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Cholesterol, like long-chain fatty acids, is made
from acetyl-CoA, but the assembly plan is quite different in the two cases.
In early experiments animals were fed acetate labeled with 14C in
either the methyl carbon or the carboxyl carbon. The pattern of labeling in
the cholesterol isolated from the two groups of animals (Fig. 20-30) provided
the blueprint for working out the enzymatic steps in cholesterol
biosynthesis.
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| Figure 20-30 |
Figure 20-30 The origin of the carbon atoms of
cholesterol, deduced from tracer experiments with acetate labeled in the methyl
carbon (black) or the carboxyl carbon (red). The individual rings in the
fused-ring system are designated A through D.
The process occurs in four stages (Fig. 20-31).
In stage 1 the three acetate units condense to form a six-carbon intermediate,
mevalonate. Stage 2 involves the conversion of mevalonate into activated
isoprene units, and stage 3 the polymerization of six 5-carbon isoprene units
ta form the 30-carbon linear structure of squalene. Finally (stage 4, the
cyclization of squalene forms the four rings of the steroid nucleus, and a
further series of changes (oxidations, removal or migration of methyl groups)
leads to the final product, cholesterol.
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| Figure 20-31 |
Figure 20-31 A summary of
cholesterol biosynthesis, showing the four stages discussed in the text. The
isoprene units in squalene are set off by red dashed lines.
1. Synthesis of Mevalonate from Acetate
The first stage in cholesterol biosynthesis leads
to the intermediate mevalonate (Fig. 20-32). Two molecules of
acetyl-CoA condense, forming acetoacetyl-CoA, which condenses with a third
molecule of acetyl-CoA to yield the six-carbon compound β-hydroxy-β-methylglutaryl-CoA
(HMG-CoA). These first two reactions, catalyzed by thiolase
and HMG-CoA synthase, respectively, are reversible and do not
commit the cell to the synthesis of cholesterol or other isoprenoid compounds.
The third reaction is the committed step: the
reduction of HMGCoA to mevalonate, for which two molecules of NADPH each donate
two electrons. HMG-CoA reductase, an integral membrane protein
of the smooth endoplasmic reticulum, is the major point of regulation on the
pathway to cholesterol, as we shall see.
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| Figure 20-32 |
Figure 20-32 Formation of
mevalonate from acetyl-CoA. The origin of C-1 and C-2 of mevalonate from
acetyl-CoA is shown in red.
2. Conversion of Mevalonate to Two
Activated Isoprenes In the next stage of cholesterol synthesis, three
phosphate groups are transferred from three ATP molecules to mevalonate (Fig.
20-33). The phosphate attached to the C-3 hydroxyl group of mevalonate in the
intermediate 3-phospho-5-pyrophosphomevalonate is a good leaving group; in the
next step this phosphate and the nearby carboxyl group both leave, producing a
double bond in the five-carbon product, Δ3-isopentenyl
pyrophosphate. This is the first of the two activated isoprenes
central to cholesterol formation. Isomerization of Δ3-isopentenyl
pyrophosphate yields the second activated isoprene, dimethylallyl
pyrophosphate (Fig. 20-33)
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| Figure 20-33 |
Figure 20-33 Conversion of
mevalonate into activated isoprene units. Six of these units will combine to
form squalene. The leaving groups of 3-phospho-5-pyrophosphomevalonate are
shaded in red.
3. Condensation of Six ActiUated Isoprene
Units to Form Squalene
Isopentenyl pyrophosphate and dimethylallyl
pyrophosphate now undergo a "head-to-tail" condensation in which one
pyrophosphate group is displaced and a 10-carbon chain, geranyl
pyrophosphate, is formed (Fig. 20-34). (The "head" is the
end to which pyrophosphate is joined.) Geranyl pyrophosphate undergoes another
head-to-tail condensation with isopentenyl pyrophosphate, yielding the
15-carbon intermediate farnesyl pyrophosphate. Finally, two
molecules of farnesyl pyrophosphate join head to head, with the elimination of
both pyrophosphate groups, forming squalene (Fig. 20-34). The
common names of these compounds derive from the sources from which they were
first isolated. Geraniol, a component of rose oil, has the smell of geraniums,
and farnesol is a scent found in the flowers of a tree, Farnese acacia. Many
natural scents of plant origin are synthesized from isoprene units. Squalene,
first isolated from the liver of sharks (genus Squalus), has 30 carbons, 24 in
the main chain and 6 in the form of methyl group branches.
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| Figure 20-34 |
Figure 20-34 Formation of
squalene (30 carbons) by successive condensations of activated isoprene
(five-carbon) units.
4.Conversion of Squalene to the
Four-Iling Steroid Nucleus
When the squalene molecule is represented as in
Figure 20-35, the relationship of its linear structure to the cyclic structure
of the sterols is apparent. All of the sterols have four fused rings (the
steroid nucleus) and all are alcohols, with a hydroxyl group at C-3; thus the
name "sterol." The action of squalene monooxygenase adds one
oxygen atom from O2 to the end of the squalene chain, forming an
epoxide. This enzyme is another mixed-function oxidase (Box 20-1); NADPH
reduces the other oxygen atom of O2 to H2O. The double
bonds of the product, squalene2,3-epoxide, are positioned so that a
remarkable concerted reaction can convert the linear squalene epoxide into a
cyclic structure. In animal cells, this cyclization results in the formation of
lanosterol, which contains the four rings characteristic of the steroid
nucleus. Lanosterol is finally converted into cholesterol in a series of about
20 reactions, including the migration of some methyl groups and the removal of
others. Elucidation of this extraordinary biosynthetic pathway, one of the most
complex known, was accomplished by Konrad Bloch, Feodor Lynen, John Cornforth,
and George Popjak in the late 1950s.
Cholesterol is the sterol characteristic of
animal cells, but plants, fungi, and protists make other, closely related
sterols instead of cholesterol, using the same synthetic pathway as far as
squalene-2,3-epoxide. At this point the synthetic pathways diverge slightly,
yielding other sterols: stigmasterol in many plants and ergosterol in fungi,
for example (Fig. 20-35).
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| Figure 20-35 |
Figure 20-35 Ring closure converts linear squalene into the
condensed steroid nucleus. The first step in this sequence is catalyzed by a
mixed-function oxidase (a monooxygenase), for which the cosubstrate is NADPH.
The product is an epoxide, which in the next step is cyclized to the steroid
nucleus. The final product of these reactions in animal cells is cholesterol,
but in other organisms, slightly different sterols are produced
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3 komentar:
I’ve trying to understand biosynthesis of cholestrol.In the second stage of the conversion of mevalonate to two activated isoprenes, the 3-phospo-5-pyrophospomevalonate release the phospate that located below,why did it not release the phospate in the side?
Why lanosterol release methyl group in C 14 n C4 position to form cholestrol? What will form from methyl group that release? How can it happen?
Why squalene epoxide 2,3 form three different compounds in fungi and plant?
Cholesterol is formed from lanosterol after the removal of three methyl groups from lanosterol molecule that two of the carbon atoms C-4 and one of the C-14. The removal of the three methyl groups takes place in stages, starting from the methyl group at C-14 and the rest of C-4. The two methyl groups at both C-4 removed as carbon dioxide, after both suffered oxidation to carboxylate groups. whereas the methyl group on C-14 eliminated as formic acid as a methyl group was oxidized to aldehyde group.
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