Page 181 - Color Atlas of Biochemistry

172 Metabolism
Biosynthesis of cholesterol
Cholesterol is a major constituent of the cell
membranes of animal cells (see p. 216). It
wouldbepossiblefor thebodyto provide its
full daily cholesterol requirement (ca. 1 g) by
synthesizing it itself. However, with a mixed
diet, only about half of the cholesterol is de- boxylated to isopentenyl diphosphate, with
rived from endogenous biosynthesis,which
takes place in the intestine and skin, and
mainly in the liver (about 50%). The rest is
taken up from food. Most of the cholesterol
is incorporated into the lipid layer of plasma
membranes, or converted into bile acids (see
p. 314). A very small amount of cholesterol is
used for biosynthesis of the steroid hormones
(see p. 376). In addition, up to 1 g cholesterol tenyl diphosphate produces farnesyl diphos-
per day is released into the bile and thus
excreted.
A. Cholesterol biosynthesis
Cholesterol is one of the isoprenoids, synthe-
sis of which starts from acetyl CoA (see p. 52). linear isoprenoid, is cyclized, with O 2 being
In a long and complex reaction chain, the C 27
sterol is built up from C 2 components. The
biosynthesis of cholesterol can be divided
into four sections. In the first (1),
mevalonate, aC 6 compound, arises from
three molecules of acetyl CoA. In the second
part (2), mevalonate is converted into isopen-
tenyl diphosphate, the “active isoprene.” In
the third part (3), six of these C 5 molecules
are linked to produce squalene, aC 30 com-
pound. Finally, squalene undergoes cycliza-
tion, with three C atoms being removed, to
yield cholesterol (4). The illustration only
shows the most important intermediates in
biosynthesis.
(1) Formation of mevalonate. The conver-
sion of acetyl CoA to acetoacetyl CoA and then
to 3-hydroxy-3-methylglutaryl CoA (3-HMG
CoA) corresponds to the biosynthetic path-
way for ketone bodies (details on p. 312). In
this case, however, the synthesis occurs not in
the mitochondria as in ketone body synthesis,
but in the smooth endoplasmic reticulum. In
the next step, the 3-HMG group is cleaved
from the CoA and at the same time reduced
+
to mevalonate with the help of NADPH+H . 3-
HMG CoA reductase is the key enzyme in cho-
lesterol biosynthesis. It is regulated by repres-
sion of transcription (effectors: oxysterols
such as cholesterol) and by interconversion
Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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(effectors: hormones). Insulin and thyroxine
stimulate the enzyme and glucagon inhibits it
by cAMP-dependent phosphorylation. A large
supply of cholesterol from food also inhibits
3-HMG-CoA reductase.
(2) Formation of isopentenyl diphosphate.
After phosphorylation, mevalonate is decar-
consumption of ATP. Thisisthe component
from which all of the isoprenoids are built
(see p. 53).
(3) Formation of squalene. Isopentenyl
diphosphate undergoes isomerization to
form dimethylallyl diphosphate. The two C 5
molecules condense to yield geranyl diphos-
phate, and the addition of another isopen-
phate. This can then undergo dimerization, in
a head-to-head reaction, to yield squalene.
Farnesyl diphosphate is also the starting-
point for other polyisoprenoids, such as doli-
chol (see p. 230) and ubiquinone (see p. 52).
(4) Formation of cholesterol. Squalene, a
consumed, to form lanosterol, a C 30 sterol.
Three methyl groups are cleaved from this
in the subsequent reaction steps, to yield the
end product cholesterol. Some of these reac-
tions are catalyzed by cytochrome P450 sys-
tems (see p. 318).
The endergonic biosynthetic pathway de-
scribed 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 .
The division of the intermediates of the
reaction pathway into three groups is charac-
teristic: CoA compounds, diphosphates, and
highly lipophilic, poorly soluble compounds
(squalene to cholesterol), which are bound to
sterol carriers in the cell.