Cholesterol is major sterol which is found in human. Cholesterol is an amphipathic liquid which can be synthesized by most of the cells and is obtained from the diet which involved food of animal orgin. It is not synthesized in plants. The major source of cholesterol is egg yolk and meat.

Location: It occurs in the cytosol and endoplasmic reticulum of liver and intestine.

All the 27 carbon atoms of the cholesterol are derived from acetyl-CoA. There are 5 stages of reactions for the biosynthesis of cholesterol.

Stages of synthesis of cholesterol

stage 1: synthesis of Mevalonate from acetyl-CoA through HMG-CoA.

This stage occur in the cytosol of cell and has similar reaction as for the synthesis of ketone bodies.

1. two molecules of acetyl-CoA condense and form aceto-acetyl-CoA. this reaction is catalyzed by cytosolic thiolase.
2. the third molecule of acetyl-CoA condense with aceto-acetyl-CoA to form HMG-CoA. This is catalyzed by HMG-CoA synthase.
3. HMG-CoA reductase enzyme uses two molecules of NADH and releases CoA-SH and this is the rate limiting step of cholesterol synthesis. This enzyme converts HMG-CoA to mevalonate.

Stage 2: Decarboxylation of mevalonate to form Isopentenyl pyrophosphate (Isoprenoid unit)

This reaction also occur in the cytoplasm. Mevalonate is firstly phosphorylated by ATP and then decarboxylated to form 5 carbon isoprene unit; known as isopentenyl pyrophosphate (IPP)

Stage 3: condensation of isoprenoid units to form squalene

This stage occurs in endoplasmic reticulum. Six IPP molecules condense and loose their pyrophosphate groups and form hydrocarbon squalene (30 carbon atom compound).

Stage 4: Cyclization of squalene to form Lanosterol

This stage occurs in endoplasmic reticulum. squalene undergoes a series of complex enzymatic reactions, in which it changes it structure from linear and becomes cyclic to form lanosterol. Lanosterol has 4 condensed ring that form steroid nucleus of cholesterol.

Stage 5: formation of cholesterol from lanosterol

This stage occurs in endoplasmic reticulum. Conversion of lanosterol to cholesterol is a multistep process which includes:

1. shortening of carbon chain from 30 to 27
2. removal of three methyl group at C₄
3. migration of double bond from C₈ to C₅
4. reduction of 1 double bond between C₂₄ and C₂₅ by NADPH.

Regulation of De novo synthesis of cholesterol

HMG-CoA reductase is a principal enzyme for the synthesis of cholesterol. The synthesis of cholesterol is largely controlled by the cellular level of cholesterol. HMG-CoA reductase is inhibited by mevalonate and cholesterol.

1. Hormonal regulation of HMG-CoA reductase:-
   • Insulin and thyroid hormone T₃ increases the HMG-CoA reductase activiy
   • glucagon and glucocorticoid inhibits the rate limiting step
2. Nutritional Regulation of HMG-CoA reductase:-
   • During starvation, the HMG-CoA reductase is inhibited due to the reduced activity of enzyme
   • Increased intake of calories stimulates the synthesis of cholesterol by increasing the availability of acetyl-CoA and NADPH.

Multiple choice questions (MCQs)

1. What is the major source of cholesterol?
   A. meat B. fish
   C. egg yolk D. both A and C
2. Which of the following is the major site for cholesterol synthesis?
   A. liver B. intestine
   C. pancreas D. both A and B
3. What is the location for synthesis of cholesterol?
   A. cytoplasm B. mitochondria
   C. endoplasmic reticulum D. both A and C
4. Match the following enzyme with its substrate-
   a. thiolase 1. Acetyl-CoA
   b. HMG-CoA reductase 2. Aceto-acetyl-CoA
   c. HMG-CoA synthase 3. squalene
   d. cyclase 4. HMG-CoA
5. How many carbon atoms are present in a cholesterol molecule?
   A. 23 B. 27
   C. 30 D. 20
6. What is the starting molecule of cholesterol synthesis?
   A. acetyl-CoA B. acyl-CoA
   C. glucose D. pyruvate
7. Reactions of stage 1 are similar to which process?
   A. catabolism of fatty acid B. synthesis of fatty acid
   C. synthesis of ketone bodies D. all of the above
8. Which enzyme catalyzes the conversion of acetyl-CoA to aceto-acetyl-CoA?
   A. mitochondrial thiolase D. hydratase
   C. cytosolic thiolase D. both A and C
9. Which of the following statement is NOT true?
   A. cholesterol is amphipathic in nature
   B. starvation inhibits synthesis of cholesterol
   C. T4 increases cholesterol synthesis
   D. in stage 5, carbon chain become short from 30 to 27
10. How many IPP molecules are required for the formation of squalene?
    A. 4 B. 5
    C. 7 D. 6
11. Which of the following events occur in the stage 5?
    A. removal of three methyl group from C4
    B. movement f double bond from C8 to C5
    c. shortening of carbon from 30 to 27
    D. all of the above
12. Which enzyme is termed as the rate limiting enzyme of cholesterol synthesis?
    A. thiolase B. HMG-CoA reductase
    C. HMG-CoA carboxylase D. none of the above
13. Which of the following inhibits the cholesterol synthesis?
    A. insulin B. T3
    C. intake of calories D. none of the above
14. Which form of energy is required in the rate limiting step of cholesterol synthesis?
    A. ATP B. NADH
    C. AMP D. FAD
15. Where is cholesterol not synthesized?
    A. plants B. animals
    C. insects D. all of the above

ANSWERS:-

1. both A and C

2. both A and B

3. both A and C

4. a – 1 b – 4 c – 2 d – 3

5. 27

6. acetyl-CoA

7. synthesis of ketone bodies

8. cytosolic thiolase

9. T4 increases cholesterol synthesis

10. 6

11. all of the above

12. HMG-CoA reductase

13. none of the above

14. NADH

15. plants

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REFERENCE:- Pankaja Naik- Biochemistry; 4^th edition; page no:- 207-210 .