2.Triacylglycerols - 2. Phospholipids, triacylglycerols and...

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Unformatted text preview: 2. Phospholipids, triacylglycerols and complex lipids Membranes contain a variety of glycerophospholipids and sphingolipids O CH2-O-C stearic acid (C18:0) O CH-O-C O + CH2-O-P-O-CH2CH2-N(CH3)3 Oglycerol phosphocholine oleic acid (C18:1(∆ 9)) 1-stearoyl-2-oleoylphosphatidylcholine other common glycerophospholipids: phosphatidylethanolamine phosphatidylserine phosphatidylglycerol phosphatidylinositol HO-CH O CH-N-C H O + CH2-O-P-O-CH2CH2-N(CH3)3 O- sphingomyelin sphingolipids with carbohydrate groups serve as recognition factors on cell surfaces Lipids in rat hepatocyte (liver cell) membranes Membrane Fluidity The fluidity of a phospholipid bilayer increases at a characteristic temperature (Tm), where the side chains become more disordered more unsaturated fats more saturated fats Temperature Tm depends on the composition of the phospholipids. Phospholipids with unsaturated side chains or short side chains melt at lower temperatures Most natural unsaturated fatty acids have cis double bonds. Phospholipids with unsaturated fatty acid side chains don’t pack well with phospholipids that have saturated side chains. CO2linolenic acid Unsaturated fatty acids and short-chain fatty acids make natural fats more fluid C16 & C18 saturated C16 & C18 unsaturated C4 to C14 saturated Cells adjust their phospholipid composition so that Tm typically is slightly below the growth temperature 3 Ratio of unsaturated to saturated fatty acids in E. coli 2 grown at different temperatures Pig living outdoors in winter 1 0 10 20 30 Culture Temperature (C) cool warm A.G. Marr & J.L. Ingraham, J. Bact. 84: 1260 (1962) 40 Animals snthesize oleic acid (C18:1) from stearoylCoA by an enzyme system that uses molecular O2 as an oxidant CO-S-CoA stearoylCoA, C18:0 O2 + NADPH CO-S-CoA 2H2O + NADP+ oleoylCoA C18:1(∆ 9) This process occurs in the ER. The fatty acid and NADPH each provides two electrons for the reduction of O2 to water, which requires 4 electrons: O2 + 4 e- + 4 H + 2 H 2O A cytochrome (cytochrome b5) and a flavoprotein (cytochrome b5 reductase) carry electrons from NADPH to the oxidase. palmitoleate (C16:1(∆ 9)) is synthesized similarly from palmitate Animals can’t synthesize unsaturated fatty acids with two or three double bonds CO2- linoleate, 18:2(∆ 9,12) CO2- linolenate, 18:3(∆ 9,12,15) Linoleate and linolenate are required in the diet. They’re “essential” fatty acids. But once ingested, they can be converted into other polyunsaturated fatty acids such as arachidonate (20:4(∆ 5,8,11,14)). Triacylglycerols are synthesized from glycerol-3-phosphate and fatty acyl CoA thioesters O CH2-OH HO-C-H O R-C-S-CoA CH2-O-C-R HO-C-H O CH2-O-P-O- CoA-SH O- O O R-C-S-CoA O R-C-O-CH O CH2-O-P-O- CoA-SH O- O CH2-O-P-OOphosphatidic acid glycerol-3phosphate R-C-S-CoA CH2-O-C-R R-C-O-CH O O CH2-O-C-R R-C-O-CH O CH2-O-C-R triacylglycerol H2O O O O CH2-O-C-R CH2-OH CoA-SH diacylglycerol Pi Adipose tissue can generate glycerol-3-phosphate from glucose or by glyceroneogenesis CO2- ADP Pi ATP CO2 CO2- GTP C=O C=O CO2 GDP CO2 C O -P-O CH2 O CH2 CH3 CO2 - pyruvate carboxylase pyruvate phosphoenolpyruvate carboxykinase phosphoenolpyruvate oxaloacetate ADP O ATP 1,3-bisphosphoglycerate 3-phosphoglycerate 2-phosphoglycerate NAD+ NADH, Pi glyceraldehyde3-phosphate CH2OH C=O NADH O CH2-O-P-O Odihydroxyacetonephosphate NAD+ CH2OH HO-C-H O CH2-O-P-O Oglycerol-3-phosphate Glyceroneogenesis and gluconeogenesis are regulated reciprocally by changes in the amounts of PEPcarboxykinase in liver and adipose tissue adipose tissue liver triacylglycerol fatty acids fatty acids triacylglycerol glycerol-3-phosphate glycerol-3-phosphate dihydroxyacetonephosphate dihydroxyacetonephosphate PEP carboxykinase X glucose glucocorticoid hormones PEP carboxykinase pyruvate pyruvate thiazolidinedione drugs used to treat type-2 diabetes (Thiazolidinediones also affect expression of many other