Cholesterol blood levels biosynthesis

The subsequent conversion of HMG-CoA into MVA involves a two-step reduction of the thioester group to a primary alcohol (see Section 7.11), and provides an essentially irreversible and rate-limiting transformation. Drug-mediated inhibition of this enzyme, HMG-CoA reductase (HMGR), can be used to regulate the biosynthesis of the steroid cholesterol. High levels of blood cholesterol are known to contribute to the incidence of coronary heart disease and heart attacks. 

Control of blood cholesterol levels. In most cases, the administration of pangamic acid causes a fall in both cholesterol biosynthesis and blood levels. 

The interest of drugs interfering with cholesterol metabolism, is based on the assumption that high blood levels of this sterol are correlated with atherosclerosis. In fact, hypercholesterolaemia is considered a major risk factor for coronary heart disease. It is possible to act on cholesterol metabolism with drugs interfering either with cholesterol absorption and biosynthesis or with its catabolism and excretion. 

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. 

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

Elevated levels of cholesterol in the blood, or hypercholesterolemia, have been linked to heart disease. Cholesterol, a necessary component of all cell membranes, is available to the body by two routes through the diet and through synthesis by the body itself. When changes to one s diet fail to reduce cholesterol levels, medication that inhibits cholesterol biosynthesis may be necessary. The biosynthetic pathway for cholesterol synthesis starts with acetyl-CoA (2.15) (Scheme 2.3). Through a series of steps, three... 

One class of antihyperlipidemic drugs is the statins. Statins interfere with the biosynthesis of cholesterol (A.103) and specifically inhibit the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (Scheme A.l). The statins that have been approved by the FDA include lovastatin (Mevacor, A.104), simvastatin (Zocor, A.105), pravastatin (Prava-chol, A.106), atorvastatin (Lipitor, A.107), rosuvastatin (Crestor, A.108), and fluvastatin (Lescol, A.109) (Figure A.29). All six compounds are drawn here to highlight the similarities between HMG-CoA (A.99) and mevalonic acid (A.100), and the top portion of the various statins. As a class, the statins have been extremely successful in terms of sales and effective in decreasing LDL cholesterol levels in the blood. 

Two molecules of acetyl CoA initially condense to form acetoacetyl CoA in a reaction which is essentially the reverse of the thiolysis step in (3-oxidation. The acetoacetyl CoA reacts with another molecule of acetyl CoA to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA) (Fig. 5). This molecule is then cleaved to form acetoacetate and acetyl CoA. (HMG CoA is also the starting point for cholesterol biosynthesis see Topic K5.) The acetoacetate is then either reduced to D-3-hydroxybutyrate in the mitochondrial matrix or undergoes a slow, spontaneous decarboxylation to acetone (Fig. 5). In diabetes, acetoacetate is produced faster than it can be metabolized. Hence untreated diabetics have high levels of ketone bodies in their blood, and the smell of acetone can often be detected on their breath. 

HMG CoA reductase can be inhibited therapeutically by administering the drug lovastatin, based on the fungal products mevinolin and compactin, which competitively inhibit the enzyme and hence decrease the rate of cholesterol biosynthesis. Therefore, these compounds are routinely used for the treatment of hypercholesterolemia (high levels of blood cholesterol) (see Topic K6). 

Another approach to the reduction in blood cholesterol levels has been the development of pravastatin (50) and its congeners as potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase, the rate-limiting enzyme in cholesterol biosynthesis.52 It has also been discovered that the biological activity of such compounds is dependent largely on the P-hydroxy-8-lactone moiety within the compound.53 This led to the development of more potent compounds, such as NK-104 (51), a congener of pravastatin. 

Situations in which the blood insulin/glucagon ratio is higher than normal lead to fatty acid and cholesterol biosynthesis, whereas low insulin/glucagon ratios are characterized by lipolysis, increased activity of the /3-oxidation pathway, and a low level of cholesterol biosynthetic activity. Enzymes that are either activated by insulin or derepressed by low glucagon levels are lipoprotein lipase, which... 

Hence we study the level of LDL lipoperoxides in patients with atherosclerosis who had been for a long-time treated with HMG-CoA-reductase inhibitors in monotherapy as well as in combination with natural or synthetic antioxidants such as ubiquinon Qio and probucol in double-blind placebo cmitrolled trials [36,37]. The treatment of patients with inhibitor of cholesterol and ubiquinon Qio biosynthesis pravastatine alone in daily dose 40 mg during 6 months was followed by accumulation of LDL lipohydropooxides in the blood plasma [36] (Figure 17). On the other hand the 6 months administration of the same dose of pravastatine in combination with natural antioxidant ubiquinon Qw in daily dose 60 mg sharply decreased even initial LDL lipoperoxides level in the plasma of patients [36] (Figure 17). 

A number of plants and phytochemicals have attracted attention for their ability to reduce many of the risk factors associated with cardiovascular disease. Research into these diseases has shown the relationship between lesions, fatty streaking and plaque formation in blood vessels and the development of strokes and myocardial infarctions. These effects are linked to levels of plasma lipids which comprise triglycerides, cholesterol and other fat substances. It is known that the biosynthesis of lipids involves the condensation of several molecules of acetylcoenzyme A and malonylcoenzyme A in a gradual process of elongation of the fatty acid chain involving the sequential addition of two carbon units giving rise to fatty acids such as lauric acid (12 carbons) and eventually to palmitic acid (16 carbons). Palmitic acid is the precursor... 

Angelin et al. reported recently that treatment with a bile-salt-sequestering agent reduced the postprandial but not the fasting serum bile acid levels in human [219]. It was concluded that the postprandial bile acid inflow to the liver may be more important as a regulator of bile acid biosynthesis than the fasting level of bile acids, supporting the contention that a certain concentration of bile acids must be reached in the portal blood to obtain an efficient inhibition of the cholesterol 7a-hydroxyl-ase. 

Inhibition of cholesterol biosynthesis constitutes an important strategy to the lowering of higher blood total and LDL cholesterol levels. Several in vitro assay systems have been used as screening methods for developing novel leads for cholesterol biosynthesis inhibitors. 

In the body, the biosynthesis of cholesterol takes place through a series of steps, one of which is catalyzed by the enzyme HMG-CoA reductase and which uses mevalonate ion as a substrate. The statin interferes with this step and thereby reduces blood cholesterol levels. 

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