PATRICIA F.
VILANUEVA, RMT
CHOLESTEROL
Cholesterol also serves as a precursor for the
biosynthesis of steroid hormones, bile
acid and vitamin D.
Cholesterol is the principal sterol synthesized by all
animals.
In vertebrates, hepatic cells typically produce the
greatest amounts.
Normal adults typically synthesize about 1 g (1,000 mg)
cholesterol per day and the total body content is about
35g.
FUNCTIONS OF CHOLESTEROL
Cell membrane synthesis - required to build and
maintain membranes and modulates membrane
fluidity over the range of physiological temperatures
Cell transporters and signalling molecules - can
facilitate speed of transmission of electrical impulses along
nerve tissue
Component of myelin sheath
Hormones and Vitamin D synthesis – cortisol
and aldosterone, as well as the sex
hormones progesterone, estrogens, testosterone, and their
derivatives.
Bile synthesis
BIOSYNTHESIS OF CHOLESTEROL
The liver is the primary organ that synthesizes
cholesterol. About 20–25% of total daily cholesterol
production occurs here. Cholesterol is also
synthesized to smaller extents in the adrenal glands,
intestines, reproductive organs.
Generally takes place in the endoplasmic reticulum of
hepatic cells and begins with acetyl- CoA. This mainy
involves four stages.
1. Synthesis of Mevalonate from
Acetate
Two molecules of acetyl-CoA condense to
form acetoacetyl-CoA. This is followed by a second
condensation between acetyl-CoA and acetoacetyl-
CoA to form 3-hydroxy-3-methylglutaryl CoA (HMG-
CoA).
1. Synthesis of Mevalonate from
Acetate
The third reaction is the reduction of HMG-CoA to
mevalonate, for which two molecules of NADPH
each donate two electrons.
Production of mevalonate is the rate-limiting and
irreversible step in cholesterol synthesis and is the site
of action for statins.
2. Conversion of Mevalonate to
Two Activated Isoprenes
Three phosphate groups are transferred from three
ATP molecules to mevalonate.
2. Conversion of Mevalonate to
Two Activated Isoprenes
In the next step, the phosphate attached to the C-3
hydroxyl group of mevalonate 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-isopentenylpyrophosphate yields
the second activated isoprene, dimethylallyl
pyrophosphate.
3. Condensation of Six Activated
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.
Geranyl pyrophosphate undergoes another head-to-
tail condensation with isopentenyl pyrophosphate,
yielding the 15-carbon intermediate farnesyl
pyrophosphate.
3. Condensation of Six Activated
Isoprene Units to Form Squalene
Finally, two molecules of farnesyl pyrophosphate join
head to head, with the elimination of both
pyrophosphate groups, forming squalene.
Squalene is the biochemical precursor to cholesterol
and other steroids.
4.Conversion of Squalene
The action of squalene monooxygenase adds one
oxygen atom from O2 to the end of the squalene chain,
forming an epoxide.
NADPH reduces the other oxygen atom of O2 to H2O.
The double bonds of the product,squalene2,3-
epoxide, are positioned so that a reaction can convert
the linear squalene epoxide into a cyclic structure.
4.Conversion of Squalene
Oxidosqualene cyclase then cyclizes squalene to
form lanosterol.
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.
The final 20 steps to cholesterol contain NADPH and
oxygen to help oxidize methyl groups for removal of
carbons, mutases to move alkene groups, and NADH to
help reduce ketones.
4.Conversion of Squalene
Elucidation of this 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.
Regulation of Cholesterol Synthesis
Biosynthesis of cholesterol is directly regulated by the
cholesterol levels present.
The main step that regulates cholesterol synthesis is
the conversion of HMG-CoA to mevalonate in
presence of HMG-CoA reductase. This enzyme HMG-
CoA reductase is thus the rate limiting enzyme and
controls excessive cholesterol formation by feedback
mechanism.
When the concentration of intracellular cholesterol
increases, levels of HMG-CoA reductase are reduced
by decreasing the gene transcription of this enzyme.
Reference:
Principles of biochemistry 2nd ed. (Lehninger,
Albert L.; Nelson, David L.; Cox, Michael M.),
Chapter 20.
