMG-CoA is a substrate of the cholestrol biosynthesis via the mevalonic acid pathway. Lovastatin has a binding affinity which is 20,000 times greater than that of 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 Reducatase (HMG-COA reductase bound to NAD+, HMG, And COA) through a NADPH-dependent reduction to form mevalonate.  It is thought that HMG-CoA reductase 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]

A study done by Tabernero et al. using lovastatin and P. manovalli HMG-COA reductase helps us understand the mechanism by which lovastatin inhibits the binding of HMG-COA, which is an intermediary substrate in the biosynthetic process of producing cholesterol. There are two classes of HMG-CoA reductase that is mentioned in  this study. The first being Class I, which is the human HMG-CoA reductase, and Class II which is the P. mevalonii HMG-CoA reductase.  The Lovastatin seems to interact with four different sites within the HMG-COA reductase in P. manovalli. In the first site, LOV- 1, the c5-OH group and it does so through interactions with residues Asn-271 (Asn-755 in Class I), Lys-267 (Lys-691 in Class I) and Glu-83 (Glu-559 in Class I). The second site, LOV-2, binds to the C3-OH group through water mediated hydrogen bonds. One bond is formed with Asn-365 (Arg-590 in Class I) and two hydrogen bonds with Asn-216 through the water mediated hydrogen bonds. The third site, LOV-3 interacts with the carboxylate group and creates a hydrogen bond with Arg-261. In the Class I enzyme Lys-735 and Lys-692 form hydrogen bonds and bind in a similar manner to Arg-261 in LOV-3. Two additional hydrogen bonds are formed to the carboxylate group through a water mediated process with Ser-684 in LOV-3 as well in the Class I enzyme. The fourth and final site, LOV-4, interacts with the decalin ring and forms hydrophobic interactions with Ala-368 and Leu-372 found on the hydrophobic region of the alpha helix of the large domain. (Leu-562 and Val-683 are thought to have similar hydrophobic interactions with decalin ring in the Class I enzyme) The remaining three residues that interact within LOV-4 are Ser-85, Ile-86, and Ala-89 which is located in the alpha helix region downstream from the catalytic residue Glu-83. This binding of lovastatin to the active site inhibits binding of substrate, HMG-COA, as well as preventing the closure of the flap domain, that contains the catalytic His-381, which enables the process of reduction from taking place. The misalignment and failure to close the active site inhibits the function of the protein and prevents catalysis. [13]

Health & Disease in HumansHealth & 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].

ReferencesReferences

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