Cholesterol Squalene formation

Formation of cholesterol. Squalene, a linear isoprenoid, is cyclized, with O2 being consumed, to form lanosterol, a C30 sterol. Three methyl groups are cleaved from this in the subsequent reaction steps, to yield the end product cholesterol. Some of these reactions are catalyzed by cytochrome P450 systems (see p. 318). 

Fio. 2. Simplified scheme of cholesterol biosynthesis up to squalene formation. Dotted arrow refers to the site of feedback, control of cholesterogenesis. 

Perhaps the most spectacular of the natural carbocation rearrangements is the concerted sequence of 1,2-methyl and 1,2-hydride Wagner-Meerwein shifts that occurs during the formation oflanosterol from squalene. Lanosterol is then the precursor of the steroid cholesterol in animals. 

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 ... 

Squalene is an important biological precursor of many triterpenoids, one of which is cholesterol. The first step in the conversion of squalene to lanosterol is epoxidation of the 2,3-douhle bond of squalene. Acid-catalysed ring opening of the epoxide initiates a series of cyclizations, resulting in the formation of protesterol cation. Elimination of a C-9 proton leads to the 1,2-hydride and 1,2-methyl shifts, resulting in the formation of lanosterol, which in turn converted to cholesterol by enzymes in a series of 19 steps. 

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). 

The common immediate precursor for the biosynthetic formation of cholesterol and triterpenes is squalene (76) which is derived from the head-to-head condensation of two molecules of farnesyl pyrophosphate (73) (equation 11) . This is a complex reaction... 

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. 

Animals accumulate cholesterol from their diet, but are also able to biosynthesize it from acetate. The pioneering work that identified the key intermediates in the complicated pathway of cholesterol biosynthesis was carried out by Konrad Bloch (Harvard) and Feodor Lynen (Munich), corecipients of the 1964 Nobel Prize for physiology or medicine. An important discovery was that the triterpene squalene (see Figure 26.6) is an intermediate in the formation of cholesterol from acetate. Thus, the early stages of cholesterol biosynthesis are the same as those of terpene biosynthesis described in Sections... 

Cholesterol synthesis can be divided into three phases formation of HMG-CoA from acetyl-CoA, conversion of HMG-CoA to squalene, and conversion of squalene to cholesterol. Cholesterol is the precursor for all steroid hormones and the bile salts. Bile salts are used to emulsify dietary fat. They are the primary means by which the body can rid itself of cholesterol. 

Squalene synthase is an enzyme catalyzing the formation of squalene from farnesyl diphosphate which is a committed step in the cholesterol biosynthetic pathway. Therefore, squalene synthase is considered a better target than HMG-CoA reductase because farnesyl pyrophosphate, a downstream product of HMG-CoA reductase, is needed for prenylation of proteins and for the biosyntheses of ubiquinone and dolichol (Fig. 2). Before squalestatins and zaragozic acids were discovered, a number of squalene synthase inhibitors were synthesized that showed respectable inhibitory potencies in vitro, but none were successful in animal testing [41]. It was the discovery of squalestatins and zaragozic acids that renewed interest in this biological target, and at picomolar potencies they were the most active inhibitors of squalene synthase. 

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