Lovastatin synthesis

Cultured on glucose and glutamate, lovastatin synthesis is initiated when glucose consumption starts to level off. 

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

Simvastatin is an important cholesterol-lowering drug and is currently synthesized from the natural product lovastatin via a tedious multistep chemical synthesis. A one-step, whole-cell... 

The answer is a. (Hardman, pp 885-887.) Lovastatin decreases cholesterol synthesis in the liver by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the synthetic pathway This results in an increase in LDL receptors in the liver, thus reducing blood levels for cholesterol. The intake of dietary cholesterol must not be increased, as this would allow the liver to use more exogenous cholesterol and def eat the action of lovastatin. 

Lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin T LDL catabolism i LDL synthesis i Cholesterol Tldl... 

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

Treatment of Hypercholesterolemia Cholestyramine and other drugs that increase elimination of bile salts force the liver to increase their synthesis from cholesterol, thus lowering the internal level of cholesterol in the hepatocytes. Decreased cholesterol within the cell increases LDL receptor expression, allowing the hepatocyte to remove more LDL cholesterol from the blood. HMG-CoA reductase inhibitors such as lovastatin and simvastatin inhibit de novo cholesterol synthesis in the hepatocyte, which subsequently increases LDL receptor expression. 

Endocrine effects Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Small declines in total testosterone with no commensurate elevation in LH have been noted with the use of fluvastatin. Pravastatin showed inconsistent results with regard to possible effects on basal steroid hormone levels atorvastatin, lovastatin, rosuvastatin, and simvastatin did not reduce basal plasma cortisol concentration or basal plasma testosterone concentration or impair adrenal reserve. Appropriately evaluate patients who display clinical evidence of endocrine dysfunction. Exercise caution when administering HMG-CoA reductase inhibitors with drugs that affect steroid levels or activity, such as ketoconazole, spironolactone, and cimetidine. 

The introduction of the fungal metabolite lovastatin (26-9) has led to a sizeable class of clinically effective cholesterol lowering drugs. These agents, known familiarly as the statins, block an enzyme, HMG-CoA reductase, that is involved in the synthesis of mevalonate, an early precursor of cholesterol. Extensive work has... 

Inhibition of HMG-CoA reductase. Top The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas). 

An important dmg in the regulation of cholesterol metabolism is lovastatin [75330-75-5] which is an HMG—CoA reductase inhibitor (see Cardiovascularagents). p-Hydroxy-p-methyl glutarate—coenzyme A (HMG—CoA) reductase is the rate-limiting enzyme of cholesterol synthesis. Lovastatin is actually a prodmg, which is eventually hydrolyzed in the liver to its active, p-hydroxylated form (5). 

This category includes atorvastatin (Lipitor), fluvas-tatin (Lescol), lovastatin (Mevacor), pravastatin (Prava-chol), and simvastatin (Zocor) (Table 25-2). These drugs, known commonly as statins, are characterized by their ability to inhibit an enzyme known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.96 This enzyme catalyzes one of the early steps of cholesterol synthesis, and drugs that inhibit HMG-CoA reductase decrease cholesterol produc-... 

Examples of HMG-CoA reductase inhibitors include lovastatin, simvastatin, and pravastatin the so-called statins. These drugs inhibit the rate-limiting enzyme in the synthesis of cholesterol in the liver. In addition, the reduction in the formation of hepatic cholesterol leads to a compensatory increase in the hepatic synthesis of LDL receptors on the surface of hepatocytes. These receptors bind plasma LDL leading to a reduction in plasma LDL—the bad cholesterol. 

The HMG-CoA reductase inhibitors (Statins like simvastatin, lovastatin, pravastatin, fluvastatin, etc.) inhibit the enzyme and thereby decrease the hepatic cholesterol synthesis and increase the synthesis of LDL receptors causing increased clearance of LDL and a reduced concentration of LDL cholesterol in plasma. HMG-CoA reductase inhibitors are used to treat elevated LDL which also causes a small reduction in plasma triglycerides and an increase in HDL cholesterol. 

Lovastatin, commonly known as an inhibitor of cholesterol synthesis, is another agent that has been shown to reduce plasma levels of VLCFA and to increase the ability of X-ALD fibroblasts to metabolize VLCFA. The mechanism for this effect may involve upregulation of ABCD2, which encodes a protein (ALDR) that can substitute for the function of ALDR However, clinical trials with this agent have demonstrated variable reactions, and no clear clinical benefit has been demonstrated. 

Statins. Statins, such as atorvastatin (Lipotor), simvastatin (Zocor) and lovastatin (Mevacor), are fungal-derived HMG-CoA reductase inhibitors. Treatment results in an increased cellular uptake of LDLs, since the intracellular synthesis of cholesterol is inhibited and cells are therefore dependent on extracellular sources of cholesterol. However, since mevalonate (the product of the HMG-CoA reductase reaction) is also required for the synthesis of other important isoprenoid compounds besides cholesterol, long-term treatments carry some risk of toxicity. 

Sinensky, M., Beck, L.A., Leonard, S., and Evans, R. (1990). Differential inhibitory effects of lovastatin on protein isoprenylation and sterol synthesis. J Biol Chem 265 19937-19941. 

---