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Cholesterol Biosynthesis
CHOLESTEROL
- Maintains membrane fluidity
- Precursor for bile acids and salts
- Sterol with a double bond between C5 and C6
- Obtained from diet or de novo synthesis
Sterol
Any steroid that has a side chain at C17 with 8-10 carbons and a hydroxyl group at C3.
DE NOVO CHOLESTEROL SYNTHESIS
- All tissues can synthesize cholesterol --- mostly from liver, intestines, adrenal cortex and reproductive tissues
- Cellular level: occurs in the cytosol
Reactions
1. HMG-CoA formation:
Acetyl CoA + Acetoacetyl CoA + H2O --> HMG CoA + CoA
2. Committed step: HMG CoA reductase (rate-limiting enzyme)
HMG CoA + 2NADPH --> Mevalonate + 2NADP+
3. Phosphorylation
Mevalonate + 3ATP --> Isopentenyl pyrophosphate (IPP) + Pi + 3ADP + CO2
4. Condensation reactions
IPP + 2IPP --> Farnesyl pyrophosphate (FPP) + 2PPi
FPP + FPP + NADPH --> Squalene + 2PPi + NADP+
5. Cholesterol formation
Squalene + O2 + NADPH --> Cholesterol + H2O + NADP+
CHOLESTEROL FUNCTION
1. Bile acids and salts: emulsify fats and facilitate digestion in small intestine
- Only mechanism for cholesterol excretion
Lipoproteins
Transport lipids in circulation; contain lipids, proteins, triacylglycerol, free and esterified cholesterol
- Chylomicron: only transport dietary lipids
- LDL (low density lipoprotein): carries most esterified cholesterol
- HDL (high density lipoprotein): carries 2nd most esterified cholesterol
- VLDL (very low density lipoprotein)
Statins (HMG CoA reductase inhibitors)
Cholesterol-lowering medications
FPP
Chemotherapeutic target that links Ras (small GTP-binding protein) to the membrane.
- Ras mutations ~ 1/3 human cancers
Atherosclerosis
Narrowing of blood vessels due to plaque formation
- Vessel walls become leaky and vulnerable: LDL's accumulate
- Vessels become more vulnerable with age, smoking, poor diet and lack of exercise