MMT: cholesterol biosynthesis Flashcards
What is the significance and roles of cholesterol?
Cholesterol is a membrane component, precursor to bile salts, vitamin D, and steroid hormones.
Why is controlling cholesterol synthesis so important?
We cannot use cholesterol as fuel and there are limited elimination routes for it.
What is the basic building block for cholesterol?
Acetyl CoA.
What are the intermediates in cholesterol biosynthesis?
- Acetyl CoA
- Mevalonate
- Activated isoprene
- Squalene
- Cholesterol.
Which steps of cholesterol biosynthesis occur in the cytoplasm?
- Acetyl CoA > mevalonate
- Mevalonate > activated isoprene.
Where do later stages of cholesterol biosynthesis occur?
Endoplasmic reticulum.
Describe the production of mevalonate.
- Acetyl CoA converts to acetoacetyl CoA via thiolase
- Acetoacetyl CoA converts to HMG CoA
- HMG CoA converts to mevalonate via HMG CoA reductase.
What is the rate limiting step of cholesterol biosynthesis?
Conversion to mevalonste via HMG CoA reductase.
What is the key regulatory enzyme in cholesterol biosynthesis?
HMG CoA reductase.
Statin drugs inhibit which enzyme? How?
HMG CoA reductase; competitive inhibition.
Thiolase and HMG CoA reductase are __ enzymes.
Cytosolic.
Describe the conversion of mevalonate to activated isoprenes.
3 successive phosphorylation reactions occur via addition of ATP. High energy groups will leave the intermediate, and activated isoprenes are formed.
How do we form isoprenoids?
Addition of C5 units to the growing activated isoprene chain.
What family does squalene monooxygenase belong to?
CP450.
What is an inhibitor of CYP450?
Grapefruit! Can lead to overdose toxicity or reduced therapeutic effect.
Describe the regulation of HMG CoA reductase.
Primary method is phosphorylation and dephosphorylation via an insulin regulated phosphatase.
Describe regulation of HMG CoA reductase in the fed state.
More insulin = more phosphatase = dephosphorylation = active enzyme.
Describe regulation of HMG CoA reductase in the fasting state.
A lower energy state = more AMP = AMPK = phosphorylation = inactive enzyme.
How can cholesterol control its own synthesis?
Via negative feedback; high cellular cholesterol inhibits HMG CoA reductase gene transcription.
Describe HMG CoA reductase regulation coupled with ubiquitin-proteasome pathway.
Higher cellular cholesterol leads to faster degradation by the pathway and lowered synthesis. This is super important because we don’t have many exit routes for cholesterol.
How do insulin and glucagon impact cholesterol synthesis?
A high insulin/glucagon ratio facilitates cholesterol synthesis via promoting glycolysis/pyruvate production/acetyl CoA and NADPH production.
Insulin promotes induction of which enzymes?
Citrate lyase and malic enzyme.
How does blood LDL impact cellular cholesterol?
LDL is taken into hepatocytes, and if many are taken in this indicates high blood LDL. This will result in reduced HMG CoA reductase transcription and increased degradation of HMG CoA reductase.
How is cholesterol transported in the body?
It is converted to cholesteryl esters and packaged into VLDL.
