Cholesterol synthesis isopentenyl pyrophosphate

In addition to its role as an intermediate in cholesterol biosynthesis, isopentenyl pyrophosphate is the activated precursor of a huge array of biomolecules with diverse biological roles (Fig. 21-48). They include vitamins A, E, and K plant pigments such as carotene and the phytol chain of chlorophyll natural rubber many essential oils (such as the fragrant principles of lemon oil, eucalyptus, and musk) insect juvenile hormone, which controls metamorphosis dolichols, which serve as lipid-soluble carriers in complex polysaccharide synthesis and ubiquinone and plastoquinone, electron carriers in mitochondria and chloroplasts. Collectively, these molecules are called isoprenoids. More than... 

Fig. 2. Synthesis of squalene and cholesterol from isopentenyl pyrophosphate, (a) Isomerization of isopentenyl pyrophosphate to dimethylallyl pyrophosphate (b) synthesis of cholesterol.

HMG-CoA reductase is the major regulatory enzyme in cholesterol biosynthesis. HMG-CoA reductase is controlled hormonally by insulin and glucagon and transcription and translation of the enzyme can be suppressed by the presence of cholesterol in cells. Mevalonate is converted in the cytosol to the five carbon building blocks of isoprene synthesis-isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DPP)-in the reactions shown in Figure 19.19. Subsequently, IPP and DPP form famesyl pyrophosphate in the cytosol (Figure 19.20)... 

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate Fig. 1). Acetyl CoA and acetoacetyl CoA combine to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This process takes place in the liver, where the HMG CoA in the mitochondria is used to form ketone bodies during starvation (see Topic K2), whereas that in the cytosol is used to synthesize cholesterol in the fed state (under the influence of cholesterol). HMG CoA is then reduced to mevalonate by HMG CoA reductase Fig. 1). This is the committed step in cholesterol biosynthesis and is a key control point. Mevalonate is converted into 3-isopentenyl pyrophosphate by three consecutive reactions each involving ATP, with C02 being released in the last reaction Fig. 1). 

Stage one is the synthesis of isopentenyl pyrophosphate, an activated isoprene unit that is the key building block of cholesterol. 

The Synthesis of Mevalonate, Which Is Activated as Isopentenyl Pyrophosphate, Initiates the Synthesis of Cholesterol... 

Figure 26.9. Condensation Mechanism in Cholesterol Synthesis. The mechanism for joining dimethylallyl pyrophosphate and isopentenyl pyrophosphate to form geranyl pyrophosphate. The same mechanism is used to add an additional isopentenyl pyrophosphate to form famesyl pyrophosphate.

Cholesterol is a steroid component of eukaryotic membranes and a precursor of steroid hormones. The committed step in its synthesis is the formation of mevalonate from 3-hydroxy-3-methylglutaryl CoA (derived from acetyl CoA and acetoacetyl CoA). Mevalonate is converted into isopentenyl pyrophosphate (C5), which condenses with its isomer, dimethylallyl pyrophosphate (C5), to form geranyl pyrophosphate (Cjo)- The addition of a second molecule of isopentenyl pyrophosphate yields famesyl pyrophosphate (C15), which condenses with itself to form squalene (C30). 

D. In the synthesis of cholesterol, but not of ketone bodies, HMG CoA is reduced by NADPH + H+ to mevalonic add. The enzyme, HMG CoA reductase, is highly regulated (it is inhibited by cholesterol and bile salts and induced by insulin). Mevalonic acid is converted to isopentenyl pyrophosphate, which provides isoprenoid units for the synthesis of cholesterol and its derivatives and for many other compounds. 

This stage in the synthesis of cholesterol starts with the isomerization oi isopentenyl pyrophosphate to dimethylallyl pyrophosphate. 

Cholesterol is synthesized mainly in the liver by a three-stage process. All 27 carbon atoms in the cholesterol molecule are derived from acetyl-CoA. The first stage is the synthesis of the activated five-carbon isoprene unit, isopentenyl pyrophosphate. Six molecules of isopentenyl pyrophosphate then condense to form squalene in a sequence of reactions that also synthesize isoprenoid intermediates that are important in protein isoprenylation modifications. The characteristic four-ring structure of cholesterol is then formed by cycUzing of the linear squalene molecule. Several demethylations, the reduction of a double bond, and the migration of another double bond result in the formation of cholesterol. Figure 34-1 provides an overview of cholesterol biosynthesis. 

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. 

