Cholesterol mevalonate

See also Cholesterol Biosynthesis, Bile Acids, Steroid Hormone Synthesis, HMG-CoA Reductase, HMG-CoA, Cholesterol, Mevalonate... 

Mevalonic acid is involved in the biosynthesis of cholesterol. Mevalonic acid is 48.64% C, 8.16% H, and 43.20% O. If mevalonic acid has an experimental molar mass of 148 g, what is its molecular formula ... 

D-Mevalonic acid is the fundamental intermediate in the biosynthesis of the terpenoids and steroids, together classed as poly-isoprenoids. The biogenetic isoprene unit is isopentenyl pyrophosphate which arises by enzymic decarboxylation-dehydration of mevalonic acid pyrophosphate. D-Mevalonic acid is almost quantitatively incorporated into cholesterol synthesized by rat liver homogenates. 

The statins lower cholesterol by inhibiting the en zyme 3 hydroxy 3 methylglutaryl coenzyme A reduc tase which is required for the biosynthesis of meva Ionic acid (see Section 26 10) Mevalonic acid is an obligatory precursor to cholesterol so less mevalonic acid translates into less cholesterol... 

Trace each of the carbon atoms of mevalonate through the synthesis of cholesterol, and determine the source (i.e., the position in the mevalonate structure) of each carbon in the final structure. 

The antiinflammatory effects of statins likely result from their ability to inhibit the formation of mevalonic acid. Downstream products of this molecule include not only the end product, cholesterol, but also several isoprenoid intermediates that covalently modify ( pre-nylate ) certain key intracellular signaling molecules. Statin treatment reduces leukocyte adhesion, accumulation of macrophages, MMPs, tissue factor, and other proinflammatory mediators. By acting on the MHC class II transactivator (CIITA), statins also interfere with antigen presentation and subsequent T-cell activation. Statin treatment can also limit platelet activation in some assays as well. All these results support the concept that in addition to their favorable effect on the lipid profile, statins can also exert an array of antiinflammatory and immunomodulatory actions. 

Statins lower plasma cholesterol levels by inhibiting HMG-CoA reductase in the mevalonate pathway (Fig. 4). Some research has shown that certain statins (but not all) stimulate BMP-2 expression in osteoblasts, increase bone formation and mimic N-BP in that they inhibit bone resorption. The use of statins in osteoporosis is presently being investigated. 

Isoprenoids are intermediates and products of the biosynthetic pathway that starts with mevalonate and ends with cholesterol and other sterols. 

The biosynthesis of cholesterol may be divided into five steps (l) Synthesis of mevalonate occurs from acetyl-CoA (Figure 26-1). (2) Isoprenoid units are formed... 

Cholesterol is synthesized in the body entirely from acetyl-CoA. Three molecules of acetyl-CoA form mevalonate via the important regulatory reaction for the pathway, catalyzed by HMG-CoA reductase. Next, a five-carbon isoprenoid unit is formed, and six of these condense to form squalene. Squalene undergoes cychzation to form the parent steroid lanos-terol, which, after the loss of three methyl groups, forms cholesterol. 

In more recent studies the use of HPLC allowed isolation and counting of individual sterols after administration of labelled precursors. The sterols isolated from mantles and viscera of the nudibranch Doris verrucosa were identified as cholestanol, cholesterol, 24-dehydrocholesterol and 7-dehydrocholesterol [103]. After injection of dl-[2-14C]-mevalonic acid DBED salt, cholesterol (57) and 7-dehydrocholesterol (58) were isolated as the acetates by reversed phase HPLC. Both sterols were found significantly labelled specific radioactivity associated with 7-dehydrocholesterol was higher by one order of magnitude than that associated with cholesterol. This fact would indicate either that the reduction of the A1 double bond of 7-dehydrocholesterol to afford cholesterol occurs at a low rate, or that the cholesterol found in D. verrucosa comes partly from a dietary source. 

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interrupting the conversion of HMG-CoA to mevalonate, the rate-limiting step in de novo cholesterol biosynthesis. Reduced synthesis of LDL and enhanced catabohsm of LDL mediated through LDL-Rs appear to be the principal mechanisms for lipid-lowering effects. 

Mevalonate pyrophosphate, role in cholesterol synthesis, 5 142 Mevalonic acid, 2 93 14 132 alkaloid precursor, 2 78 Mexican Molango ore, 15 544 Mexican oregano, 23 169 Mexico... 

