3.Cholesterol - 3 Cholesterol& lipoproteins 3 HO...

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Unformatted text preview: 3. Cholesterol & lipoproteins 3. HO cholesterol Membrane Fluidity Cholesterol makes phospholipid membranes more plastic with cholesterol without cholesterol Temperature Cholesterol associates with sphingolipids and certain proteins to form “rafts” in the plasma membrane lipid raft other phospholipids sphingolipids & other phospholipids protein protein with glycosylphosphatidylinositol (GPI) anchor at carboxyl end cholesterol Lipids probably are more ordered in rafts than elsewhere in the membrane Lipids because sphingolipids usually have long, saturated fatty acid side chains Cholesterol serves as a precursor for steroid hormones & bile acids O cholesterol HO progesterone O OH testosterone O O O O CH2OH OH cortisone estradiol HO OH CO2- HO OH cholate (a bile acid) Steroids are members of a large group of natural products with structures based on isoprene CH2 H2C CH3 isoprene squalene (30 carbons) O CH3 CH3O O CH3O ubiquinone-7 (35-carbon side chain) β -carotene (40 carbons) HO cholesterol (27 carbons) Experiments with radioactive tracers showed that rats synthesize cholesterol and squalene from acetate. CH3CO2acetate squalene HO cholesterol The labeling patterns in squalene and cholesterol were similar, supporting the hypothesis that squalene is an intermediate in cholesterol biosynthesis. A 5-carbon isoprenoid building block is synthesized from acetate by way of a 6-carbon intermediate, mevalonate CH3 HO CO2CH3 CH3 CO2- CO2- three molecules of acetate C CH3 CH3 CH2 CH2OH H2C CH2 CO2- C mevalonate CO2 CH2 CH2O P isopentenyl pyrophosphate P Mevalonate is synthesized from three molecules of acetylCoA via β -hydroxy-β -methylglutarylCoA (HMG-CoA) HMG-CoA CH3 CoA-SH CH 3 HO CO-SCoA C=O CH3 CH3 CH3 CO-SCoA CO-SCoA CO-SCoA 2 acetylCoA CoA-SH C CH3 CH2 CH2 CO2- CO-SCoA acetoacetylCoA 2 NADPH + 2H+ HO C CH3 CH2 CH2 CO CH2OH 2 mevalonate 2 NADP+ + CoA-SH HMG-CoA reductase key control point for cholesterol biosynthesis! Formation of isopentenyl pyrophosphate from mevalonate consumes three molecules of ATP HO CH3 C HO ATP CH2 CH2 CO2- CH2OH C CH3 HO ATP CH2 CH2 CO2- CH3 C CH2 CO2- CH2O P CH2 CH2O P P mevalonate ATP PO C CH3 CH2 CH2O P P Pi C H2C CH2 CO2- CH3 CO2 CH2 CH2O P P isopentenyl pyrophosphate Isopentenyl pyrophosphate tautomerizes to dimethylallyl pyrophosphate, which can form a relatively stable carbonium ion CH3 C H2C CH3 C CH H3C CH2 CH2-O P P CH2O P P isopentenyl pyrophosphate dimethylallyl pyrophosphate HO- P P CH3 H3C CH3 C C + - CH2 + CH 2 H3C CH2 CH2 allyl carbonium ion Isopentenyl pyrophosphate and dimethylallyl pyrophosphate combine to form geranyl pyrophosphate CH3 dimethylallylpyrophosphate HO- P P C H3C CH3 - C H3C CH CH H2C CH2-O P P CH2 H+ C H3C Isopentenyl pyrophosphate CH2 CH2O P P CH2 C H3 C CH CH2O P P geranyl pyrophosphate (10 carbons) This creates a new allyl-pyrophosphate derivative that can combine with a second molecule of isopentenyl pyrophosphate to form farnesyl pyrophosphate (15 carbons). Two molecules of farnesyl pyrophosphate condense head-to-head to form squalene CH2O- P P NADPH NADP+ + H+ P P -OCH2 2 P P -O- Formation of squalene epoxide requires O2 and NADPH squalene O2 + NADPH + H+ H2O + O NADP+ squalene monooxygenase squalene 2,3-epoxide Cyclization of squalene epoxide zips up the sterol rings + H+ O HO + HO Protonation opens the epoxide and generates a carbonium ion that reacts with the nearby C=C double bond, creating a new carbonium ion … + + + HO HO HO there’s more … The cyclase reaction continues + + HO + HO HO Hydrogen atoms ( ) jump between adjacent carbons … and then … + HO + HO H+ HO methyl groups ( ) jump … and then a proton departs, and we have lanosterol. I don’t expect you to remember these details. Cholesterol biosynthesis is controlled primarily by HMG-CoA reductase β-Hydroxy-β-methylglutarylCoA insulin HMG-CoA reductase glucagon mevalonate enzyme synthesis Phosphorylation by AMP-dependent protein kinase inactivates HMGCoA reductase; dephosphorylation activates it. enzyme proteolysis cholesterol Cholesterol Cholesterol or a cholesterol derivative inhibits synthesis and stimulates proteolysis of HMG-CoA reductase. Synthesis of the