Cholesterol Flashcards
What 3 steps can the cholesterol synthesis pathway be split into?
Where do each of these steps take place?
- Synthesis of isopentenyl pyrophosphate - activated isoprene unit which serves as a key building block (cytoplasm)
- Condensation of six molecules of isopentenyl pyrophosphate to form squalene (cytoplasm)
- Cyclisation and demethylation of squalene by monooxygenases to give cholesterol (ER)
What are the first 3 steps in the biosynthesis of cholesterol?
1) condensation of 2 acetyl-CoA molecules to form acetoacetyl CoA.
2) condensation of another Acetyl CoA molecule (+ acetoacetyl CoA) to form HMG-CoA
3) HMG-CoA is reduced by the enzyme HMG-CoA reductase to generate mevalonate.
- > HMG CoA reductase is under neg feedback by the end product cholesterol, the intermediate mevalonate & bile salts.
What happens to mevalonate to form 3-isopentenyl pyrophosphate?
Mevalonate undergoes sequential phosphorylation at hydroxyl groups at position 3 & 5, followed by decarboxylation to form 3-isopentenyl pyrophosphate.
What are the lipophilic properties of the isoprene unit useful for?
What is dolichol phosphate?
The lipophilic properties of the isoprene unit confine ubiquinone to the inner membrane of mitochondria.
Dolichol phosphate is a specialised lipid molecule located in the ER membrane that is involved in N-linked glycosylation of proteins.
Via what type of reaction is dimethyallyl pyrophosphate generated from isopentenyl PP
Dimethylallyl then condenses with a unit of isopentenyl PP to form what?
The product of the above reaction then reacts with a 3rd isopentenyl PP to form what?
Isopententenyl pyrophosphate ——> dimetheylallyl pyrophosphate.
- via an Isomerisation reaction
Isopentenyl PP + dimethyallyl pyrophosphate—> geranyl PP (C10)
Geranyl PP + isopentenyl PP —-> Farnesyl-PP (C15)
What two molecules condense to form C30 squalene plus 2 molecules of pyrophosphate?
2 farnesyl-PP molecules
Detail the 3 steps involved in the cyclisation of squalene to form cholesterol
1) what is squalene reduced in the presence of and why?
2) what enzyme based on squalene catalyses the formation of a 4 ring compound
3) what does this 4 ring compound undergo in order to generate cholesterol?
- Squalene is reduced in the presence of oxygen and NADPH to form squalene epoxide, which has a diff C=C bond distribution, preparing the molecule for carbon ring fusion
- The enzyme squalene epoxide lanosterol-cyclase catalyses the formation of lanosterol-cyclase.
- Lanosterol is then reduced and 3 methyl units removed to generate cholesterol
What are some products generated from cholesterol?
+ include byproducts and enzymes needed
-bile salts. Cholesterol can be converte into the primary bile salt, glucocholate & taurocholate
-precursor to steroids - pregnenolone - is generated from cholesterol by the action of enzyme desmolase.
5 classes of steroids: progestagens, glucocorticoids, mineralocorticoids, androgens and oestrogens (all come from pregnenolone)
-vitamin D
What is vitamin D a collective term for?
What is our main source of vitamin D?
What is the most active vitamin D metabolite and what does it play a key role in?
What does a deficiency of vitamin D3 in childhood lead to?
Vitamin D = collective term for a group of steroids which are vital for the intestinal absorption of important ions needed for bone development - calcium, phosphate and magnesium.
Western diet is low in vit D, main source of vitamin D is from the activity of UV light upon 7-dehydrocholesterol in the epidermis of the skin.
Calcitriol is the most active vitamin D metabolite. Key role in calcium metabolism.
Deficiency of vitamin D3 in childhood —> rickets, a defect of bone development in children
What is familial hypercholesterolaemia (FH)?
Describe effect of FH in individuals heterozygous and homozygous for the mutant gene
Familial hypercholesterolaemia = monogenic dominant trait in which cholesterol transportation is defective.
Heterozygotes for FH (single copy of mutant gene) - have cholesterol levels ~2-3x higher than normal ppl. Susceptible to atherosclerosis (hardening of arteries) in middle age
Homozygotes for FH (2 mutated copies of gene) - serum cholesterol levels 5x higher than healthy individuals. Severer atherosclerosis and coronary infarction may be observed in adolescence.
What is the disease mechanism for familial hypercholesterolaemia?
Mutations where result in FH? What are the effects of these mutations?
Cholesterol in the LDL form is taken up specific receptor molecules - the LDL receptor (LDLR)
Fibroblasts from patients with severe FH lack functional LDLRs.
Mutations in several domains of the LDLR lead to FH. Can affect receptor expression, LDL binding or LDLR endocytosis and recycling —> FH.
How do you control hypercholesterolaemia?
2 main strategies:
- inhibition of de novo cholesterol synthesis by the liver - via HMG-CoA reductase inhibitors/statins
- reduction of dietary cholesterol absorption by the intestines - via resins/sequestrants: bind/sequester bile acid cholesterol complexes preventing their reabsorption by the intestine. Can lower LDL 15-30% and raise HDL 3-5%
Mechanism of lovastatin: competitive inhibitor of HMG-CoA reductase.
