Cholesterol

Question 1

What is the key initial building block ?

Answer 1

isopentenyl pyrophosphate

Question 2

What is the second key building block?

Answer 2

squalene

Question 3

What is the enzyme to get from Squalene to Cholesterol?

Answer 3

monooxygenases

Question 4

What do 2 Acetyl coA condense to form?

What enzyme is used for this reaction and what bond is broken?

Answer 4

Acetoacetyl CoA

Beta kethothiolase + CoA released. Thioester bond

Question 5

For the reaction:

Acetoacetyl CoA + Acetyl CoA what enzyme is used and what product is formed?

Answer 5

3-hydroxy-3,methylglutaryl CoA (HMG-CoA) + HMG-CoA synthase.

(water used to displace CoA)

Question 6

How does Mevalonate get produced?

Answer 6

HMG-CoA is reduced by:

HMG-CoA reductase

uses 2 NADPH and 2 H+

*Releases a CoA

Question 7

Describe the negative feedback associated with HMG-CoA reductase?

Answer 7

Mevalonate, cholesterol, bile salts produced act against it

Question 8

How to get from Mevalonate to activated Isoprene and the enzyme involved?

Answer 8

Mevalonate –>
5 phosphomevalonate –>
5 pyrophosphomevalonate –>
3-isopentylpyrophosphate –>

Enzymes:
Mevalonate kinase
Phosphomevalonate kinase
Phosphomevaolnate decarboxylase

Question 9

What do Isoprene units do?

Answer 9

can make bimolecules lipophilic

Dolichol Phosphate (ER membrane involved N glycosylation

oxidised Coenzyme Q (makes it lipophilic)

Question 10

How can proteins be modified for lipid affinity through prenylation?

Answer 10

addition of farnesyl / geranyl-geranyl moiety to C-terminal cysteine residues)

Question 11

Describe the steps to go from Isopentyl PP to Farneysl PP

Why is Farnesyl 15 carbons?

Answer 11

Dimethylallyl PP produced (+isopentyl PP isomerase) from isopentyl PP.

Then it condenses using another unit Isopentyl PP (5 C) to give 10 C Geranyl PP

condenses again with 5C –> 15C Farnesyl PP

Question 12

Why is Squalene 30 carbons?

Answer 12

Farnesyl PP –>

[(Squalene synthase) + reduction by Farnesyl PP + NADPH losing 2PP + NADP + H+]

Squalene

( 2 Farnesyl PPs )

Question 13

Reaction to get from Squalene to Lanosterol?

Answer 13

• Reduced in presence of O2 —> squalene epoxide –> prosterol cation
• Enzyme: squalene epoxide lanosterol cyclase. forms 4 rings

Question 14

How to get from Lanosterol to Cholesterol?

Answer 14

Reduced

3 methyl groups removed

Question 15

What Bile salts are made by Cholesterol?

Answer 15

Primarily : Glycocholate and taurocholate

Question 16

What are the five classes of steroids?

Answer 16

Progestagens

Glucocorticoids

Mineralocorticoids

Androgens

Oestrogens

Question 17

What is the precursor to steroids and how is it made?

Answer 17

Pregnenolone

Cholesterol –> ( Desmolase ) Pregnenolone

Question 18

How is Cholesterol linked to Ion absorption in the body?

Answer 18

Vitamin D metabolites are a group of steroids needed for intestinal absorption of ions calcium, phosphate, magnesium

The metabolites are generated by cholesterol

Question 19

What is Calcitriol?

Answer 19

An active VD metabolite

Involved in calcium metabolism

Binds to VDREs in promoter of target genesindicing key genes. Such as those involved in bone metabolism

Lack of VD3 in childhood - rickets

Question 20

What is Familial hypercholesterolaemia?

Answer 20

Monogenic, dominant

Cholesterol transportation is defective leading to higher cholesterol

Susceptibility to Atherosclerosis increases - hardening of arteries

• in adolescence atherosclerosis and coronary infarction may be observed

Question 21

Give an example of a Resins/sequestrant?

Answer 21

Cholestryramine

Question 22

What does Cholestyramine do?

Answer 22

Brand names: Questran/Prevalite

Bind to ‘sequester’ bile acid-cholesterol complexes

Prevents their reabsorption by the intestine.

Lowers LDL and raises HDL

Question 23

What are statins?

Answer 23

HMG-CoA reductase inhibitors. acts as a competitive inhibitor e.g. lovastatin.