Biosynthesis of Cholesterol

Question 1

What are the 3 biological functions of cholesterol?

Answer 1

1. structural component of cell membranes, particularly the plasma membranes
2. constituent of lipoproteins
3. precursor for bile acids and steroid hormones

Question 2

All of cholesterols carbon atoms are derived from acetate, where can we get acetate?

Answer 2

Acetyl-CoA

Question 2

All of cholesterols carbon atoms are derived from acetate, where can we get acetate?

Answer 2

Acetyl-CoA

Question 3

3 stages of cholesterol biosynthesis (liver)

Answer 3

1. condensation of acetate to form mevalonate intermediates (C6 unit)
2. polymerization of mevalonate to form squalene (C30 unit)
3. cyclization of squalene and further modifications to form cholesterol (C27 unit)

Question 4

Stage 1- condensation (liver cholesterol biosynthesis)

Answer 4

from acetyl-CoA (C2) to mevalonate (C6)

-HMG-CoA reductase catalyzes the rate limiting step of cholesterol biosynthesis.
-HMG-CoA reductase is an integral membrane protein
-HMG-CoA reductase can be found in the ER and peroxisome

Question 5

Do you recognize the first 2 steps of stage 1 condensation (liver biosynthesis)?

Answer 5

Used in ketogenesis (but in mitochondrial matrix) whereas this reaction occurs in the cytosol, so they both catalyze the same reaction but they are not identical due to compartmentalization

Question 5

Do you recognize the first 2 steps of stage 1 condensation (liver biosynthesis)?

Answer 5

Used in ketogenesis (but in mitochondrial matrix) whereas this reaction occurs in the cytosol, so they both catalyze the same reaction but they are not identical due to compartmentalization

Question 6

What is HMG-CoA

Answer 6

precursor for cholesterol and ketone bodies

Question 7

Enzymes involved in the formation of HMG-CoA that is the precursor for ketone bodies are found in

Answer 7

the mitochondria

Question 8

Enzymes catalyzing formation of HMG-CoA that is utilized for the synthesis of cholesterol are found in the

Answer 8

Cytosol and peroxisomes

Question 9

Function of statin

Answer 9

Statin catalyzes rate limiting step (hmg-Coa) for heart disease to reduce cholesterol production by binding to hmg-coa reductase and inhibits its function of producing cholesterol

Question 10

Function of statin

Answer 10

Statin catalyzes rate limiting step (hmg-Coa) for heart disease to reduce cholesterol production by binding to hmg-coa reductase and inhibits its function of producing cholesterol

Question 11

Function of the peroxisome

Answer 11

is the breakdown of very long chain fatty acids through beta-oxidation. In animal cells, the long fatty acids are converted to medium chain fatty acids, which are subsequently shuttled to mitochondria where they are eventually broken down to carbon dioxide and water.

Question 12

Stage 1 condensation part 1

Answer 12

from mevalonate (C6) to dimethylallyl pyrophosphate (C5)

NOTE: Nucleophilic substitution on the gamma-phosphate of ATP
-Goal of adding phosphate is to make molecule a better substrate (becomes activated) for the following reactions

Question 13

Stage 2 condensation part 2

Answer 13

from mevalonate (C6) to dimethylallyl pyrophosphate (C5)

NOTE: ATP-dependent decarboxylation
allyl: unsaturated hydrocarbon chain

Question 14

Isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate are

Answer 14

isoprenoids

Question 15

What are isoprendoids

Answer 15

-Isoprenoids are the oldest know biomolecules.
-Recovered from sediments which were roughly 2.5 billion years old.
-Family of around 30,000 known compounds

Definition of isoprenoids: any compound biosynthesized from or containing isoprene units

Question 16

Stage 2 polymerisation (Part 1)

Answer 16

Polymerization of isoprenoids (C5) to form farnesyl pyrophosphate (C15)
-Reactions 1 and 2 are catalyzed by prenyltransferase
-Nucleophilic substitutions
-Final product is Farnesyl pyrophosphate (C15)

Question 17

Stage 2 polymerisation part 2

Answer 17

Polymerization of farnesyl pyrophosphate (C15) to form squalene (C30)
-Reactions 3 is catalyzed by squalene synthase
-This enzyme is located in the ER membrane
-Join two molecules of Farnesyl pyrophosphate in a head-to-head conformation
-Final product is Squalene
-First cholesterol specific step

Question 18

Stage 3 Cyclization (Part 1)

Answer 18

Cyclization of squalene to form lanosterol (C30)

Question 19

Stage 3 cyclization (Part 2)

Answer 19

Synthesis of cholesterol (C27) from lanosterol (C30)

NOTE: 19 steps involving 9 enzymes located in the ER and peroxisomes. Double bond reductions and demethylation occur in these 19 steps.

Question 20

T or F: cholesterol and ispoprenoids are precursors of other compounds

Answer 20

True

Question 21

How many Acetyl-CoA do I need to form 1 molecule of mevalonate/activated isoprene?

Answer 21

3

Question 22

How many activated isoprenes do I need to form 1 molecule of farnesyl pyrophosphate?

Answer 22

3

Question 23

How many farnesyl pyrophosphate do I need to form 1 molecule of squalene/cholesterol?

Answer 23

2

Question 24

How many Acetyl-CoA do I need to form 1 molecule of cholesterol?

Answer 24

332 =18
If the try to do 18*2 carbons, it gives 36 carbons for squalene but it doesn’t add up to 30 for squalene. They have to take into consideration that there is a decarboxylation between mevalonate and the activated isoprenoids, therefore they have to do 36- 6C (6 isprenoids per squalene)

Question 24

How many Acetyl-CoA do I need to form 1 molecule of cholesterol?

Answer 24

332 =18
If the try to do 18*2 carbons, it gives 36 carbons for squalene but it doesn’t add up to 30 for squalene. They have to take into consideration that there is a decarboxylation between mevalonate and the activated isoprenoids, therefore they have to do 36- 6C (6 isprenoids per squalene)