Squalene Isopentenyl pyrophosphate

Stage (J) Condensation of Six Activated Isoprene Units to Form Squalene Isopentenyl pyrophosphate and dimethylallyl pyrophosphate now undergo a head-to-tail condensation, in which one pyrophosphate group is displaced and a 10-carbon chain, geranyl pyrophosphate, is formed (Fig. 21-36). (The head is the end to which pyrophosphate is joined.) Geranyl pyrophosphate undergoes another head-to-tail condensation with isopentenyl pyro-... 

Whereas dimerization of two famesyl pyrophosphates (35) generates squalene (114) on the path to steroids (89), the addition of one more C unit, as isopentenyl pyrophosphate (31) or its isomer, 3,3-dimethyl ally pyrophosphate (32), to the C compound famesyl pyrophosphate produces the C2Q diterpene precursor geranylgeranyl pyrophosphate [6699-20-3] (122). 

Cholesterol is formed from acetyl-CoA in a complex series of reactions, through the intermediates /3-hydroxy-/3-methylglutaryl-CoA, mevalonate, and two activated isoprenes, dimethylallyl pyrophosphate and isopentenyl pyrophosphate. Condensation of isoprene units produces the noncyclic squalene, which is cyclized to yield the steroid ring system and side chain. 

Like all other classes of steroid hormones, the androgens are synthesized from acetyl coenzyme A via mevalonic acid, isopentenyl pyrophosphate, farnesyl pyrophosphate, squalene. lanosterol. and cholesterol. Enzyme... 

The biosynthesis of steroids begins with the conversion of three molecules of acetyl-CoA into mevalon-ate, the decarboxylation of mevalonate, and its conversion to isopentenyl pyrophosphate. Six molecules of isopentenyl pyrophosphate are polymerized into squalene, which is cyclized to yield lanosterol. Lanos-terol is converted to cholesterol, which is the precursor of bile acids and steroid hormones. 

All 27 carbon atoms of cholesterol are derived from acetyl Co A. First acetyl CoA and acetoacetyl CoA combine to form HMG CoA which, in turn, is reduced to mevalonate by HMG CoA reductase. Mevalonate is converted into the five-carbon isoprene compounds 3-isopentenyl pyrophosphate and its isomer dimethylallyl pyrophosphate. These two compounds condense to form the CIO geranyl pyrophosphate, which is elongated to the C15 farnesyl pyrophosphate by the addition of another molecule of isopentenyl pyrophosphate. Two molecules of farnesyl pyrophosphate condense to form the C30 squalene, which is then converted via squalene epoxide and lanosterol to cholesterol. 

The C5 isoprene units in isopentenyl pyrophosphate are then condensed to form the C30 compound squalene (Fig. 2). First, isopentenyl pyrophosphate isomerizes to dimethylallyl pyrophosphate (Fig. 2a), which reacts with another molecule of isopentenyl pyrophosphate to form the CIO compound geranyl pyrophosphate (Fig. 2b). Another molecule of isopentenyl pyrophosphate then reacts with geranyl pyrophosphate to form the C15 compound farnesyl pyrophosphate. Next, two molecules of farnesyl pyrophosphate condense to form squalene (Fig. 2b). 

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

Mevalonate molecules are condensed to a 30-carbon compound, squalene. The alcohol groups of mevalonate are first phosphorylated. Then they multiply phosphorylated mevalonate decarboxylates to make the two compounds isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). 

Some isopentenyl pyrophosphate is converted to the isomer dimethylallyl pyrophosphate, by an isomerase that produces a mixture, isopentenyl pyrophosphate dimethylallyl pyrophosphate. From this point on, the carbon chain-length of the intermediates progressively increase this is followed by reduction to squalene, which has 30 carbon atoms in a folded chain and no oxygen atoms (Chap. 6). The conversion of isopentenyl pyrophosphate to squalene is shown in Fig. 13-22. 

HMG CoA synthase HMG CoA reductase mevalonate kinase phosphomevalonaie kinase pyrophosphomevalonale decarteaylase isopentenyl pyrophosphate isoincraae diiBethylallyl transferase presqualene synthase squalene synthase... 

Stage two is the condensation of six molecules of isopentenyl pyrophosphate to form squalene. 

Squalene (C30) Is Synthesized from Six Molecules of Isopentenyl Pyrophosphate... 

Squalene is synthesized from isopentenyl pyrophosphate by the reaction sequence... 

Figure 26.10. Squalene Synthesis. One molecule of dimethyallyl pyrophosphate and two molecules of isopentenyl pyrophosphate condense to form famesyl pyrophosphate. The tail-to-tail coupling of two molecules of famesyl pyrophosphate yields squalene.

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). 

Key intermediates in cholesterol biosynthesis are HMG CoA, mevalonic acid, isopentenyl pyrophosphate, and squalene. 

The answer is d. (Murray, pp 505-626. Scrivei, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) In the first stage ol cholesterol formation, acetyl coenzyme A condenses to form mevalonate, which is then phosphorylated and decarboxylated to form isopentenyl pyrophosphate. Half of the isopentenyl pyrophosphate isomerizes to form dimethylallyl pyrophosphate. These two isomeric C5 pyrophosphate units (isopentenyl pyrophosphate and dimethylallyl pyrophosphate) condense to form a CIO compound called geranyl pyrophosphate. Isopentenyl pyrophosphate then condenses with geranyl pyrophosphate to form the C15 compound farne-syl pyrophosphate. Finally, two farnesyl pyrophosphates condense in the presence of NADPH to form the C30 compound squalene. Squalene is ultimately cyclized through a series of steps to form cholesterol. Thus, the correct sequence of events leading from C5 units to C30 squalene is sequential condensation of 5-carbon units until a 15-carbon unit is formed, then condensation of two 15-carbon units to form squalene. 

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. 

Mevalonate is first phosphorylated and decarboxylated through four steps to give isopentenyl pyrophosphate and dimethylallyl pyrophosphate. Through three new steps these compounds react with each other to give squalene, an aliphatic hydrocarbon with 30 carbons and 6 double bonds. A hydroxyl group is introduced into squalene and formation of the typical ring system of the sterols takes place (Figure 5.1). 

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