genes.) choline + (CH3)3N-CH2CH2-OH Mammals synthesize phosphatidylcholine and phosphatidylethanolamine from cytidine nucleotide derivatives of the bases NH2 ATP ADP N CDP-choline O PPi CTP + (CH3)3N-CH2CH2-O-P-O O- O C OO + (CH3)3N-CH2CH2-O-P-O-P-O-CH2 O- OO C N phosphocholine O O OH OH CH2-O-C-R CMP R-C-O-CH diacylglycerol O CH2-OH O CH2-O-C-R R-C-O-CH phosphatidylcholine O + CH2-O-P-O-CH2CH2-N(CH3)3 O- CH CH Phosphatidylinositol and some other glycerophospholipids are formed from CDP-diacylglycerol NH2 O O O CH2-O-C-R R-C-O-CH CTP N CH2-O-C-R PPi O R-C-O-CH O O C C O O N CH CH CH2-O-P-O-P-O-CH2 CH2-O-P-O- O- O- O O- CDP-diacylglycerol phosphatidic acid OH OH OH OH O O HO CH2-O-C-R R-C-O-CH O OH CH2-O-P-O Ophosphatidylinositol H OH OH HO HO H OH OH CMP OH inositol Phosphatidylinositol participates in intracellular signaling O CH2-O-C-R O CH-O-C-R phosphatidylinositol O O CH2-O-P-O- OH OH O HO H OH OH monoacylglycerol H2O 2 ATP 2 ADP phosphatidylinositol 4,5-bisphosphate CH2-O-P-O- OH OH O P--O H O--P H2O OH hormone-sensitive phospholipase in plasma membrane diacylglycerol activation of protein kinase C inositol-1,4,5-trisphosphate release of intracellular Ca2+ free fatty acids regulation of other enzymes regulation of other enzymes Eicosanoids are 20-carbon lipids that act locally to stimulate a variety of processes O CO2 CH3 OH OH Prostaglandins: act through cAMP to stimulate contraction of smooth muscle, affect blood flow, elevate body temperature, or cause inflamation & pain Prostaglandin E1 CO2 O O CH3 OH Thromboxane A2 O CO2 CH3 Leukotriene A4 Thromboxanes: produced by platelets; act in formation of blood clots & reduction of blood flow at the site of a clot Leukotrienes: induce contraction of muscle lining airways to the lungs. I won’t expect you to remember these structures. Mammalian cells synthesize eicosanoids from arachidonic acid Arachidonic acid is released by breakdown of phospholipids in response to cell damage or hormonal stimuli. phospholipids containing arachidonic acid phospholipase A2 H2O lysophospholipid stimulus CO2- 2 O2 cyclooxygenase aspirin, ibuprofin Aspirin, ibuprofin and acetaminophen Aspirin, (nonsteroidal anti-inflamatory drugs, NSAIDS) block prostaglandin synthesis by inhibiting cyclooxygenase. Mammals have two isozymes of cyclooxygenase -- COX-1 & COX-2. The prostaglandins produced by COX-1 participate in “house-keeping” functions such as secretion of gastric mucin; those produced by COX-2 play roles in inflamation. arachidonate (20:4) X O CO2- O OOH cyclooxygenase prostaglandin G2 O CO2- O OH prostaglandin H2 other eicosanoids Phospholipase A2 and cyclooxygenase operate on substrates in the plasma membrane view normal to membrane view parallel to membrane 90° membrane phospholipid bilayer note the tunnels leading from the membrane to the active sites The cyclooxygenase-2 dimer with bound arachidonate, viewed from two perspectives 1cvu.pdb Cyclooxygenases 1 and 2 have homologous structures view parallel to membrane view normal to membrane heme 90° ibuprofin membrane phospholipid bilayer the heme is at the peroxidase site cyclooxygenase-1 dimer viewed from two perspectives 1eqg.pdf Non-steroidal anti-inflamatory drugs (NSAIDs) have been used widely to treat osteoarthritis and rheumatoid arthritis Aspirin, taken regularly in small amounts, decreases the risk of atherosclerosis. Aspirin and other drugs that inhibit both COX-1 & COX-2 (e.g., ibuprofin & naproxin) have anti-inflamatory effects, but also decrease secretion of gastric mucin, causing stomach irritation. Drugs that specifically inhibit COX-2 cause less stomach irritation. But the COX-2 inhibitors celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra) were found to increase the risk of heart attacks and stroke. Similar effects were found with naproxin (Naprosin, Aleve), which inhibits both COX-1 & COX-2. ...
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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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