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
Cholesterol biosynthesis. Location of pathway The pathway is located in the cytosol, beginning with acetyl-CoA. Most cells can make cholesterol, but liver is most active. Four stages (summary) Condensation of 3 acetate units to mevalonate Conversion of mevalonate into activated isoprene - PowerPoint PPT Presentation
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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: