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Biosynthesis of Membrane Lipids and Steroids

Biosynthesis of Membrane Lipids and Steroids. Membrane Lipids and Steroids. Phospholipids. Phosphatidate is a common intermediate in synthesis of phospholipids and triacylglycerols Cholesterol is synthesized from acetyl-CoA Regulation of cholesterol synthesis at several levels

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Biosynthesis of Membrane Lipids and Steroids

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  1. Biosynthesis of Membrane Lipids and Steroids

  2. Membrane Lipids and Steroids Phospholipids • Phosphatidate is a common intermediate in synthesis of phospholipids and triacylglycerols • Cholesterol is synthesized from acetyl-CoA • Regulation of cholesterol synthesis at several levels • Derivates of cholesterols -> bile salts, steroid hormones,…

  3. Synthesis of Phospholipids and Triacylglycerols

  4. Phosphatidate is a Common Intermediate in Synthesis of Phospholipids and Triacylglycerols Phosphatidic acid (mammalians) is synthesized in the endoplasmic reticulum and outer mitochondrial membran Phosphatidic acid mainly synthesized from dihydroxyacetone phosphate (glycolysis) R1 is usually saturated R2 is usually unsaturated

  5. Synthesis of Triacylglycerols Synthesized in Endoplasmic reticulum of the liver Transport of TAG from liver to muscles (for energy conversion) or adipocytes (storage)

  6. Phospholipids

  7. Phospholipids

  8. Activation of Intermediate for Synthesis of Phospholipids (Cytidine diphosphate)

  9. Synthesis of Phospholipids Phosphatidic acid

  10. Synthesis of Phospholipids

  11. Ether Lipids are Found in Archae Bacteria

  12. Special Ether Phospholipid PAF involved in allergic and inflammatory responses

  13. Plasmalogen: Special case of Phosphatidycholine In many tissues plasmalogens -> minor constituents, In heart tissue nearly 50% of phosphatidylcholine contains the alkenyl ether at position sn-1. Nervous tissues, testes and kidneys also contain significant amounts of plasmalogens. Ether-containing phospholipids can protect cells against the damaging effects of singlet oxygen, which at high concentrations can kill cells.

  14. Sphingolipids X=H -> Ceramide Sphingolipids are found in plasma membrane of Eukaryotes -> Produced from Ceramides Highest concentration in central nervous system Possible role of lipids: second messangers -> i.e. initiate cell death

  15. Synthesis of Sphingolipids Gangliosides Cholera doxin -> binds to gangliosides -> Development of cholera (severe diarrhea) Gangliosides are crucial for binding of immune System cells to sites of injury (inflammation) Sphingolipids

  16. Usage of Lipids

  17. Steroids Cholesterol

  18. Synthesis of Cholesterol Cytosol Endoplasmatic Reticulum

  19. Synthesis of Cholesterol: 1st stage takes place in the cyctosol

  20. Regulation of Cholesterol Biosynthesis • Cholesterol obtained from: • 1. Diet • 2. Synthesized de novo • Synthesis in mammals: Liver and Intestine • Regulation of synthesis mainly by feedback regulation of 3-hydroxy-3-methylglutary CoA reductase (HMG CoA reductase) • Rate of synthesis of mRNA of reductase (controlled by transcription factor SREBP) • Rate of translation of reductase • Degradation of reductase • Phosphorylation decreases activity • Regulatory mechanism are modulated by receptors that sense cholesterol on blood

  21. Transport of Cholesterol and Triacylglycerols -> Cholesterol + Triacylglycerols are transported as lipoprotein particles -> Synthesized and secreted by liver and intestine Role of protein component (Apoproteins): solubilize hydrophobic lipids + contain cell targeting signal Lipoprotein particles are classified according to their density

  22. Core of hydrophobic lipids surrounded by a shell of more hydrophilic lipids

  23. In the liver: -> some cholesterol converted into bile salt Diet Triacylglycerols + Cholesterol High in Triacylglycerol content (99%) -> low density Cholesterol of diet LDL is major carrier of cholesterol in blood and regulates de novo synthesis -> High LDL -> “Bad Cholesterol” -> Atherosclerosis HDL (“Good cholesterol”) is a shuttle that moves cholesterol throughout the body -> to use it or to produce hormones

  24. Regulation of Cholesterol Biosynthesis Diet

  25. LDL Regulates Cholesterol Metabolism • Endocytosis of LDL bound to its receptor • Apoprotein B-100 (on surface of LDL) binds to specific receptor • Receptor-LDL complex initiates endocytosis • Vesicles fuse with Lysosomes ->Break down of Protein and Lipids (Lipase) • Cholesterol can be used for membrane biosynthesis or reesterfied for storage Cholesterol synthesis Liver cell engaged in synthesis and secretion of VLDL

  26. Receptor-Mediated Endocytosis

  27. Cholesterol Biosynthesis Blocker Potent blocker of HMG CoA reductase -> reduce level of synthesized cholesterol

  28. Cholesterol Derivates – Bile Salts The only way we can get rid of excess of cholesterol -> cholesterol derivates -> mainly produced bile salts !!! cysteine Major bile salt Bile salts are cholesterol derivates. -> highly efficient detergents, help to solubilize dietary lipids -> synthesized in liver, stored in gall bladder, released into small intestine

  29. Cholesterol Derivates – Steroid Hormones (Androgens)

  30. Nomenclature of Steroid Hormones Steroid hormones are hydroxylated by Cyt P450 3α or 3β hydroxy 5α or 5β hydrogen Below plane Above plane Trans fusion Steroid hormones Cis fusion Bile salts

  31. Synthesis of Precursor for Steroid Hormones

  32. Synthesis of Progesterone and Corticosteroids

  33. Synthesis of Androgens and Estrogens

  34. Synthesis of Vitamin D In the liver + kidney Plays an important role in Calcium and Phosphorus metabolism

  35. Isoprenoids

  36. β-Carotinoids

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