Cholesterol biosynthetics

Fluvastatin is an inhibitor of the cholesterol biosynthetic pathway and may be used to reduce the risk of coronary conditions, e.g. strokes and heart attacks, in susceptible patients. It has the structure shown, though drag material is supplied as the racemic form. A partial numbering system is given, and the rest of the molecule may be abbreviated to aryl in answers. 

The synthesis of all isoprenoids starts with acetyl-CoA, which in a series of six different enzyme reactions is converted into isopentenyl-diphosphate (-PP), the basic C-5 isoprene unit that is used for the synthesis of all subsequent isoprenoids (Fig. 5.1.1). At the level of farnesyl-PP the pathway divides into several branches that are involved in the production of the various isoprenoid end products. One of the major branches involves the cholesterol biosynthetic part of the pathway, of which squalene is the first committed intermediate in the production of sterols. Following cycliza-tion of squalene, lanosterol is produced. To eventually produce cholesterol from la-... 

In the past decade, eight inherited disorders have been linked to specific enzyme defects in the isoprenoid/cholesterol biosynthetic pathway after the finding of abnormally increased levels of intermediate metabolites in tissues and/or body fluids of patients (Table 5.1.1) [7, 9, 10]. Two of these disorders are due to a defect of the enzyme mevalonate kinase, and in principle affect the synthesis of all isoprenoids (Fig. 5.1.1) [5]. The hallmark of these two disorders is the accumulation of mevalonic acid in body fluids and tissues, which can be detected by organic acid analysis, or preferably, by stable-isotope dilution gas chromatography (GC)-mass spectrometry (GC-MS) [2]. Confirmative diagnostic possibilities include direct measurement of mevalonate kinase activities in white blood cells or primary skin fibroblasts [3] from patients, and/or molecular analysis of the MVK gene [8]. 

Edwards, P.A. Ericsson, J. (1999) Sterols and isoprenoids signaling molecules derived from the cholesterol biosynthetic pathway. Annu. Rev. Biochem. 68, 157-185. 

Addition of Isoprenyl Groups A number of eukaryotic proteins are modified by the addition of groups derived from isoprene (isoprenyl groups). A thioether bond is formed between the isoprenyl group and a Cys residue of the protein (see Fig. 11-14). The isoprenyl groups are derived from pyrophosphorylated intermediates of the cholesterol biosynthetic pathway (see Fig. 21-33), such as famesyl pyrophosphate (Fig. 27-30). Proteins modified in this way include the Ras proteins, products of the ras oncogenes and proto-oncogenes, and G proteins (both discussed in Chapter 12), and lamins, pro-... 

The rearrangement of this initially created C-20 carbocation to lanosterol (Fig. 22-6, step c) is also a remarkable reaction that requires the shift of a hydride ion and of two methyl groups, as indicated by the arrows in the figure. In addition, a hydrogen at C-9 (sterol numbering) is lost as a proton. Lanosterol is named for its occurrence in lanolin, the waxy fat in wool. Although the principal component of lanolin is cholesterol, lanosterol is its precursor both in sheep and in all other animals. Cholesterol is in turn the precursor to other animal sterols. The cholesterol biosynthetic pathway also provides cells with a variety of important signaling molecules.1603... 

Stereospecific 2,3-epoxidation of squalene. followed by a non-concerted carbocationic cyclization and a seiies of carbocationic rearrangements, forms lanosterol (26) in the first steps dedicated solely toward steroid synthesis. Cholesterol is the principal starting material for steroid hormone biosynthesis ill animals. The cholesterol biosynthetic pathway is composed of at least 30 enzymatic reactions. Lanosterol and squalene appear to he normal constituents, in trace amounis. in tissues that are actively synthesizing cholesterol,... 

In recent years, there has been great interest in the pleiotropic effects of statins (Table 3). Many of these effects have been attributed to HMG-CoA reductase inhibition and the subsequent impairment in the synthesis of isoprenoid intermediates, which are downstream products of the cholesterol biosynthetic pathway. As a consequence, isoprenylation of proteins involved in intracellular signaling may be prevented, resulting in a variety of effects, such as an increase in bioavailability of endothelium-derived nitric oxide (53). 

It has been clear for several decades that an elevated concentration of plasma cholesterol attributable to increased concentrations of atherogenic lipoproteins (low-density lipoproteins [LDL] and remnant lipoproteins) is a major risk factor for the development of coronary heart disease (CHD) (Castelli et al., 1992 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 1993). The cholesterol biosynthetic pathway (Fig. 1) was a natural target in the search for drugs to reduce plasma cholesterol concentrations in the hope that these treatments would reduce the risk of CHD. However, early attempts to reduce cholesterol biosynthesis were disastrous. Tri-paranol, which inhibits the penultimate step in the pathway, was introduced into clinical use in the mid-1960s but was withdrawn from the... 

Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme in the cholesterol biosynthetic pathway (Fig. 1). In contrast to desmosterol and other late-stage lipid-soluble intermediates, HMG is water-soluble, and there are alternative metabolic pathways for its breakdown when HMG-CoA reductase is inhibited so that there is no buildup of potentially toxic precursors. Therefore, of the more than 30 enzymes involved in the biosynthesis of cholesterol, HMG-CoA reductase was a natural target. Substances that have a powerful inhibitory effect on this enzyme, including ML236B (compactin), were first discovered by Endo in a fermentation broth of Penicillium citrinum in the... 

Mevinolin produced by the fungus Aspergillus tereus, competitively inhibits HMG-Co-A reductase, a key enzyme in the cholesterol biosynthetic pathway, and thereby lowers cholesterol level (Wang and Ng, 1999). 

Understand the biosynthesis of cholesterol compare this process with that of ketone body production know what controls cholesterol biosynthetic reactions. 

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... 

Lovastatin works by inhibiting 3-hydroxy-3-methylglutary 1 coenzyme A (HMG-(3oA) reductase, a key rate-limitingenzyme in the cholesterol biosynthetic pathway. However, the first specific inhibitors of this enzyme were discovered several years earlier by Endo et al. at Sankyo (157). The compounds, which are structurally related to lovastatin, were isolated from Penicillium citrinum and shown to block cholesterol synthesis in rats and lower cholesterol levels in the blood. Development of the most active compound, designated ML-236B (123), is believed to have been curtailed because of toxicity problems (158). 

High serum cholesterol levels are an important risk factor for coronary heart disease and an effective way of reducing serum cholesterol is to inhibit sterol biosynthesis. The "statins" work by inhibiting 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase), a major regulatory enzyme in the cholesterol biosynthetic pathway which catalyses the rate-limiting conversion of HMG CoA to mevalonic acid. 

Lovastatin is a member of a class of drugs (atorvastatin and simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase. These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins are bound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Recent studies indicate that there may be important secondary effects of statin therapy because some of the medical benefits of statins are too rapid to be a result of decreasing atherosclerotic lesions. Statin therapy has been associated with reduced risks of dementia, Alzheimer disease, ischemic cerebral stroke, and other diseases that are not correlated with high cholesterol levels. Although this is still an active area of research, it appears that the pleiotropic effects of statins may be a result of a reduction in the synthesis of isoprenoid intermediates that are formed in the pathway of cholesterol biosynthesis. 

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