Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages

Figure 26.5. Lysosome with Lipids. An electron micrograph of a lysosome containing an abnormal amount of lipid.
[Courtesy of Dr. George Palade.]
III. Synthesizing the Molecules of Life
26. The Biosynthesis of Membrane Lipids and Steroids
26.2. Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages
We now turn our attention to the synthesis of the fundamental lipid cholesterol. This steroid modulates the fluidity of
animal cell membranes (Section 12.6.2) and is the precursor of steroid hormones such as progesterone, testosterone,
estradiol, and cortisol. All 27 carbon atoms of cholesterol are derived from acetyl CoA in a three-stage synthetic process
(Figure 26.6).
Cholesterol"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
Nobel Lectures (1985)
© The Nobel Foundation, 1985
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 in an astounding reaction and the tetracyclic product is subsequently converted into
cholesterol.
26.2.1. The Synthesis of Mevalonate, Which Is Activated as Isopentenyl Pyrophosphate,
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, which takes place in the cytosol, 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
(Figure 26.7). Recall that mitochondrial 3-hydroxy-3-methylglutaryl CoA is processed to form ketone bodies (Section
22.3.5).
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 an important control site in cholesterol
biosynthesis, as will be discussed shortly.
HMG-CoA reductase is an integral membrane protein in the endoplasmic reticulum.
Mevalonate is converted into 3-isopentenyl pyrophosphate in three consecutive reactions requiring ATP (Figure 26.8).
Decarboxylation yields isopentenyl pyrophosphate, an activated isoprene unit that is a key building block for many
important biomolecules throughout the kingdoms of life. We will return to a discussion of this molecule later in the
chapter.
26.2.2. Squalene (C30) Is Synthesized from Six Molecules of Isopentenyl Pyrophosphate
(C5)
Squalene is synthesized from isopentenyl pyrophosphate by the reaction sequence
This stage in the synthesis of cholesterol starts with the isomerization of isopentenyl pyrophosphate to dimethylallyl
pyrophosphate.
These isomeric C5 units condense to form a C10 compound: isopentenyl pyrophosphate attacks an allylic carbonium ion
formed from dimethylallyl pyrophosphate to yield geranyl pyrophosphate (Figure 26.9). The same kind of reaction takes
place again: geranyl pyrophosphate is converted into an allylic carbonium ion, which is attacked by isopentenyl
pyrophosphate. The resulting C15 compound is called farnesyl pyrophosphate. The same enzyme, geranyl transferase,
catalyzes each of these condensations.
The last step in the synthesis of squalene is a reductive tail-to-tail condensation of two molecules of farnesyl
pyrophosphate catalyzed by the endoplasmic reticulum enzyme squalene synthase.
The reactions leading from C5 units to squalene, a C30 isoprenoid, are summarized in Figure 26.10.
26.2.3. Squalene Cyclizes to Form Cholesterol
The final stage of cholesterol biosynthesis starts with the cyclization of squalene (Figure 26.11). 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 by oxidosqualene cyclase (Figure 26.12). This remarkable transformation proceeds
in a concerted fashion. The enzyme holds squalene epoxide in an appropriate conformation and initiates the reaction by
protonating the epoxide oxygen. The carbocation formed spontaneously rearranges to produce lanosterol. Lanosterol is
converted into cholesterol in a multistep process by the removal of three methyl groups, the reduction of one double
bond by NADPH, and the migration of the other double bond (Figure 26.13).
III. Synthesizing the Molecules of Life
26. The Biosynthesis of Membrane Lipids and Steroids
26.2. Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages
Figure 26.6. Labeling of Cholesterol. The results of isotope-labeling experiments reveal the source of carbon atoms in
cholesterol synthesized from acetate labeled in its methyl group (blue) or carboxylate atom (red).
III. Synthesizing the Molecules of Life
26. The Biosynthesis of Membrane Lipids and Steroids
26.2. Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages
Figure 26.7. Fates of 3-Hydroxy-3-Methylglutaryl CoA. In the cytosol, HMG-CoA is converted into mevalonate. In
mitochondria, it is converted into acetyl CoA and acetoacetate.
III. Synthesizing the Molecules of Life
26. The Biosynthesis of Membrane Lipids and Steroids
26.2. Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages
Figure 26.8. Synthesis of Isopentenyl Pyrophosphate. This activated intermediate is formed from mevalonate in three
steps, the last of which includes a decarboxylation.
III. Synthesizing the Molecules of Life
26. The Biosynthesis of Membrane Lipids and Steroids
26.2. Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages
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 farnesyl pyrophosphate.
III. Synthesizing the Molecules of Life
26. The Biosynthesis of Membrane Lipids and Steroids
26.2. Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages
Figure 26.10. Squalene Synthesis. One molecule of dimethyallyl 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.
III. Synthesizing the Molecules of Life
26. The Biosynthesis of Membrane Lipids and Steroids
26.2. Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages
Figure 26.11. 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.
III. Synthesizing the Molecules of Life
26. The Biosynthesis of Membrane Lipids and Steroids
26.2. Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages
Figure 26.12. Oxidosqualene Cyclase. The structure of an enzyme homologous to oxidosqualene cyclase shows a
central cavity lined primarily with hydrophobic side chains (shown in red) in which the cyclization reaction takes
place.