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CHOLESTEROL | CHOLESTEROL METABOLISM | CHOLESTEROL BIOSYNTHESIS
- 2. CHOLESTEROL • Cholesterol isfound in animals, therefore it is called as animal sterol. • Total content of cholesterol in an adult is• Total content of cholesterol in an adult is around 2 g/kg body weight. • It is amphipathic in nature, (hydrophilic and hydrophobic).
- 3. Functions of cholesterol 1.Structural component of cell membrane. 2. Precursor for the synthesis of all other steroids in the body. E.g. steroid hormones, vitamin D and bile acids.bile acids. 3. Essential ingredient in the structure of lipoproteins. 4. Fatty acids are transported to liver as cholesteryl esters for oxidation.
- 4. CHOLESTEROL BIOSYNTHESIS • Alltissues can produce cholesterol. But the largest is produced by: – Liver (50%), Intestine (15%), Skin, Adrenal Cortex, Reproductive Tissue etc. • Enzymes are found: In the cytosol and microsomal fractions of the cell. • Acetate of acetyl CoA provides : carbon atoms.• Acetate of acetyl CoA provides : carbon atoms. • The reducing equivalents are supplied by NADPH while ATP provides energy. • Requirement for the production of 1 mole of cholesterol: – 18 moles of acetyl CoA – 36 moles of ATP – 16 moles of NADPH.
- 5. 5 stages ofsynthesis of cholesterol 1. Synthesis of HMG CoA 2. Formation of mevalonate (6C) 3. Production of isoprenoid units (5C)3. Production of isoprenoid units (5C) 4. Synthesis of squalene (30C) 5. Conversion of squalene to cholesterol (27C).
- 6. Synthesis of β-hydroxyβ -methylglutaryl CoA (HMG CoA): • Two moles of acetyl CoA condense to form acetoacetyl CoA. Another molecule of acetyl CoA is then added to produce HMG CoA. Stage 1 then added to produce HMG CoA. • Cholesterol synthesis occurs in cytosol. • Two isoenzymes of HMG CoA synthase are known. Cytosomal enzyme: for cholesterol synthesis Mitochondrial enzyme: for ketone body synthesis
- 8. Formation of mevalonate: •HMG CoA reductase is the rate limiting enzyme in cholesterol biosynthesis. • This enzyme is present in endoplasmic Stage 2 • This enzyme is present in endoplasmic reticulum and catalyses the reduction of HMG CoA to mevalonate. • The reducing equivalents are supplied by NADPH.
- 10. Production of isoprenoidunits: • 3 step reaction catalysed by kinases, mevalonate is converted to 3-phospho 5 pyrophosphomevalonate which on decarboxylation forms isopentenyl pyrophosphate (IPP). Stage 3 pyrophosphate (IPP). • The latter isomerizes to dimethylallyl pyrophosphate (DPP). • Both IPP and DPP are 5-carbon isoprenoid units.
- 12. Synthesis of squalene: •IPP and DPP condense to produce a 10-carbon geranyl pyrophosphate (GPP). • Another molecule of IPP condenses with GPP Stage 4 • Another molecule of IPP condenses with GPP to form a 15-carbon farnesyl pyrophosphate (FPP). • Two units of farnesyl pyrophosphate unite and get reduced to produce a 30-carbon squalene.
- 14. Conversion of squaleneto cholesterol: • Squalene undergoes hydroxylation and cyclization utilizing O2 and NADPH and gets converted to lanosterol. • The formation of cholesterol from lanosterol is a multistep process with a series of about 19 enzymatic reactions. • The following are the most important reactions: – Reducing the carbon atoms from 30 to 27. Stage 5 – Reducing the carbon atoms from 30 to 27. – Removal of two methyl groups from C4 and one methyl group from C14. – Shift of double bond from C8 to C5. – Reduction in the double bond present between C24 and C25.
- 15. • 14- Desmethyllanosterol, zymosterol, cholestadienol and desmosterol: Intermediates in the cholesterol biosynthesis.in the cholesterol biosynthesis. • The penultimate product is 7-dehydrocholesterol which, on reduction, finally yields cholesterol.
- 17. Outline of cholesterolbiosynthesis
- 18. Synthesis of bileacids from Cholesterol The bile acids possess 24 carbon atoms, 2 or 3 hydroxyl groups in the steroid nucleus and a side chain ending in carboxyl group. The bile acids are amphipathic in nature.The bile acids are amphipathic in nature. They serve as emulsifying agents in the intestine and helps in the digestion and absorption of lipids. The synthesis takes place in the liver.
- 19. • The stepcatalysed by 7 α-hydroxylase is the rate limiting reaction. And the reaction is inhibited by bile acids. • Cholic acid and chenodeoxycholic acid are the primary bile acids.bile acids. • On conjugation with glycine or taurine, conjugated bile acids (glycocholic acid, taurocholic acid etc.) are formed . • In the bile, the conjugated bile acids exist as sodium and potassium salts which are known as bile salts.
- 20. In the intestine,a portion of primary bile acids undergoes deconjugation and dehydroxylation to form secondary bile acids (deoxycholic acid and lithocholic acid).and lithocholic acid). These reactions are catalysed by bacterial enzymes in the intestine.
- 22. Synthesis of steroidhormones from cholesterol Cholesterol is the precursor for the synthesis of all the five classes of steroid hormones (a) Glucocorticoids (e.g. cortisol) (b) Mineralocorticoids (e.g. aldosterone)(b) Mineralocorticoids (e.g. aldosterone) (c) Progestins (e.g. progesterone) (d) Androgens (e.g. testosterone) (e) Estrogens (e.g. estradiol).
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- 26. Synthesis of vitaminD 7-Dehydrocholesterol, an intermediate in the synthesis of cholesterol, is converted to cholecalciferol (vitamin D3) by ultraviolet rays in the skin.in the skin.