low-density Synthesis lipoprotein (LDL) receptor, which mediates uptake of lipoproteins containing cholesterol, also is regulated. Cholesterol or a derivative inhibits synthesis of the receptor. Cholesterol prevents activation of transcription of the HMG-CoA reductase gene ER membrane SREBP Cholesterol Cholesterol binds reversibly to a protein that holds the Sterol Regulatory Element Binding Protein (SREBP) in the ER membrane to nucleus In the absence of cholesterol, the proteins separate and SREBP is cleaved by proteases A soluble fragment of SREBP diffuses to the nucleus, where it activates transcription Inhibitors of HMG-CoA reductase (statins) are used clinically to decrease cholesterol biosynthesis HO HO CO2OH H3C CO2OH mevalonate R1 O O CH3 CH3 R2 R1 R2 H CH3 H CH3 Compactin Simvastatin (Zocov) H H OH CH3 Prevastatin (Prevacol) Lovastatin (Mevacor) In addition to decreasing LDL cholesterol, statins decrease the level of C-reactive protein in the blood. C-reactive protein is a marker of acute inflamation. Its role in atherosclerosis is unclear. Ridker et al., New Engl. J. Med. 325: 20 (2005) Nissen et al., New Engl. J. Med. 352: 29 (2005) Lipoproteins carry cholesterol between the liver and other tissues plasma membrane monolayer of phospholipids & some free cholesterol core core of triacylglycerols & cholesterol esters apolipoprotein LDL blood This is a cartoon. The structures of lipoproteins are not known. LDL receptor cytosol Low-density lipoproteins (LDL and VLDL) carry cholesterol from the liver to other tissues; highdensity lipoproteins carry it in the other direction chylomicrons Density (g/mL) Composition (wt%) protein phospholipids cholesterol & cholesterol esters triacylglycerols < 0.95 VLDL 0.95 - 1.006 1.006 - 1.063 1.063 - 1.210 10 18 23 20 55 24 8 84 19 50 45 10 17 4 LDL liver HDL Triacylglycerols from VLDLs and chylomicrons are hydrolyzed in capillaries of muscle and adipose cells by lipoprotein lipase HDL 1-2 7 chylomicrons intestine LDL adipose tissue, muscle other tissues The liver both synthesizes cholesterol and removes it from the blood for conversion to bile acids. LDL particle LDL Cells take up low-density lipoproteins by receptormediated endocytosis LDL receptor Golgi receptor resynthesis endosome ER ER cholesterol Ebola virus uses parts of this pathway to enter cells. nucleus nucleus lipids lysosome amino acids High levels of cholesterol in the blood can result in atherosclerosis -- deposition of cholesterol and other materials in the inner walls of blood vessels Coronary artery disease is the leading cause of death in industrialized countries. Major risk factors: •high blood cholesterol (especially LDL cholesterol > 100 mg/dL) •smoking •diabetes mellitus •obesity •physical inactivity atherosclerotic plaque Blood clot There usually are no symptoms until blood flow to the heart is seriously compromised. Individuals with defective LDL receptors have exceptionally high plasma cholesterol (familial hypercholesterolemia). Because cholesterol does not enter their cells, HMGCoA reductase is not regulated properly and cholesterol biosynthesis remains switched on. If untreated, people with this condition tend to die of atherosclerosis at a young age. Variant forms of apolipoproteins E and A are associated with different risks of heart disease Apo-E, Apo-E, a major component of chylomicrons and VLDLs, has 3 common alleles: Apo-E3 is the most common form. Apo-E4 has been linked to Alzheimer’s disease & elevated risk of heart disease. Apo-E2 binds poorly to LDL receptors, & is associated with hyperlipidemia. High levels of HDLs generally are linked to lower risk of heart disease High Exercise increases HDLs. But people with Apo-A1(Milano) have very low levels of HDL and also have very low risk of heart disease. Some drugs that increase HDLs have unexpected adverse (off-target) effects. Gene Therapy for Atherosclerosis? R. Flynn et al. Expression of apolipoprotein A-1 in rabbit carotid endothelium protects against atherosclerosis. Molecular Therapy 10, 1833-1841 (2011). ...
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This note was uploaded on 02/17/2012 for the course CHEM 212 taught by Professor Staff during the Fall '10 term at Rutgers.

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