Post on 13-Jan-2016
description
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
2 CH3COSCoA CH3COCH2COSCoAThiolase
CH3COSCoA
Acetoacetyl CoA
HO2C-CH2-C-CH2COSCoA
OH
CH3
-Hydroxy--methyl-glutaryl CoA (HMG CoA)
HMG CoASynthase
HO2C-CH2-C-CH2CH2OH
OH
CH3
3R-Mevalonic acid
HMGCoAreductase
CoASH
Key control stepin cholesterolbiosynthesis
Liver is primary site of 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
COSCoA
HOCO2
-CH3
C -S -CoA
HOCO2
-CH3
H
OH
][HO
CO2-
CH3
OH
HOCO2
-
H
OH
CH2CH2
NF
C6H5NHCO
Atorvastatin (Lipitor):resembles intermediate
HMG CoA MevalonateIntermediate
HMGCoAreductase
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Cholesterol Biosynthesis: Processing of Mevalonate
-O2C-CH2-C-CH2CH2OH
OH
CH3
Mevalonate
-O2C-CH2-C-CH2CH2OPOP
CH3
OH
2 Steps
ATP
5-Pyrophospho-mevalonate
CH2=C-CH2CH2OPOP
CH3
- CO2
- H2O
Isopentenylpyrophosphate
CH3-C=CH2CH2OPOP
CH3
Dimethylallylpyrophosphate
Isomerase
Cholesterol Synthesis: Stage 2
Cholesterol Biosynthesis:Isoprenoid Condensation
H
OPOP
OPOP
Head
TailHead
Tail
IsopentenylPyrophosphate (IPP)
Dimethylallylpyrophosphate Head to tail
Condensation
OPOP
Geranyl Pyrophosphate (GPP)
OPOP
Farnesyl Pyrophosphate (FPP)
Head to tailcondensationof IPP and GPP
Tail to tailcondensationof 2 FPPs
Squalene
Head Tail
Head Tail
Isoprenes
Geranyl transferase
Geranyl transferase
Squalene synthase
Cholesterol Synthesis: Stage 3
Isoprenoids• Widely distributed in nature• Generally contain multiple of 5 carbons:
• Monoterpene; 10 carbons• Sesquiterpene: 15 carbons• Diterpene: 20 carbons
OHOH
Menthol: a monoterpene
Lycopene: a tetraterpene
Natural Products Derived from Activated Isoprene Units
Conversion of Squalene to Cholesterol
O
H +
CH3H3C
CH3
HO
CH3
CH3
CH3
HO
CH3
CH3
RCO2
Squalene
Squalenemonooxygenase
2,3-Oxidosqualenecyclase
Lanosterol
20 Steps
Cholesterol
Acyl-CoA:cholesterolacyltransferase Cholesterol esters
(principal transport form in blood)
O2
Squalene-2,3-epoxide
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
CO2-
HO
CH3
HO OHH
CH3
CONHCH2RCH3
CH3
HO
CH3
Cholesterol Cholic acid
R = CH2SO3- Taurocholate
R = CO2- Glycocholate
Detergents
Transformations of Cholesterol: Steroid Hormones
O
O
O
OH
OHHO
O
CH3
HO
CH3
Cholesterol
Estradiol
Progesterone
Cortisol
O
OH
TestosteroneHO
OH
CH2
HO
OH
OH Vitamin D