Download Lipogenesis. Metabolism of cholesterol

Lipogenesis.
Metabolism of
cholesterol.
Functions of Cholesterol
• a precursor of steroid
hormones (progesterone,
testosterone, estradiol,
cortisol, etc.)
• a precursor of bile acids
• a precursor of vitamin D
• important component of many mammalian
membranes (modulates the fluidity)
Sources of Cholesterol
• from the diet
• can be synthesized de novo (about 800 mg of
cholesterol per day)
- in the liver (major site)
- in the intestine
• Liver-derived and
dietary cholesterol are
both delivered to body
cells by lipoproteins
Synthesis of Cholesterol
Three stages of cholesterol biosynthesis
1. Synthesis of isopentenyl pyrophosphate, that is
the key building block of cholesterol, from acetyl
CoA
2. Condensation of six molecules of isopentenyl
pyrophosphate to form squalene
3. Squalene cyclizes and the tetracyclic product is
converted into cholesterol
Acetyl CoA (C2)
Isopentenyl pyrophosphate (C5)
Squalene (C30)
Cholesterol (C27)
A. Stage 1:
Acetyl CoA to Isopentenyl Pyrophosphate
• All carbons of cholesterol come from cytosolic
acetyl CoA (transported from mitochondria via
citrate transport system)
• Sequential condensation of three molecules
of acetyl CoA
Two molecules of
acetyl CoA
condense to form
acetoacetyl CoA.
Enzyme – thiolase.
Acetoacetyl CoA reacts with acetyl CoA and
water to give 3-hydroxy-3-methylglutaryl
CoA (HMG-CoA) and CoA.
Enzyme:
HMG-CoA synthase
In cytoplasm 3-Hydroxy-3-methylglutaryl CoA is reduced to
mevalonate.
Enzyme: HMG-CoA
reductase
In mitochondria 3Hydroxy-3-methylglutaryl
CoA is cleaved to acetyl
CoA and acetoacetate.
Enzyme: HMG-CoA lyase.
HMG-CoA reductase
• HMG-CoA reductase is an integral membrane protein in
the endoplasmic reticulum
• Primary site for regulating cholesterol synthesis
• Cholesterol-lowering statin drugs (e.g. Lovastatin) inhibit
HMG-CoA reductase
Lovastatin
resembles
mevalonate
Mevalonate is converted into 3-isopentenyl
pyrophosphate in three consecutive reactions
requiring ATP and decarboxylation.
Isopentenyl pyrophosphate is a key building block for
cholesterol and many other important biomolecules.
B.Stage 2:
Isopentenyl Pyrophosphate to Squalene
Isopentenyl pyrophosphate is isomerized to
dimethylallyl pyrophosphate.
C5 units isopentenyl pyrophosphate react with C5
units dimethylallyl pyrophosphate to yield C10
compound geranyl pyrophosphate
C10 compound geranyl pyrophosphate reacts with C5
units isopentenyl pyrophosphate and C15 compound is
formed - farnesyl pyrophosphate.
Reductive tail-to-tail condensation of two molecules of
farnesyl pyrophosphate results in the formation of
C30 compound squalene
C. Stage 3:
Squalene to Cholesterol
Squalene activated by
conversion into squalene
epoxide.
Squalene epoxide is cyclized
to lanosterol.
Lanosterol is converted into cholesterol in a multistep
process.
THE REGULATION OF
CHOLESTEROL BIOSYNTHESIS
Regulatory enzyme - 3-hydroxy-3-methylglutaryl
CoA reductase.
Tetrameric
enzyme.
NADPH coenzyme
HMG CoA reductase is controlled in multiple ways:
1. The rate of synthesis of reductase mRNA is controlled
by the sterol regulatory element binding protein (SREBP).
When cholesterol levels fall this protein migrates to the
nucleus and enhance transcription.
2. The rate of translation of reductase mRNA is inhibited
by cholesterol
3. The degradation of the reductase is controlled.
The increase of cholesterol concentration makes the enzyme
more susceptible to proteolysis.
4. Phosphorylation decreases the activity of the reductase.
Enzyme is switched off by an AMP-activated protein kinase.
Thus, cholesterol synthesis ceases when the ATP level is
low.
Products of Cholesterol
Metabolism