CLINICAL CASES
313
Isoprenoid: Any of a number of hydrophobic compounds derived from the
polymerization of isopentenyl pyrophosphate and its isomer, dimethy-
lallyl pyrophosphate. The isoprene unit is a five-carbon branched hydro-
carbon (2-methyl-1,3-butadiene).
Statin: Any of a number of drugs that competitively inhibit the rate-
limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase.
D ISC U SSIO N
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 inter-
mediates that are important in protein isoprenylation modifications. The charac-
teristic four-ring structure of cholesterol is then formed by cyclizing 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.
The key enzyme in the synthesis of cholesterol is
P-hydroxy-P-
methylglutaryl-CoA reductase (HMG-CoA reductase), which catalyzes the
synthesis of mevalonate from HMG-CoA in an irreversible, rate-limiting
reaction. Mevalonate is the immediate six-carbon precursor to isopentenyl
pyrophosphate. HMG-CoA reductase is localized on the membrane of the
endoplasmic reticulum and spans the membrane. The active site for this
enzyme is found on the cytosolic side of the membrane. HMG-CoA reductase
is inhibited by cholesterol in a feedback mechanism and the levels of mRNA
for the enzyme are also regulated by the levels of cholesterol. Low concentra-
tions of cholesterol increase the level of mRNA for HMG-CoA reductase,
whereas high concentrations of cholesterol decrease the mRNA level. Because
the enzyme HMG-CoA reductase is the rate-limiting step of cholesterol
biosynthesis, this enzyme is the target for many cholesterol lowering drugs.
The five major classes of steroid hormones are derived from cholesterol by
the pathway illustrated in Figure 34-2. Hydroxylation is important in these con-
versions. The hydroxylation reactions require NADPH and O2 and are carried
out by the cytochrome P450 enzyme system. The enzyme 21-hydroxylase is
required for the synthesis of mineralocorticoids and glucocorticoids.
Another important hormone derived from cholesterol is vitamin D. This
steroid-like hormone is involved in regulating calcium and phosphorus metab-
olism. The complete synthesis of vitamin D requires ultraviolet light to con-
vert 7-dehydrocholesterol to previtamin D3. The reaction scheme is shown in
Figure 34-3. The active hormone 1,25-dihydroxycholecalciferol (calcitriol)
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