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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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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,…
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
Synthesis of Triacylglycerols Synthesized in Endoplasmic reticulum of the liver Transport of TAG from liver to muscles (for energy conversion) or adipocytes (storage)
Activation of Intermediate for Synthesis of Phospholipids (Cytidine diphosphate)
Synthesis of Phospholipids Phosphatidic acid
Special Ether Phospholipid PAF involved in allergic and inflammatory responses
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.
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
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
Steroids Cholesterol
Synthesis of Cholesterol Cytosol Endoplasmatic Reticulum
Synthesis of Cholesterol: 1st stage takes place in the cyctosol
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
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
Core of hydrophobic lipids surrounded by a shell of more hydrophilic lipids
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
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
Cholesterol Biosynthesis Blocker Potent blocker of HMG CoA reductase -> reduce level of synthesized cholesterol
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
Cholesterol Derivates – Steroid Hormones (Androgens)
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
Synthesis of Vitamin D In the liver + kidney Plays an important role in Calcium and Phosphorus metabolism