9. CHOLESTEROL biochemistry of biomolecules lipids cholesterol.ppt

CHOLESTEROL a biomolecules derived from lipids

1. Naureen Shehzadi
University College of Pharmacy, University of
the Punjab, Lahore, Pakistan
Cholesterol Metabolism

2. WHAT IS CHOLESTEROL?
•Cholesterol is the major sterol in human body.
Chemistry
•Molecular formula of cholesterol is C27H45OH
•Possesses a cyclopentanoperhydrophenanthrene ring nucleus
•Has an -OH group at C3
• A double bond between C5 and C6
• Two- CH3 groups at C10 and C13
•An eight carbon side chain attached to C17

4. FUNCTIONS
•Cholesterol is an essential lipid constituent of cell membranes,
provides fluidity to the cell membrane.
•Cholesterol is a precursor of steroid hormones and of bile acids
•Intermediates of cholesterol biosynthesis are required to make
vitamin D.

5. SITE OF CHOLESTEROL
SYNTHESIS
•Cholesterol is synthesized in the cytosol and endoplasmic
reticulum (ER).
•Liver is the main site of cholesterol synthesis; also, it is synthesized
in intestine, skin and other nucleated cells in the body

6. THE SUBSTRATE OF
CHOLESTEROL
•Cholesterol is synthesized from acetyl groups of cytosolic acetyl
coenzyme A (acetyl-CoA).
•Glucose and fatty acids are the major sources of acetyl-CoA

7. STEPS IN CHOLESTEROL
BIOSYNTHESIS
Starter Reaction
catalyzed by
End product By product
Acetyl CoA (2
molecules)
Thiolase, water Acetoacetyl CoAThioyl CoA
Acetoacetyl CoA
+ Acetyl CoA
HMG-CoA
synthase +
water
Beta-Hydroxy
beta-methyl
glutaryl CoA
(HMG-CoA)
Thioyl CoA
Beta-Hydroxy
beta-methyl
glutaryl CoA
HMG-CoA
reductase
(involves
2NADPH/H+)
Mevalonic acidThioyl CoA
+2NADP+

8. CONTI…
Starter Reaction
catalyzed by
End product By product
Mevalonic acidATP 5-phospho
mevalonic acid
ADP
5-
phosphomevalo
nic acid
ATP 5-pyrophospho
mevalonic acid
ADP
5-pyrophospho
mevalonic acid
ATP 3-phospho, 5-
pyrophospho
mevalonic acid
ADP

9. CONTI…
Starter Reaction
catalyzed by
End product By product
3-phospho, 5-
pyrophospho
mevalonic acid
DecarboxylaseIsopentenyl
pyrophosphate
Carbon dioxide
+ Phosphate
Isopentenyl
pyrophosphate
Isopentenyl
pyrophosphate
isomerase
3,3-dimethyl
allyl
pyrophosphate
-
3,3-dimethyl
allyl
pyrophosphate
+ isopentenyl
pyrophosphate
Geranyl
pyrophosphate
synthetase
Geranyl
pyrophosphate
Pyrophosphate

10. CONTI…
Starter Reaction
catalyzed by
End product By product
Geranyl
pyrophosphate
+ isopentenyl
pyrophosphate
Farnesyl
pyrophosphate
synthetase
Farnesyl
pyrophosphate
Pyrophosphate
2 molecules of
farnesyl
pyrophosphate
2NADPH/H+ Squalene 2NADP+,
2pyrophosphate
Squalene 1 -Squalene
monooxidase
(NADPH/H+,
Oxygen)
2 -Cyclase
1 -Squalene 2, 3
epoxide
2 -Lanosterol
NADP+

11. CONTI…
Starter Reaction
catalyzed by
End product By product
Lanosterol NADPH Zymosterol Three methyl
groups as
carbon dioxide
+ NAD+
Zymosterol Isomerase Desmosterol
DesmosterolReduction at C-
24, reductases,
NADPH/H+
Cholestreol

12. Initial activation steps in cholesterol synthesis
© Michael Palmer 2014

13. Formation of a C
10
intermediate
© Michael Palmer 2014

14. Formation of C
15
and C
30
intermediates
© Michael Palmer 2014

15. Squalene cyclization yields the first sterol
intermediate
© Michael Palmer 2014

16. Demethylation, desaturation and saturation
steps convert lanosterol to cholesterol
© Michael Palmer 2014