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Cholesterol

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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  1. Cholesterol

  2. Steran skeleton

  3. 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

  4. 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

  5. Saturated derivatives of cholesterol

  6. Biosynthesis of cholesterol I. Ac-CoA - Mevalonate

  7. 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

  8. Acetyl-CoA – HMG-CoA - Mevalonate • Acetoacetyl-CoA – HMG-CoA • Acetoacetyl-CoA + acetyl-CoA

  9. Acetyl-CoA – HMG-CoA - Mevalonate • HMG-CoA – Mevalonate • Two stage reduction • NADPH • Microsomal enzyme • The rate limiting step of cholesterol biosynthesis Statins

  10. HMG-CoA inhibitors

  11. Treatment of Hypercholesterolemia

  12. 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).

  13. HMG CoA Reductase + CoAHMG CoA Reductase + Rosuvastatin

  14. Biosynthesis of cholesterol II. Active isoprenoid units

  15. Mevalonate – active isoprenoid units • Phosphorylation of ATP • Intermediers

  16. Biosynthesis of cholesterol 6 izoprenoid units squalene III.

  17. Synthesis of Squalene • Geranyl-PP • Farnesyl-PP • 2 Farnesyl-PP • Squalene

  18. Biosynthesis of cholesterol Squalene - Lanosterol IV.

  19. Squalene – lanosterol átalakulás ER Mixed function oxygenase: Squalene epoxydase

  20. Biosynthesis of cholesterol Lanosterol - cholesterol V.

  21. Squalene – lanosterol conversion ER Squalene & Sterol carrier protein

  22. Farnesyl-PP precursor of other compounds • Ubiquinone • Dolichol

  23. Regulation of Cholesterol biosynthesis

  24. Bile acids Tauro ~ Glyko ~ Tauro ~ Glyko ~ Cholesterol Chenodeoxycholic acid Litocholic acid Cholic acid Primary bile acids Deoxycholic acid Secondary bile acids

  25. Taurocholicacid

  26. Compartmentalisation of bile acid synthesis 7a-hydroxylase Monooxygenase, NADPH, Cit P450 Conjugation of Taurin & Glycine + Bile acids Side chain -”cleavage”

  27. Enterohepatic circulation

  28. Treatment of Hypercholesterolemia

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