29.2 Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages

DID YOU KNOW?

“Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.”

—Michael Brown and Joseph Goldstein, on the occasion of their receipt of the Nobel Prize for elucidating the control of blood levels of cholesterol. Nobel Lectures (1985); © The Nobel Foundation, 1985

We now turn our attention to the synthesis of a different kind of lipid, which lacks the long hydrocarbon chains characteristic of triacylglycerols and membrane lipids—cholesterol. Cholesterol has a much higher profile than the other lipids because of its association with heart disease. Despite its lethal reputation with the public, cholesterol is vital to the body: it maintains proper fluidity of animal cell membranes and is the precursor of steroid hormones such as progesterone, testosterone, estradiol, and cortisol.

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Cholesterol is synthesized in the liver and, to a lesser extent, in other tissues. The rate of its synthesis is highly responsive to the cellular level of cholesterol. All 27 carbon atoms of cholesterol are derived from acetyl CoA in a three-stage synthetic process:

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

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

  3. In stage three, squalene cyclizes and the tetracyclic product is subsequently converted into cholesterol.

The first stage takes place in the cytoplasm, and the second two in the lumen of the endoplasmic reticulum.

The Synthesis of Mevalonate Initiates the Synthesis of Cholesterol

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate from acetyl CoA. This set of reactions starts with the formation of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) from acetyl CoA and acetoacetyl CoA. This intermediate is reduced to mevalonate for the synthesis of cholesterol.

The synthesis of mevalonate is the committed step in cholesterol formation. The enzyme catalyzing this irreversible step, 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), is the key control site in cholesterol biosynthesis, as will be discussed shortly. The importance of cholesterol is vividly illustrated by the observation that mice lacking HMG-CoA reductase die very early in development.

Mevalonate is converted into 3-isopentenyl pyrophosphate in three consecutive reactions requiring ATP (Figure 29.8). Stage one ends with the production of isopentenyl pyrophosphate, an activated 5-carbon isoprene unit.

Figure 29.8 Isopentenyl pyrophosphate synthesis. This activated intermediate is formed from mevalonate in three steps, the last of which includes a decarboxylation.

Squalene (C30) Is Synthesized from Six Molecules of Isopentenyl Pyrophosphate (C5)

The next major precursor on the path to cholesterol is squalene, which is synthesized from isopentenyl pyrophosphate by the following reaction sequence:

Before the condensation reactions take place, isopentenyl pyrophosphate isomerizes to dimethylallyl pyrophosphate:

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The two isomer C5 units (one of each) condense to begin the formation of squalene. The reactions leading from the six C5 units to squalene, a C30 isoprenoid, are summarized in (Figure 29.9).

Figure 29.9 Squalene synthesis. One molecule of dimethylallyl pyrophosphate and two molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate. The tail-to-tail coupling of two molecules of farnesyl pyrophosphate yields squalene.
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Squalene Cyclizes to Form Cholesterol

DID YOU KNOW?

An epoxide is a three-member cyclic ether. An ether is an oxygen atom bonded to two carbon atoms.

In the final stage of cholesterol biosynthesis, squalene cyclizes to form a ringlike structure (Figure 29.10). Squalene is first activated by conversion into squalene epoxide (2,3-oxidosqualene) in a reaction that uses O2 and NADPH. Squalene epoxide is then cyclized to lanosterol. Lanosterol (C30) is subsequently converted into cholesterol (C27) in a multistep process, during which three carbon units are removed (Figure 29.10).

Figure 29.10 Squalene cyclization. The formation of the steroid nucleus from squalene begins with the formation of squalene epoxide. This intermediate is protonated to form a carbocation that cyclizes to form a tetracyclic structure, which rearranges to form lanosterol. Then, lanosterol is converted into cholesterol in a complex process.
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