Cholesterol biosynthesis
Location of pathway
1. The pathway is located in the cytosol, beginning with
acetyl-CoA.
2. Most cells can make cholesterol, but liver is most
active.
Four stages (summary)
1. Condensation of 3 acetate units to mevalonate
2. Conversion of mevalonate into activated isoprene
3. Polymerization of six 5-carbon isoprene units (30
carbons) to form squalene
4. Cyclization of squalene to create the steroid nucleus
Four Stages of
Cholesterol
Biosynthesis
Cholesterol Biosynthesis:
Formation of Mevalonate
Liver is primary site of cholesterol biosynthesis
Thiolase
2 CH3COSCoA
CH3COCH2COSCoA
CH3COSCoA
Acetoacetyl CoA
HMG CoA
Synthase
OH
HO2C-CH2-C-CH2CH2OH
CH3
3R-Mevalonic acid
HMGCoA
reductase
CoASH
OH
HO2C-CH2-C-CH2COSCoA
CH3
-Hydroxy--methylKey control step glutaryl CoA (HMG CoA)
in cholesterol
biosynthesis
HMG-CoA
Reductase
HMG-CoA reductase
1.
integral membrane protein in the ER
2.
carries out an irreversible reaction
3.
is an important regulatory enzyme in cholesterol synthesis
Inhibitors of
HMG-CoA
Reductase
Inhibition of Cholesterol Biosynthesis
HO
CH3
CO2 -
HMGCoA
reductase
COSCoA
[
HO
CO2 -
CH3
H
C -S -CoA
OH
HMG CoA
Intermediate
HO
]
HO
CH3
CO2OH
Mevalonate
CO2 -
H
OH
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Atorvastatin (Lipitor):
resembles intermediate
CH2 CH2
N
F
C6 H5NHCO
Cholesterol Biosynthesis:
Processing of Mevalonate
OH
-O C-CH -C-CH CH OH
2
2
2
2
CH3
Mevalonate
OH
2 Steps
ATP
-O C-CH -C-CH CH OPOP
2
2
2
2
CH3
5-Pyrophosphomevalonate
- CO2
- H2O
CH3
Isomerase
CH3-C=CH2CH2OPOP
CH2=C-CH2CH2OPOP
Isopentenyl
Dimethylallyl
CH3
pyrophosphate
pyrophosphate
Cholesterol Synthesis: Stage 2
Cholesterol Biosynthesis:
Isoprenoid Condensation
Dimethylallyl
pyrophosphate
Tail
Head to tail
Condensation
OPOP
Head
Tail
OPOP
Head
H
Head
Tail
Isopentenyl
Pyrophosphate (IPP)
Geranyl
Pyrophosphate (GPP)
Isoprenes
Tail to tail
condensation
of 2 FPPs
Squalene
OPOP
Geranyl transferase
Squalene
synthase
Geranyl
transferase
Head to tail
condensation
of IPP and GPP
OPOP
Head
Tail
Farnesyl
Pyrophosphate (FPP)
Cholesterol Synthesis: Stage 3
Isoprenoids
• Widely distributed in nature
• Generally contain multiple of 5 carbons:
• Monoterpene; 10 carbons
• Sesquiterpene: 15 carbons
• Diterpene: 20 carbons
OH
Menthol: a monoterpene
Lycopene: a tetraterpene
OH
Natural
Products
Derived from
Activated
Isoprene Units
Conversion of Squalene to Cholesterol
Squalene2,3-epoxide
Squalene
monooxygenase
O2
O
Squalene
H
2,3-Oxidosqualene
cyclase
+
CH 3
CH3
CH 3
20 Steps
CH3
CH3
HO
CH 3
Cholesterol
Acyl-CoA:
cholesterol
acyltransferase
HO
H3 C
CH3
RCO2
Cholesterol esters
(principal transport form in blood)
Lanosterol
Cholesterol
Synthesis:
Stage 4
Export of Cholesterol Synthesized in Liver
• Secretion into the small intestine via the bile fluid.
• Conversion to bile acids followed by secretion
into the small intestine in the bile fluid. (Bile
acids function to emulsify dietary lipid.)
• Conversion to cholesterol esters, packaging into
lipoproteins and export into the blood.
Cholesterol
Transport to
Peripheral
Tissues
Synthesis
of
Cholesterol
Esters
Regulation of
Cholesterol
Production
Transformations of
Cholesterol: Bile Salts
HO
CH3
CH3
CO 2-
CH3
CH3
HO
HO
Cholesterol
H
OH
Cholic acid
CH 3
CONHCH 2 R
R = CH2SO3- Taurocholate
R = CO2- Glycocholate
Detergents
Transformations of
Cholesterol: Steroid Hormones
OH
CH3
O
O
OH
HO
CH3
O
HO
O
Cortisol
Cholesterol
Progesterone
OH
OH
OH
O
Testosterone
HO
CH 2
Estradiol
HO
OH
Vitamin D