Bio-Synthesis of Cholesterol and its regulation in the body

1. CHOLESTEROL
BIOSYNTHESIS
And Regulation
Group C
Aayush Kafle
Suman Kapri

2. CHOLESTEROL
• C27 H46 O
• It is the most abundant animal sterol.
• Cholesterol content: 2g/kg body weight. So in an adult man weighing 70 kg, about
140g in present.
• It is the structural component of cell membrane.
• It is the precursor of all steroids in the body including steroid hormones, vit.D and
bile acids.

3. • About 1g of cholesterol is synthesized per day in adults.
• Major sites of its synthesis are- Liver(50%), intestine(15%), skin, adrenal cortex,
reproductive tissue, etc.
• The enzymes involved are found in the cytosol and microsomal fractions of the cell.
BIOSYNTHESIS

4. BIOSYNTHESIS
Acetyl CoA+Acetyl CoA
Acetoacetyl CoA
CoA Acetyl CoA synthase
ß-Hydroxy ß-methylglutaryl CoA
(HMG CoA)
Acetyl
CoA
CoA
HMG CoA synthase
H2O
Mevalonate (6C)
HMG CoA reductase
2NADPH+2H
2NADP++CoA
5-Phospho mevalonate
ATP
ADP
HMG CoA synthase
+Mg2
+
Rate limiting

5. BIOSYNTHESIS
5-Phospho mevalonate
5-Pyrophospho mevalonate
ATP
ADP
Phospho mevalonate kinase
+Mg2
+
3-phospho-5-Pyrophospho
mevalonate
ATP
ADP
Pyrohospho mevalonate kinase
+Mg2
+
Isopentenyl Pyrophosphate (5C)
Pi+CO2 Pyrohospho mevalonate decarboxylase
Dimethyl allyl pyrophosphate
(5C)
Isomerase
Geranyl pyrophosphate (10C)
(Cis-prenyl transferase) + Isopentenyl pyrophosphate

6. Geranyl pyrophosphate
BIOSYNTHESIS
Farnesyl pyrophosphate (15C)
(Cis-prenyl transferase) + Isopentenyl pyrophosphate
Squalene (30C)
(Squalene Synthase) + Farnesyl pyrophosphate
Lanosterol (30C)
NADPH+H +
NADP+
O2
H2O
Epoxidase
Hydroxylase
Cyclase
Cholesterol (27C)
NADPH, O2
NADP+
HCOOH
2CO2
A series of reactions
(about 19)

7. Regulation
Cholesterol biosynthesis is controlled by the rate limiting enzyme
HMG CoA reductase, at the beginning of the pathway. HMG is
associated to endoplasmic reticulum and is subjected to different
metabolic controls

9. Regulation
1.Feedback Control: The level of cholesterol is controlled by its
feedback mechanism. Increase in cellular concentration of
cholesterol reduces the synthesis of enzyme HMG CoA
reductase by decreasing the transcription of gene responsible
for its production.
2.Sterol independent Phosphorylation and dephoporylation:
The enzyme HMG CoA reductase exist in two forms- More active
dephosphorylated form and Less active phosphorylated form.
This phosphorylation is controlled by AMP activated protein
kinase, the HMG CoA reductase Kinase.

10. 3. Hormonal regulation: The enzyme HMG CoA reductase exist in
two forms- More active dephosphorylated form and Less active
phosphorylated form. The hormone Glucagon and
Glucocorticoids favors formation of inactive HMG CoA
reductase(phosphorylated form) and thus decreases cholesterol
synthesis. Likewise, Insulin and Thyroxine enhances the formation
of active HMG CoA reductase (dephosphorylated form) and thus
increases cholesterol synthesis.
Regulation

11. 3. Inhibition by drugs: The drugs Compactin
and Lovastatin are used to decrease the serum
cholesterol level in patients with
hypercholesterolemia. These drugs competitively
inhibit the enzyme HMG CoA reductase and
therefore, reduces cholesterol synthesis.
4. HMG CoA reductase activity is inhibited by
bile acids. Fasting also reduces the activity of this
enzyme.
Regulation

14. THANK YOU