CHOLESTEROL | CHOLESTEROL METABOLISM | CHOLESTEROL BIOSYNTHESIS

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CHOLESTEROL, CHOLESTEROL METABOLISM & CHOLESTEROL BIOSYNTHESIS.

Books referred: https://www.amazon.in/Biochemistry-2019-Satyanarayana-Satyanarayana-Author/dp/B07WGHCTKZ/ref=sr_1_1?dchild=1&qid=1591114482&refinements=p_27%3AU+Satyanarayana&s=books&sr=1-1

2. CHOLESTEROL
•Cholesterol is found in animals, therefore it is
called as animal sterol.
•Total content of cholesterol in an adult is •Total content of cholesterol in an adult is
around 2 g/kg body weight.
•It is amphipathicin nature, (hydrophilic and
hydrophobic).

3. Functions of cholesterol
1. Structural componentof cell membrane.
2. Precursorfor the synthesis of all other steroidsin
the body. E.g. steroid hormones, vitamin D and
bile acids.bile acids.
3. Essential ingredient in the structure of
lipoproteins.
4. Fatty acids are transported to liver as cholesteryl
estersfor oxidation.

4. CHOLESTEROL BIOSYNTHESIS
•All tissues can produce cholesterol. But the largest is produced by:
–Liver (50%), Intestine (15%), Skin, AdrenalCortex, Reproductive
Tissue etc.
•Enzymes are found: In the cytosoland microsomalfractions of the cell.
•Acetate of acetyl CoAprovides : carbon atoms.•Acetate of acetyl CoAprovides : carbon atoms.
•The reducing equivalents are supplied by NADPH while ATP provides
energy.
•Requirement for the production of1 mole of cholesterol:
–18 moles of acetyl CoA
–36 moles of ATP
–16 moles of NADPH.

5. 5 stages of synthesis of cholesterol
1.Synthesis of HMG CoA
2.Formation of mevalonate(6C)
3.Production of isoprenoidunits (5C)3.Production of isoprenoidunits (5C)
4.Synthesis of squalene(30C)
5.Conversion of squaleneto cholesterol (27C).

6. Synthesis of β-hydroxyβ -methylglutarylCoA(HMG
CoA):
•Two moles of acetyl CoAcondense to form
acetoacetylCoA. Another molecule of acetyl CoAis
then added to produce HMG CoA.
Stage 1
then added to produce HMG CoA.
•Cholesterol synthesis occurs in cytosol.
•Two isoenzymesof HMG CoAsynthaseare known.
Cytosomalenzyme:for cholesterol synthesis
Mitochondrial enzyme:for ketonebody synthesis

8. Formation of mevalonate:
•HMG CoAreductaseis the rate limiting
enzyme in cholesterol biosynthesis.
•This enzyme is present in endoplasmic
Stage 2
•This enzyme is present in endoplasmic
reticulum and catalyses the reduction of HMG
CoAto mevalonate.
•The reducing equivalents are supplied by
NADPH.

10. Production of isoprenoidunits:
•3 step reaction catalysedby kinases, mevalonateis
converted to 3-phospho 5 pyrophosphomevalonate
which on decarboxylationforms isopentenyl
pyrophosphate (IPP).
Stage 3
pyrophosphate (IPP).
•The latter isomerizes to dimethylallylpyrophosphate
(DPP).
•Both IPP and DPP are 5-carbon isoprenoidunits.

12. Synthesis of squalene:
•IPP and DPP condense to produce a 10-carbon
geranylpyrophosphate (GPP).
•Another molecule of IPP condenses with GPP
Stage 4
•Another molecule of IPP condenses with GPP
to form a 15-carbon farnesylpyrophosphate
(FPP).
•Two units of farnesylpyrophosphate unite and
get reduced to produce a 30-carbon squalene.

14. Conversion of squaleneto cholesterol:
•Squaleneundergoes hydroxylation and cyclizationutilizing
O2 and NADPH and gets converted to lanosterol.
•The formation of cholesterolfrom lanosterolis a multistep
process with a series of about 19 enzymatic reactions.
•The following are the most important reactions:
–Reducing the carbon atoms from 30 to 27.
Stage 5
–Reducing the carbon atoms from 30 to 27.
–Removal of two methyl groups from C4 and one methyl group
from C14.
–Shift of double bond from C8 to C5.
–Reduction in the double bond present between C24 and C25.

15. •14-Desmethyllanosterol, zymosterol,
cholestadienolanddesmosterol: Intermediates
in the cholesterol biosynthesis. in the cholesterol biosynthesis.
•The penultimate product is 7-dehydrocholesterol
which, on reduction, finally yields cholesterol.

17. Outline of cholesterol biosynthesis

18. Synthesis of bile acids from Cholesterol
The bile acids possess 24 carbon atoms, 2 or 3
hydroxyl groups in the steroid nucleus and a side
chain ending in carboxyl group.
The bile acids are amphipathicin nature. The bile acids are amphipathicin nature.
They serve as emulsifying agents in the intestine
and helps in the digestion and absorption of
lipids.
The synthesis takes place in the liver.

19. •The step catalysedby 7 α-hydroxylaseis the rate
limiting reaction. And the reaction is inhibited by bile
acids.
•Cholicacidandchenodeoxycholicacid are the primary
bile acids. bile acids.
•On conjugation with glycineor taurine, conjugated bile
acids (glycocholicacid, taurocholicacid etc.) are
formed .
•In the bile, the conjugated bile acids exist as sodium
and potassium salts which are known as bile salts.

20. In the intestine, a portion of primary bile acids
undergoes deconjugationand dehydroxylation
to form secondary bile acids (deoxycholicacid
andlithocholicacid). andlithocholicacid).
These reactions are catalysedby bacterial
enzymes in the intestine.

22. Synthesis of steroid hormones from
cholesterol
Cholesterol is the precursor for the synthesis of
all the five classes of steroid hormones
(a) Glucocorticoids(e.g. cortisol)
(b) Mineralocorticoids(e.g. aldosterone)(b) Mineralocorticoids(e.g. aldosterone)
(c) Progestins(e.g. progesterone)
(d) Androgens (e.g. testosterone)
(e) Estrogens (e.g. estradiol).

23. Overview

24. Pathway contined…

26. Synthesis of vitamin D
7-Dehydrocholesterol, an intermediate in the
synthesis of cholesterol, is converted to
cholecalciferol(vitamin D3)by ultraviolet rays
in the skin.in the skin.