Cholesterol synthesis from mevalonic acid

The weight of evidence supports the conclusion that the more expressed inhibition of HMG-CoA reductase by a higher statin blood level reduces the concentrations of other essential products, primarily of isoprenylated proteins and possibly ubiquinone, synthetized downstream from mevalonic acid within the peripheral cells. In parallel, it was also recognized that statins exert pleiotropic effects in various cells far beyond the originally described inhibition of hepatic cholesterol synthesis. All of these effects are considered to be class-specific for the statins. It is important to emphasize that the frequency of untoward side effects observed with the various statins can be related to their potency, the number of metabolic inter-... 

Cellular metabolites derived from mevalonic acid are required for cell proliferation. Cholesterol Is an essential component of cell membranes, farnesyl pyrophosphate is required to covalently bind to intracellular proteins and modify their function, ubiquinone is required for mitochondrial electron transport, and dolichol phosphates are required for glycoprotein synthesis. 

The steroids are another group of compounds derived from mevalonic acid. They inciude i synthesis of the steroids is sex hormones such as testosterone and progesterone, and the cholesterol needed to build cell discussed in the online chapter membranes but also implicated in the damage to arteries caused by atherosclerosis. Natural products. ... 

Cholesterol consists of four fused rings and an eight-membered hydrocarbon chain. It is synthesized from acetyl CoA. The first two reactions of the pathway are similar to that of ketogenesis, with the formation of HMG CoA. The rate limiting step is the synthesis of mevalonic acid, catalysed by HMG CoA reductase. It requires the reducing properties of 2NADPH and releases acetyl CoA. A five-carbon isoprene unit is then formed from mevalonic acid using ATP. A series of condensation reactions between isoprene units follows, which ends in the formation of squalene, a 30-carbon compound. Squalene is converted to lanosterol by hydroxylation then cyclization. The conversion of lanosterol to cholesterol is a multi-step process that involves many enzymes located in the endoplasmic reticulum. Thus, cholesterol synthesis occurs in the endoplasmic reticulum and the cytoplasm of all cells in the body. 

The liver meets the larger part (60%) of its requirement for cholesterol by de novo synthesis from acetylcoen-zyme-A. Synthesis rate is regulated at the step leading from hydroxymethyl-glutaryl CoA (HMG CoA) to mevalonic acid (p. 157A), with HMG CoA reductase as the rate-limiting enzyme. 

LDL is catabolized chiefly in hepatocytes and other cells by receptor-mediated endocytosis. Cholesteryl esters from LDL are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes. Cells also obtain cholesterol by synthesis via a pathway involving the formation of mevalonic acid by HMG-CoA reductase. Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell. Normally, about 70% of LDL is removed from plasma by hepatocytes. Even more cholesterol is delivered to the liver via IDL and chylomicrons. Unlike other cells,... 

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]. 

The rate-limiting step for cholesterol synthesis is the production of mevalonate from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) by the enzyme HMG-CoA reductase. Cholesterol synthesised in the hep-atocyte can be further metabolised by lecithin cholesterol acyl transferase (LCAT) to cholesterol ester, which is packaged into lipoproteins and secreted into the bloodstream. Alternatively, it can be excreted via the biliary system either as a neutral lipid or following conversion to bile acids. 

Cholesterol is formed in the liver (85%) and intestine (12%) - this constitutes 97% of the body s cholesterol synthesis of 3.2 mmol/day (= 1.25 g/day). Serum cholesterol is esterized to an extent of 70-80% with fatty acids (ca. 53% linolic acid, ca 23% oleic acid, ca 12% palmitic acid). The cholesterol pool (distributed in the liver, plasma and erythrocytes) is 5.16 mmol/day (= 2.0 g/day). Homocysteine stimulates the production of cholesterol in the liver cells as well as its subsequent secretion. Cholesterol may be removed from the pool by being channelled into the bile or, as VLDL and HDL particles, into the plasma. The key enzyme in the synthesis of cholesterol is hydroxy-methyl-glutaryl-CoA reductase (HGM-CoA reductase), which has a half-life of only 3 hours. Cholesterol is produced via the intermediate stages of mevalonate, squalene and lanosterol. Cholesterol esters are formed in the plasma by the linking of a lecithin fatty acid to free cholesterol (by means of LCAT) with the simultaneous release of lysolecithin. (s. figs. 3.8, 3.9) (s. tab. 3.8)... 

C. Reduction of HMG CoA to mevalonic acid is an early step in cholesterol synthesis. Inhibition of this step would lead to an increase in cellular levels of HMG CoA and a decrease in squalene, an intermediate beyond this step, and cholesterol. The decreased cholesterol levels in cells cause ACAT activity to decrease and synthesis of LDL receptors to increase. Because the receptors function (but at a less than normal rate), more receptors cause more LDL to be taken up from the blood. Consequently, blood cholesterol levels decrease, but blood triacylglyc-erol levels do not change much, since LDL does not contain much triacylglycerol. 

Mevalonic acid was discovered by Folker s group at Merck, Sharpe, and Dohme. The initial isolation was based upon the fact that it acted as a growth factor, or vitamin, for a strain of bacteria [35]. Once the structure had been determined, it was apparent that the molecule might well be the isoprenoid precursor that had been sought for many years. Subsequent experiments demonstrated that the sole (or nearly so) fate of the molecule was polyisoprenoid synthesis. In examining the role of cofactors necessary for the synthesis of cholesterol from mevalonate, only ATP and NADPH were found to be required. Experiments with a solubilized preparation from yeast demonstrated that there were 3 phosphorylated intermediates that could be isolated. These were shown to be mevalonic-5-phosphate, mevalonic-5-pyrophos-phate, and isopentenyl pyrophosphate [9]. These intermediates are derived from mevalonate in a sequence of phosphorylations, and the enzymes for all reactions have been obtained in homogeneous form. These enzymes, as well as the rest that lead to the synthesis of famesyl pyrophosphate, are cytosolic proteins. 

The first recognized human metabolic defect in the biosynthesis of cholesterol and isoprenoids was mevalonic aciduria [10]. Mevalonic aciduria is an autosomal recessive disorder that is quite rare, with only 30 known patients (D. Haas, 2006). In normal individuals, a small amount of mevalonic acid diffuses from cells into the plasma at levels proportional to the rate of cellular cholesterol formation. Patients with the severe, classical form of mevalonic aciduria excrete 10,000-200,000 times the normal amount of mevalonic acid because they have severely reduced amounts of mevalonate kinase activity. Their clinical features include failure to thrive, anemia, gastroenteropathy, hepatosplenomegaly, psychomotor retardation, hypotonia, ataxia, cataracts, and dysmorphic features [10]. Surprisingly, patients with severe deficiencies in mevalonate kinase show normal plasma cholesterol levels and cultured mevalonic aciduria fibroblasts have a rate of cholesterol synthesis that is half that of normal cells. Close examination of cholesterogenic enzymes in mevalonic aciduria fibroblasts has revealed a 6-fold increase in HMG-CoA reductase activity, which is postulated to compensate for the low mevalonate kinase activity. Thus, mevalonate is overproduced. 

Mevalonic Acid. 3,5-Di/tytf/-ojiy-3-methylpentan-oic acid 3,S-dihydroxy-3-metkylvaleric acid /3,5-dihydroxy-0-methytvaleric acid hiochic acid. C(Hl204 mol wt 148.16. C 48.64%, H 8.16%, O 43.20%. Precursor in the binsynthesis of cholesterol. Occurs in equilibrium with the 5-lactone. Isoln from distillers solos Wright et al, J. Am. Chem. Soc. 78, 5273 (1956). Synthesis Wolt cl al. ibid. 79, I486... 

Statins are the newest class of cholesterol-reducing drugs. Statins reduce serum cholesterol levels by inhibiting the enzyme that catalyzes the reduction of hydroxymethylglu-taryl-CoA to mevalonic acid (Section 26.8). Decreasing the mevalonic acid concentration decreases the isopentenyl pyrophosphate concentration, so the biosynthesis of all terpenes, including cholesterol, is diminished. As a consequence of diminished cholesterol synthesis in the liver, the liver expresses more LDL receptors— the receptors that help clear LDL from the bloodstream. Studies show that for every 10% that choles-... 

In hypophysectomized rats, the synthesis of cholesterol from acetate (19,20)—but not from mevalonate (21)—is inhibited, indicating that pituitary hormones have an effect on a metabolic step between acetate and mevalonate, probably on hydroxymethylglutaryl-coenzyme A reductase. In terms of tissue cholesterol concentrations, the hypophysectomized rat differs little from the normal. Although bile acid synthesis and excretion are reduced, these animals reach a steady state in which normal cholesterol concentrations in plasma and tissue are maintained (21,22). This is true, however, only when the hypophysectomized rat is maintained on a low-cholesterol diet. When cholesterol intake is increased, both serum and tissue cholesterol reach high levels, presumably because of the decreased ability of the hypophysectomized rat to eliminate that sterol by conversion to bile acids (10, 11,23). 

Mosbach et al, (35) have used cholestyramine to confirm that the la-hydroxylation of cholesterol is the rate-limiting step in bile acid synthesis. Because of the loss of cholesterol from the enterohepatic circulation, there is a marked increase in cholesterol synthesis during administration of cholestyramine to rats (27) or man (36). Mosbach et aL, using perfused rabbit liver, showed that the biliary content of glycocholic acid rose from 0.34 to 3.3 mg, while the content of glycodeoxycholic acid fell from 7.4 to 3.7 mg. The conversion of radioactive acetate, mevalonate, or cholesterol to bile acids was increased from five- to twentyfold, but the conversion rate of 7a-hy-droxycholesterol to cholic acid was unchanged. The formation of 7a-hy-droxycholesterol from cholesterol is enhanced by treatment with cholestyramine (37,38). 

In an analogous manner, a carboxyl group may also be transferred to propionyl-CoA (for the biosynthesis of branched or odd-numbered fatty acids, isoleucine synthesis, or cholesterol metabolism) or to 3-methylcrotonyl-CoA (a degradation product of leucine after addition of water, there results hydroxymethyl-glutaryl-CoA, the precursor of mevalonic acid cf. section 7.1.2). [117] Oxaloacetic acid is derived from pyruvate, which is of central importance for gluco-neogenesis. [108] In addition, biotin participates also in the transfer of carboxylic acid functions. In prokaryotes, biotin functions as a cofactor for decarboxylases (Tab. 7.6). 

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