Cholesterol Flashcards
3 main parts of cholesterol synthesis
- Synthesis of isopentenyl pyrophosphate
- Condensation of 6 molecules of isopentyl pyrophosphate to form squalene
- Cyclisation & demethylation of squalene by monooxygenase to form cholesterol
First reaction in cholesterol biosynthesis
Acetyl CoA + Acetyl CoA ➡️ Acetoacetyl CoA
Condensation X 2
B ketothiolase
Breaking thioester bond + CoA leaves
What is the product of the reaction between acetoacetyl CoA and acetyl CoA
HMG CoA
3 hydroxy 3 methylglutaryl CoA
Enzyme that catalyses production of
3 Hydroxy 3 methylglutaryl CoA
HMG CoA synthase
What reaction does HMG CoA reductase synthesise?
HMG CoA +2NADPH +H+ ===)
Mevalonate +2NADP+ CoA
HMG CoA Reductase under negative feedback control.
What is responsible?
Mevalonate (product inhibition)
Cholesterol
Bile salts (manufactured from cholesterol)
Mevalonate is not activated. What series of reactions (briefly) does it under go to form an activate isoprene?
Sequential phosphorylation at OH groups position 3 &5
Decarboxylation
Activated isoprene formed
3 isopentenyl pyrophosphate
Name in order the intermediates from
3 isopentenyl pyrophosphate to Squalene.
I did get funny shit
3 isopentenyl pyrophosphate Dimethylallyl pyrophosphate Geranyl pyrophosphate Farnesyl pyrophosphate Squalene
Versatility of cholesterol is shown in its ability to synthesise…
Bile salts
Steroid hormones
Vitamin D metabolites
Bile salts synthesised from cholesterol
Glycocholate
Taurocholate
Steroid hormones synthesised from cholesterol
Glucocorticoids
Mineralocorticoids
Androgens ———> estrogens
What is vitamin D
Group of steroids
Vital for intestinal absorption of ions needed for bone development e.g calcium, phosphate, magnesium
Main source of vitamin D
Activity of UV light on 7 Dehydrocholesterol in epidermis of skin
FH
Familial hypercholesterolaemia
What is Familial Hypercholesterolaemia
Monogenic dominant trait.
Cholesterol transportation is defective
Body unable to remove LDL/bad cholesterol from blood
Heterozygotes for FH
Single copy of mutant gene
Cholesterol levels 2/3 X higher
Susceptible to atherosclerosis (hardening of arteries) in middle age
Homozygotes for FH
2 defective copies of gene
Serum cholesterol 5X higher
Severe atherosclerosis & coronary infarction in adolescence
What does deposition of LDL derived cholesterol in coronary arteries lead to
Occlusion (Blockage of blood vessel) & myocardial infarction
What receptors take up cholesterol in LDL form?
LDL receptors (LDLR)
What is notable about the fibroblasts from patients with severe familial hypercholesterolaemia?
Lack functional LDLRs
How to control hypercholesterolaemia
- Inhibition of de novo cholesterol synthesis by liver.
HMG CoA reductase inhibitors - Reduction of dietary cholesterol absorption by intestines.
Resins
How do HMG CoA reductase inhibitors (aka statins) work. Examples.
Competitive inhibitor
E.g lovastatin- part of it resembles the enzyme substrate 3-HMG
Lipitor, Crestor
How do resins work
Attach to bile from liver & prevent it from being absorbed back into blood.
Bile - made from cholesterol.
So resins whittle down body’s supply of cholesterol LDL
