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Cholesterol biosynthesis

Cholesterol biosynthesis

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Cholesterol biosynthesis

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  1. 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

  2. Four Stages of Cholesterol Biosynthesis

  3. 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

  4. 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

  5. Inhibitors of HMG-CoA Reductase

  6. Inhibition of Cholesterol Biosynthesis HMGCoA reductase HMG CoA Mevalonate Intermediate Atorvastatin (Lipitor): resembles intermediate

  7. 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

  8. Cholesterol Synthesis: Stage 2

  9. 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)

  10. Cholesterol Synthesis: Stage 3

  11. 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

  12. Natural Products Derived from Activated Isoprene Units

  13. 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)

  14. Cholesterol Synthesis: Stage 4

  15. 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.

  16. Cholesterol Transport to Peripheral Tissues

  17. Synthesis of Cholesterol Esters

  18. Regulation of Cholesterol Production

  19. Transformations of Cholesterol: Bile Salts Cholesterol Cholic acid R = CH2SO3- Taurocholate R = CO2- Glycocholate Detergents

  20. Transformations of Cholesterol: Steroid Hormones Cortisol Cholesterol Progesterone Testosterone Estradiol Vitamin D