2. STEPS
INVOLVED
The biosynthesis of cholesterol may be divided into five
steps:
Biosynthesis of mevalonate occurs from acetyl-CoA.
Formation of Isoprenoid units formed from mevalonate
by loss ofC02.
Condensation of six isoprenoid units form squalene.
Cyclization of squalene give rise to the parent steroid,
lanosterol.
Formation Of Cholesterol from lanosterol.
3.
4.
5. STEP1
The first stage in the synthesis of cholesterol is the
formation of mevalonate from acetyl CoA.
This set of reactions takes place in the cytosol.
Initially, two molecules of acetyl-CoA condense to form
Acetoacetyl-CoA catalyzed by cytosolic thiolase.
•Acetoacetyl-CoA condenses with a further molecule of
acetyl-CoA catalyzed by HMGCOA synthase to form ß-
hydroxy-ßmethylgIutaryI-CoA (HMG-CoA), that is
reduced to mevalonate by NADPH catalyzed by beta-
hydroxy-beta—methylglutaryl COA reductase (HMG-
CoA reductase).
6.
7. STEP2 Mevalonate is phosphorylated by 2 sequential P
transfers from ATP, yielding the pyrophosphate
derivative.
ATP-dependent decarboxylation, with dehydration,
yields isopentenyl pyrophosphate.
Isopentenyl Pyrophosphate Isomerase inter-converts
isopentenyl pyrophosphate & dimethylallyl
pyrophosphate. protonation followed by deprotonation.
8.
9. STEP3
Squalene (C30) is synthesized from six molecules of
Isopentenyl Pyrophosphate (C5) and the reaction
sequence is:
C5 C10 C15 C30
Isopentenyl diphosphate is isomerized by a shift of the
double bond to form dimethylallyl diphosphate, then
condensed with another molecule of isopentenyl
diphosphate to form the ten-carbon (C10) intermediate
geranyl diphosphate.
A further condensation with isopentenyl diphosphate
forms farnesyl diphosphate.Two molecules of farnesyl
diphosphate condense at the diphosphate end to form
squalene.
Initially, inorganic pyrophosphate is eliminated,
forming presqualene diphosphate, which is then
reduced by NADPH with elimination of a further
inorganic pyrophosphate molecule.
10.
11. STEP4
Squalene can fold into a structure that closely
resembles the steroid nucleus .Before ring closure
occurs, squalene is converted to squalene 2,3-epoxide
by a mixed-function oxidase (i.e.) squalene epoxidase in
the endoplasmic reticulum.
The methyl group on C14 is transferred to C13 and
that on C8, to C14 as cyclization occurs, catalyzed by
oxidosqualene: lanosterol cyclase.
The newly formed cyclized structure is Lanosterol.
12.
13. STEP5
The formation of cholesterol from lanosterol takes
place in the membranes of the endoplasmic reticulum
and involves changes in the steroid nucleus and side
chain .
The methyl groups on C14 and C4 are removed to form
14-desmethyl lanosterol and then zymosterol.The
double bond at C8—C9 is subsequently moved to C5-
C6 in two steps, forming desmosterol.
Finally, the double bond of the side chain is reduced,
producing cholesterol.
14.
15. SIGNIFICANCE
Cholesterol is the most abundant sterol in humansIt is
a major constituent of the plasma membrane and of
plasma lipoproteins.
It is a precursor of bile salts.It is a precursor of steroid
hormones that include adrenocortical hormones, sex
hormones, placental hormones etc.
Also a precursor of vitamin D.It is required for the
nerve transmission.Cholesterol is a major constituent
of gallstones.
It has chief role in pathologic processes as a factor in
the genesis of atherosclerosis of vital arteries, causing
cerebrovascular, coronary, and peripheral vascular
disease.
16. SIGNIFICANCE
Cholesterol is the major sterol in the animal tissues.
Cholesterol is present in tissues and in plasma either
as free cholesterol or as a storage form, combined with
a long-chain fatty acid as cholesteryl ester.
In plasma, both forms are transported in
lipoproteins.Plasma low-density lipoprotein (LDL) is
the vehicle of uptake of cholesterol and cholesteryl
ester into many tissues.
Free cholesterol is removed from tissues by plasma
high-density lipoprotein (HDL) and transported to the
liver, where it is eliminated from the body either
unchanged or after conversion to bile acids in the
process known as reverse cholesterol transport.