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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

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cholesterol biosynthesis
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

Polymerization of six 5-carbon isoprene units (30 carbons) to form squalene

Cyclization of squalene to create the steroid nucleus

cholesterol biosynthesis formation of mevalonate
Cholesterol Biosynthesis: Formation of Mevalonate

Liver is primary site of cholesterol biosynthesis

Thiolase

CH3COSCoA

2 CH3COSCoA CH3COCH2COSCoA

Acetoacetyl CoA

HMG CoA

Synthase

OH

OH

HMGCoA

reductase

HO2C-CH2-C-CH2COSCoA

HO2C-CH2-C-CH2CH2OH

CH3

CH3

CoASH

-Hydroxy--methyl-

glutaryl CoA (HMG CoA)

3R-Mevalonic acid

Key control step

in cholesterol

biosynthesis

hmg coa reductase
HMG-CoA Reductase

HMG-CoA reductase

integral membrane protein in the ER

carries out an irreversible reaction

is an important regulatory enzyme in cholesterol synthesis

inhibition of cholesterol biosynthesis
Inhibition of Cholesterol Biosynthesis

HMGCoA

reductase

HMG CoA

Mevalonate

Intermediate

Atorvastatin (Lipitor):

resembles intermediate

cholesterol biosynthesis processing of mevalonate
Cholesterol Biosynthesis: Processing of Mevalonate

OH

OH

-O2C-CH2-C-CH2CH2OH

-O2C-CH2-C-CH2CH2OPOP

2 Steps

CH3

CH3

ATP

Mevalonate

5-Pyrophospho-

mevalonate

- CO2

- H2O

CH3

Isomerase

CH3-C=CH2CH2OPOP

CH2=C-CH2CH2OPOP

Isopentenyl

pyrophosphate

Dimethylallyl

pyrophosphate

CH3

cholesterol biosynthesis isoprenoid condensation
Cholesterol Biosynthesis:Isoprenoid Condensation

Tail

Dimethylallyl

pyrophosphate

Head to tail

Condensation

Head

Tail

Head

Tail

Geranyl transferase

Isopentenyl

Pyrophosphate (IPP)

Geranyl

Pyrophosphate (GPP)

Head

Isoprenes

Head to tail

condensation

of IPP and GPP

Geranyl

transferase

Tail to tail

condensation

of 2 FPPs

Squalene

synthase

Squalene

Head

Tail

Farnesyl

Pyrophosphate (FPP)

isoprenoids
Isoprenoids
  • Widely distributed in nature
  • Generally contain multiple of 5 carbons:
    • Monoterpene; 10 carbons
    • Sesquiterpene: 15 carbons
    • Diterpene: 20 carbons

Menthol: a monoterpene

Lycopene: a tetraterpene

conversion of squalene to cholesterol
Conversion of Squalene to Cholesterol

Squalene-

2,3-epoxide

Squalene

monooxygenase

O2

2,3-Oxidosqualene

cyclase

Squalene

20 Steps

Lanosterol

Cholesterol

Acyl-CoA:

cholesterol

acyltransferase

Cholesterol esters

(principal transport form in blood)

export of cholesterol synthesized in liver
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.
transformations of cholesterol bile salts
Transformations of Cholesterol: Bile Salts

Cholesterol

Cholic acid

R = CH2SO3- Taurocholate

R = CO2- Glycocholate

Detergents

transformations of cholesterol steroid hormones
Transformations of Cholesterol: Steroid Hormones

Cortisol

Cholesterol

Progesterone

Testosterone

Estradiol

Vitamin D