The therapeutic class that uniquely exemplifies lactone prodrugs are the statins, i.e., the cholesterol-lowering agents that act by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34). This microsomal enzyme catalyzes conversion of HMG-CoA to mevalonate, an important rate-limiting step in cholesterol biosynthesis. Cholesterol synthesis occurs mainly... 

Warfarin CoA to mevalonic acid for the synthesis of cholesterol Anticoagulant Inhibits synthesis of clotting factors II (prothrombin), VII, IX,... 

In our body cholesterol is manufactured from mevalonate (1), which in turn is derived from (S)HMG-CoA (2). 

This cholesterol formation reaction is catalyzed by the enzyme HMG-CoA reductase. One means to stop or reduce the production of cholesterol is to interfere with the supply of mevalonate. This is the function of Lipitor, which acts as an inhibitor of HMG-CoA reductase. 

Hydroxy-3-methylglutaryl (HMG)-CoA reductase on the smooth endoplasmic reticulum (SER) is the rate-limiting enzyme. Insulin acth"ates the enzyme (dephosphorylation), and glucagon inhibits it. Mevalonate is the product, and the statin drugs competitively inhibit the enzyme. Cholesterol represses the expression o the HMG-CoA reductase gene and also increases degradation of the enzyme. 

In nature, the biologically active form of acetic acid is acetyl-coenzyme A (acetyl-CoA) (see Box 7.18). Two molecules of acetyl-CoA may combine in a Claisen-type reaction to produce acetoacetyl-CoA, the biochemical equivalent of ethyl acetoacetate. This reaction features as the start of the sequence to mevalonic acid (MVA), the precursor in animals of the sterol cholesterol. Later, we shall see another variant of this reaction that employs malonyl-CoA as the nucleophile (see Box 10.17). 

In Box 10.12 we saw that nature employs a Claisen reaction between two molecules of acetyl-CoA to form acetoacetyl-CoA as the first step in the biosynthesis of mevalonic acid and subsequenfiy cholesterol. This was a direct analogy for the Claisen reaction between two molecules of ethyl acetate. In fact, in nature, the formation of acetoacetyl-CoA by this particular reaction using the enolate anion from acetyl-CoA is pretty rare. 

Insect steroid metabolism has two biochemically distinctive components dealkylation of phytosterols to cholesterol and polyhydroxylation of cholesterol to ecdysone. We will focus on the first of these. Lacking the ability to synthesize sterols de novo, insects instead have evolved a dealkylation pathway to convert plant sterols to cholesterol(7-10). The dealkylation pathways are apparently absent in most other higher and lower organisms, which can convert mevalonate to squalene and thence into sterols( ). Specific insecticides are possible based on these biochemical differences. 

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. 

Cholesterol is one of the isoprenoids, synthesis of which starts from acetyl CoA (see p. 52). In a long and complex reaction chain, the C27 sterol is built up from C2 components. The biosynthesis of cholesterol can be divided into four sections. In the first (1), mevalonate, a Ce compound, arises from three molecules of acetyl CoA. In the second part (2), mevalonate is converted into isopen-tenyl diphosphate, the active isoprene. In the third part (3), six of these C5 molecules are linked to produce squalene, a C30 compound. Finally, squalene undergoes cycliza-tion, with three C atoms being removed, to yield cholesterol (4). The illustration only shows the most important intermediates in biosynthesis. 

Formation of mevalonate. The conversion of acetyl CoA to acetoacetyl CoA and then to 3-hydroxy-3-methylglutaryl CoA (3-HMG CoA) corresponds to the biosynthetic pathway for ketone bodies (details on p. 312). In this case, however, the synthesis occurs not in the mitochondria as in ketone body synthesis, but in the smooth endoplasmic reticulum. In the next step, the 3-HMG group is cleaved from the CoA and at the same time reduced to mevalonate with the help of NADPH+H 3-HMG CoA reductase is the key enzyme in cholesterol biosynthesis. It is regulated by repression of transcription (effectors oxysterols such as cholesterol) and by interconversion... 

The endergonic biosynthetic pathway described above is located entirely in the smooth endoplasmic reticulum. The energy needed comes from the CoA derivatives used and from ATP. The reducing agent in the formation of mevalonate and squalene, as well as in the final steps of cholesterol biosynthesis, is NADPH+H ... 

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