Cholesterol is formed biosynthetically from isopentenyl pyrophosphate (active isoprene). The majority of cholesterol in the body derives from de novo biosynthesis in the liver [1,2]. Cholesterol synthetic pathway has been assumed to occur primarily in the cytoplasm and endoplasmic reticulum (ER). However, more recent evidences have suggested that the enzymes, except squalene synthase, squalene epoxidase and oxidosqualene cyclase, are partly localized in the peroxisomes, which are essential for normal cholesterol synthesis [11]. 

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-... 

The five-carbon compound used for the synthesis of ter-penes is isopentenyl pyrophosphate. The reaction of dimethylallyl pyrophosphate (formed from isopentenyl pyrophosphate) with isopentenyl pyrophosphate forms geranyl pyrophosphate, a 10-carbon compound. Geranyl pyrophosphate can react with another molecule of isopentenyl pyrophosphate to form farnesyl pyrophosphate, a 15-carbon compound. Two molecules of farnesyl pyrophosphate form squalene, a 30-carbon compound. Squalene is the precursor of cholesterol. Farnesyl pyrophosphate can react with another molecule of isopentenyl pyrophosphate to form geranylgeranyl pyrophosphate, a 20-carbon compound. Two geranylgeranyl pyrophosphates join to... 

The synthesis of mevalonate is required not only for the synthesis of cholesterol but also for the synthesis of a number of other important compounds derived from isopentenyl pyrophosphate, including ubiquinone (CoQ), an important component of the electron transport chain. Therefore, the complete blockage of mevalonate synthesis, even if adequate cholesterol is available in the diet, would be ill-advised. 

Cholesterol, which is present in brain and in almost all tissues, is synthesised from isopentenyl pyrophosphate via squalene, farnesyl and geranyl pyrophosphates. The synthesis of squalene commences with the isomerisation of isopentenyl pyrophosphate to dimethylallyl pyrophosphate, after which successive condensations take place according to Equation 11.118. The hydrocarbon squalene is then transformed into the tetracyclic steroidal configuration of lanosterol by appropriate enzymes, and this is followed by conversion into cholesterol. Cholesterol is the precursor to most other steroids in the body. 

Cholesterol synthesis Hydroxymetylglutaryl-CoA reductase Mevalonate kinase Isopentenyl pyrophosphate isomerase... 

Carbonyl condensations are among the most widely used reactions in the biological world for the assembly of new carbon-carbon bonds. One source of carbon atoms for the synthesis of biomolecules is acetyl-CoA, a thioester of acetic acid and the thiol group of coenzyme A (Problem 25.34). In this section, we examine the series of reactions by which the carbon skeleton of acetic acid is converted to isopentenyl pyrophosphate, a key intermediate in the synthesis of terpenes, cholesterol, steroid hormones, and bile acids. Note that in the discussion that follows, we will not be concerned with the mechanism by which each of these enzyme-catalyzed reactions occurs. Rather, our concern is in recognizing the types of reactions that take place. 

Isopentenyl pyrophosphate has the carbon skeleton of isoprene, the unit into which terpenes can be divided (Section 5.4). This compound is, in fact, a key intermediate in the synthesis of terpenes, as well as of cholesterol and steroid hormones. We shall return to the chemistry of isopentenyl pyrophosphate in Section 26.4B and discuss its conversion to cholesterol and terpenes. 

F4MG-CoA is then reduced into mevalonate via a reaction catalyzed by HMG-CoA reductase, a key enzyme of cholesterol biosynthesis. In fact, HMG-CoA reductase is the major rate-limiting enzyme of de novo cholesterol synthesis. Consistently, inhibitors of HMG-CoA reductase (statins) block the whole pathway of cholesterol synthesis by preventing the formation of mevalonate. The following steps in the cholesterol synthetic pathway include the ATP-dependent transformation of mevalonate into isopentenyl pyrophosphate (Fig. 3.5). 

A second important anabolic pathway of acetyl-CoA produces the isoprenoid lipids, especially the steroids. Three molecules of acetyl-CoA condense at first to form a branched-chain compound, hydroxymethylglutaryl-CoA. With a superabundance of acetyl-CoA, such as occurs in some pathologic metabolic conditions (like diabetes, cf. Chapt. XX-10), acetoacetate can be formed from hydroxymethyl-glutaryl-CoA (ketogenesis). But normally, the reduction of the thioester group of that compound yields mevalonate which is then converted to isopentenyl pyrophosphate with an expenditure of 3 moles of ATP. The subsequent synthesis of squalene and cholesterol does not require any further energy supply. 

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