Flashcards in Lecture 23: Cholesterol Synthesis & Lipid Transport Deck (90)
How many Cs in cholesterol? Where do they all come from?
All from acetate in acetyl CoA
What are the 5 substrates in the cholesterol synthesis pathway?
2 Acetyl-coA => Acetoacetyl-coA => Mevalonate => Isoprene => Cholesterol
What are the 3 uses for cholesterol once synthesized?
1. Steroid hormones + vitamin D
2. Cholesterol esters for storage/transport
3. Bile acids
What are the 2 ways of excreting cholesterol? Which is the main way? % contribution of each way?
1. Bile acids (main way: 90%)
2. Steroid hormones (10%)
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Is cholesterol hydrophobic or hydrophilic?
Describe the steps of cholesterol synthesis. 10 steps
1. Thiolase: Acetyl CoA + Acetyl CoA = Acetoacetyl CoA + CoA-SH
2. HMG-CoA synthase: Acetoacetyl CoA + Acetyl-CoA = HMG-CoA + CoA-SH
3. HMG-CoA reductase: HMG-CoA + 2 NADPH = Mevalonate + 2 NADP+ + CoA-SH
4. Mevalonate double phosphorylation on C5 from ATP = activated isoprene
5. Phosphate added on C3 = immediate decarboxylation due to destabilization by the Pi
6. Removal of C3 phosphate
7. 2 isoprenes = geranyl pyrophosphate + isoprene pyrophphate = farnesyl pyrophosphate + farnesyl pyrophosphate + NADPH = squalene + NADP+ + 2 PPi
8. Squalene monooxygenase: squalene + NADPH + O2 => squalene 2,3-epoxide + NADP+ + H2O
9. Cyclase: squalene conversion to lanosterol
10. Lanosterol conversion to cholesterol
How many Cs in HMG-CoA?
What is the main regulatory step of cholesterol synthesis?
Reduction of HMG-CoA by HMG-CoA reductase
What do statin drugs inhibit? How do they work? How do different kinds differ?
They competitively inhibit HMG-CoA reductase as they have a similar structure to mevalonate
They have different R1 and R2 groups
How many Cs in activated isoprenes?
What is the full name of HMG-CoA?
Other than for cholesterol synthesis, what can activated isoprenes be used to make?
1. Lipid-soluble vitamins: A, E, K
3. Rubber (in plants)
4. Quinone electrons carriers
6. Phytol chain of chlorophyll
7. Plant hormones: abscisic acid and gibberellic acid
How many Cs in geranyl pyrophosphate?
How many Cs in farnesyl pyrophosphate?
How many Cs in squalene?
What are stigmasterol and ergosterol?
Lipids similar in structure to cholesterol and synthesized through same pathway in plants (stigmasterol) and fungi (ergosterol) respectively
In what form is cholesterol carried in HDLs in the blood? How is it formed?
Cholesterol ester formed by the addition of an FA from the 2' of lecithin (=phosphatidylcholine) to the 3' OH of cholesterol by the enzyme lecithin-cholesterol acyl transferase (LCAT) forming lysolecithin
What are the 2 types of cholesterol carrier proteins?
In what form is cholesterol stored within cells? How is it formed?
Cholesterol ester formed by the addition of a free FA-CoA to the 3' OH by the enzyme acyl-coA-cholesterol acyl transferase (ACAT) leaving CoA-Sh behind
Where do we get most of our cholesterol?
We synthesize it!
How much cholesterol is synthesized each day?
How much cholesterol do we ingest each day?
What are normal cholesterol blood levels?
Can you make all of the cholesterol you need via de novo synthesis?
Why is it really hard for us to control cholesterol levels?
Because if you stop eating cholesterol, you
can still make it
What are the 4 ways of regulating cholesterol levels?
1. HMG-CoA reductase regulation
2. ACAT regulation
3. LDL/HDL ratios
4. Excretion as bile acids
What is the effect of high cholesterol levels on cholesterol synthesis? Is this called feedback inhibition?
Stimulation of proteolysis of HMG-CoA reductase: long-term feedback until new enzyme produced
NOT feedback inhibition because the enzyme is destroyed, not inhibited
What stimulates HMG-CoA reductase? How? Why?
Insulin (dephosphorylation) to stimulate fat storage when acetyl-CoA levels are high