Cholesterol
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Cholesterol. Steran skeleton. Characteristics of steran-derived compound. Angular methyl group: AB,CD Substituent of C3 : R1 Double bounds: 4/5 C 5/6 C C17: R2 -OH =O Carbonic atom containing side chains ríng In position of C11, C12 -OH =O „A” ring - aromatic

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Cholesterol

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Cholesterol


Steran skeleton


Characteristics of steran-derived compound

  • Angular methyl group: AB,CD

  • Substituent of C3 : R1

  • Double bounds:

    • 4/5 C

    • 5/6 C

    • C17: R2

    • -OH

    • =O

    • Carbonic atom containing side chains

    • ríng

  • In position of C11, C12

    • -OH

    • =O

  • „A” ring - aromatic

    • no C19 angular CH3


Cholesterol

  • 8 chiral carbon atoms: 256 possible stereoisomer

  • C19 – angular methylgroup

  • C13, C17 – cis

  • C3 –OH cis

  • Reduction of cholesterol results in two different compounds


Saturated derivatives of cholesterol


Biosynthesis of cholesterol

I.

Ac-CoA - Mevalonate


Acetyl-CoA – HMG-CoA - Mevalonate

  • Ac-CoA – Acetoacetyl - CoA

    • Ketone body formation in mitochondria

    • Biosynthesis of cholesterol is extramitochondrial

    • Diffusion of excess acetoacetate into citosol

    • Acetoacetate is activated by Acetyl-CoA synthase -- acetoacetyl-CoA

      • ATP, CoA


Acetyl-CoA – HMG-CoA - Mevalonate

  • Acetoacetyl-CoA – HMG-CoA

    • Acetoacetyl-CoA + acetyl-CoA


Acetyl-CoA – HMG-CoA - Mevalonate

  • HMG-CoA – Mevalonate

    • Two stage reduction

      • NADPH

    • Microsomal enzyme

    • The rate limiting step of cholesterol biosynthesis Statins


HMG-CoA inhibitors


Treatment of Hypercholesterolemia


Mechanism of actions of Statins

  • Fig. 1.Inhibition of HMG CoA reductase reduces intracellular cholesterol levels; this activates a protease, which in turn cleaves sterol regulatory element-binding proteins (SREBP's) from the endoplasmic reticulum. The SREBP's translocate to the nucleus where they upregulate expression of the LDL receptor gene. Enhanced LDL receptor expression increases receptor-mediated endocytosis of LDL and thus lowers serum LDL. Inhibition of HMG CoA reductase also reduces intracellular levels of isoprenoids, which are intermediates in cholesterol biosynthesis. (From the American College of Cardiology. Vaughan, CJ, Gotto, AM, Basson, CT. J Am Coll Cardiol 2000; 35:1).


HMG CoA Reductase + CoAHMG CoA Reductase + Rosuvastatin


Biosynthesis of cholesterol

II.

Active isoprenoid units


Mevalonate – active isoprenoid units

  • Phosphorylation of ATP

  • Intermediers


Biosynthesis of cholesterol

6 izoprenoid units

squalene

III.


Synthesis of Squalene

  • Geranyl-PP

  • Farnesyl-PP

  • 2 Farnesyl-PP

  • Squalene


Biosynthesis of cholesterol

Squalene - Lanosterol

IV.


Squalene – lanosterol átalakulás

ER

Mixed function

oxygenase:

Squalene epoxydase


Biosynthesis of cholesterol

Lanosterol - cholesterol

V.


Squalene – lanosterol conversion

ER

Squalene &

Sterol carrier

protein


Farnesyl-PP precursor of other compounds

  • Ubiquinone

  • Dolichol


Regulation of Cholesterol biosynthesis


Bile acids

Tauro ~

Glyko ~

Tauro ~

Glyko ~

Cholesterol

Chenodeoxycholic acid

Litocholic acid

Cholic acid

Primary bile acids

Deoxycholic acid

Secondary bile acids


Taurocholicacid


Compartmentalisation of bile acid synthesis

7a-hydroxylase

Monooxygenase, NADPH, Cit P450

Conjugation of

Taurin &

Glycine + Bile acids

Side chain -”cleavage”


Enterohepatic circulation


Treatment of Hypercholesterolemia


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