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