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BIOSYNTHESIS OF CHOLESTEROL
 Cholesterol is doubtless the most publicized lipid,
notorious because of the strong correlation between high
levels of cholesterol in the blood and the incidence of
human cardiovascular diseases.
 It plays an crucial role as a component of cellular
membranes and as a precursor of steroid hormones and
bile acids.
 Cholesterol is an essential molecule in many animals,
including humans, but is not required in the mammalian
diet-all cells can synthesize it from simple precursors.
 The structure of this 27-carbon compound is formed from
acetyl-coA in a complex series of reactions ,through the
Intermediates ß-hydroxy-ß-methylglutaryl-coA,
mevalonate,and two activated isoprenes,dimethylallyl
pyrophosphate and isopentyl pyrophosphate. Condensation of
isoprene units produces the non-cyclic squalene, which is
cyclized to yeild the steroid ring system and side chain.
 Synthesis takes place in 4 stages,
1) Condensation of three acetate units to form a six carbon
intermediate, mevalonate;
2) Conversion of mevalonate to activated isoprene units;
3) Polymerization of six 5 carbon isoprene units to form the 30carbon linear squalene; and
4) Cyclization of squalene to form the four rings of the steroid
nucleus, with further series of changes to produce
CHOLESTEROL.
CHOLESTEROL HAS SEVERAL FATES
 Much of the cholesterol synthesis in vertebrates takes
place in liver.
 A small fraction of the cholesterol made there is
incorporated into the membranes of hepatocytes, but
most of it is exported in one of three forms: biliary
cholesterol, bile acids, or cholesteryl esters.
 Bile acids and their salts are relatively hydrophillic
cholesterol derivatives that are synthesized in the liver
and aid in the lipid digestion.
 Cholesteryl esters are formed in the liver through the
action of acyl-coA-cholesterol acyl transferase (ACAT). This
enzyme catalyses the transfer of a fatty acid from
coenzyme A to the hydroxyl group of cholesterol,
converting the cholesterol to a more hydrophobic form.
 Cholesteryl esters are transported in secreted lipoprotein
particles to other tissues that use cholesterol, or they are
stored in the liver.
 All growing animal tissues need
CHOLESTEROL for membrane
synthesis, and some organs
(adrenal gland and gonads, for
example).
 Use CHOLESTEROL as a
precursor for steroid hormone
production
 CHOLESTEROL is also a
precursor of vitamin D.
REGULATION OF CHOLESTEROL
BIOSYNTHESIS
 Cholesterol synthesis is a complex and energy expensive
process, so it is advantageous to an organism to
complement dietary intake.
 In mammals, cholesterol production is regulated by
intracellular cholesterol concentration and by the
hormones glucagon and insulin.
 Regulation is mediated by an elegant system of
transcriptional regulation of the gene encoding HMG-CoA
reductase.
 This gene, along with more than 20 other genes encoding
enzymes that mediate the uptake and synthesis of
Cholesterol and unsaturated fatty acids, is controlled by a
small family of protein called sterol regulatory elementbinding protein (SREBPs).
 Newly synthesized proteins are embedded in the ER.
 Only soluble amino terminal domain of an SREBP
functions as a transcriptional activator.
 To activate transcription of the HMG-CoA reductase and
other genes, the transcriptionally active domain is
separated from SREBP by proteolytic cleavage.
 When cholesterol levels are high, SREBPs are inactive,
secured to ER in a complex with another protein called
SREBP cleavage- activating protein (SCAP).
 SCAP binds cholesterol and a number of other sterols,
thus acting as a sterol sensor.
 When sterol levels are high, the SCAP-SREBP complex
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interact with another protein that retains the entire
complex in ER.
When the levels declines, conformational change in SCAP
causes the release of the complex from ER and it migrates
to golgi complex.
In golgi complex, SREBP is cleaved twice by two different
proteases.
The second cleavage releases the amino- terminal domain
into the cytosol.
The domain travels to the nucleus and activates
transcription of its target gene.
The domain of SREBP has a shorter half-life and is rapidly
degraded by proteosomes.
 When sterol level increases, the proteolytic release of
SREBP domains is again blocked, and proteosome
degradation of the existing active domains results in rapid
shut down of the gene targets.
 Hormonal control is mediated by covalent modification
of HMG-CoA reductase itself.
 Glucagon stimulates phosphorylation (inactivation), and
insulin promotes dephosphorylation, activating the
enzyme and favoring cholesterol synthesis.
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