脂类分解

metobolism of lipids⏹key words⏹essensial fatty acids⏹metobolism of lipids⏹ketone bodies⏹β-oxidationEssential Fatty Acids (EFAs)⏹Essential means that animals cannot synthesize it in a sufficient level to meet their requirement⏹Must be supplied in the diet⏹Linoleic亚油酸(18:2), Linolenic亚麻酸(18:3), and Arachidonic acid 花生四烯酸(20:4)⏹They are polyunsaturated fatty acids(PUFA)Ⅰ. Mobilization of Stored TriacylglycerolsTriacylglycerols stored in adipose tissue are hydrolyzed step by step to glycerol and free fatty acid (FFA) that are transported to those tissues （skeletal muscle, heart, etc.) in which fatty acids can be oxidized as fuels. Free fatty acid are conjugated with albumin 白蛋白in the blood and transported to tissues.G proteinFates of glycerol1) glycerol → glycerol-3-phosphate → DHAP →glycolytic pathway→pyruvate →acetyl CoA →CO2+H2O2) glycerol → glycerol-3-phosphate → DHAP →Glucose(gluconeogenesis)3) glycerol →glycerol-3-phosphate →TG, PLⅡ. Oxidation of Fatty Acids⏹Tissue: All cells except for RBCs and brain can use fatty acids for energy, predominantly in the liver⏹Site: cytosol , mitochondrion⏹Process:①Activation of FA②Transported into mitochondrion③β-oxidation of FA④Citric acid cycle1. Activation of fatty acids in cytosol (or in mito.) FA + CoA-SH + ATP acyl~SCoA + AMP + 2Pi•Site: in cytosol (or in mito.)•Enzyme: acyl-CoA synthetase•Consume two high energy bonds in ATP: -2ATP⏹The fatty acids with chain lengths of 4-10 carbons enter mitochondria without the help of membrane transporters and activated by acyl-CoA synthetase in Mito.⏹Those with 14 or more carbons, which constitute the majority of the FFA obtained in the diet or released from adipose tissue, cannot pass directly through the mitochondrial membranes—they must first undergo the three enzymatic reactions of the carnitine shuttle.2.Long chain Acyl~SCoAs are transported through the inner membrane of mitochondrion •need carnitineTransport of long-chain fatty acids through the inner mitochondrial membrane need: * Carnitine acyl transferase I(key enzyme)* Carnitine-acylcarnitine translocase* Carnitine acyl transferase IICH 2CH 2CH 2COOHCH 2COOHCH 2CH 2CH 2CH 2CH 2COOHCH 2CH 2CH 2CH 2COOH CH 2CH 2COOH COOH CH 2C ONHCH 2COOHC O NHCH 2COOH 偶碳苯脂酸奇碳苯脂酸 苯乙尿酸(苯乙酸衍生物) 马尿酸(苯甲酸衍生物)3. β-oxidation of fatty acids1904 Knoopβ-oxidation of fatty acidsIn the matrix of mitochondrion, fatty acyl-CoAs are oxidized in a series of cycles that each cycle releases two carbons from the carboxyl end in the form of acetyl-CoA. Each cycle involvesfour reactions------dehydrogenation, hydration, dehydrogenation, and thiolytic cleavage.16 10 9 8 7 6 5 4 3 2 1CH3(CH2)5CH2CH2CH2CH2CH2CH2CH2CH2CH2COOHγ βαpalmitate (16C)4. Citric acid cycle and oxidative phosphorylationEnergy production from -oxidation of 16-carbon fatty acid : palmitic acid (1 mol)7 β-oxidation ATP(mol)7×1.57 FADH27 NADH+H+7×2.58 acetyl-CoA 8×10activation -2total: 106 ATPIV. Ketone BodiesKetone bodies include acetoacetate, acetone, and β-hydroxybutyrate. They are intermediates of FA oxidation in the liver and are exported to other organs to be oxidized and utilized.Formation of Ketone Bodies⏹Take place in mitochondrial matrix of liver ⏹Materials: acetyl-CoA from fatty acidoxidation⏹Enzymes:acetoacetyl-CoA thiolaseHMG-CoA synthaseHMG-CoA lyase⏹Process:Utilization of Ketone Bodies1. Take place in extrahepatic tissues.2. Reactions and enzymes：①acetoacetate + succinyl-CoA→acetoacetyl-CoA+ succinate E: β-ketoacyl CoA transferase②acetoacetyl-CoA + CoA-SH →2 acetyl-CoAE: acetoacetyl-CoA thiolase3. acetyl-CoAs are oxidized through citric acid cycle and oxidative phosphorylation.❖Ketone bodies are formed in liver, but liver cannot use ketone bodies because it does not have β-ketoacyl CoA transferase activity.❖Extrahepatic tissues can use ketone bodies as energy sources under normal conditions. During starvation the brain uses them as an important fuel source.I. Biosynthesis of Fatty Acids(Synthesis of Palmitate from Acetyl-CoA)1. Tissues where fatty acids are synthesized:predominantly in the liver, some in adipose tissue * Take place in cytosol2. Materials: acetyl-CoA(produced inside mitochondria from glucose metabolism), NADPH, ATP Citrate pyruvate cycle:to transport acetyl-CoA from mitochondrial matrix to cytosolCitrate pyruvate cycleCitrate pyruvate cycleBoth needed for FA synthesis3. Process and key enzyme(1) Synthesis of Malonyl-CoACO 2+acetyl CoA+ATP →Malonyl-CoA +ADP+Pi ▪Irreversible▪acetyl-CoA carboxylase▪key enzyme▪Prosthetic group: biotin▪Allosteric enzyme:Monomer (inactive) polymer (active)▪Chemical modificationCitrate,isocitrateLong chain acyl CoAMalonyl CoA FormationJust like pyruvate carboxylase ingluconeogenesis ACC is the major regulatory enzyme infatty acid synthesisH 3C S CoAOCO 2BiotinATP acetyl CoA carboxylase ADP + Pi C H 2S CoA O OOC acetyl CoA malonyl CoA (ACC)Glucagon⊕⊕InsulinAcetyl groups are added successively to thecarboxy end.H 3C C OH 3C CH 2CH 2C O H 3C CH 2CH 2CH 2CH 2C O malonyl CoA malonyl CoAacetyl CoA acetyl CoAEach acetyl CoA (except for the first) must be converted to malonyl CoA for activation.Acetyl CoA(2) Synthesis of Palmitate1. Biosynthesis of cholesterol①Tissues:•Except for mature RBC and brain tissue Predominantly in the liver (70%～80%),Others: Small Intestinal mucosa (10%)Adrenal gland, Sex organs, Skin •Smooth endoplasmic reticulum and cytosol②Materials:18 acetyl-CoA36 ATP1 cholesterol16 NADPH+H+③Process▪Synthesis of Mevalonate▪Key enzyme: 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase)▪Synthesis of Squalene▪Synthesis of cholesterolCholesterolVitamin DUVSteroidal hormonesglucocorticosteroidssex hormonesBile salts2. Functions of Cholesterol • Moderates fluidity of membranes1. Chylomicrons (CM)•CM are lipoprotein complexes that carry dietary lipids(TG).▪largest▪lowest in density due to high lipid/protein ratio •Apolipoproteins making up CM include apo B48, apo AI, apo AⅣ, apo AII.2. Very Low-Density Lipoproteins (VLDL) ▪VLDL are the primary transport vehicle for TG synthesized in the liver (endogenousTG).▪VLDL are composed of the following apolipoproteins:apo B100, apo E; apo CI, apo CII, apo CIII.3. Low Density Lipoprotein (LDL)•LDL are the primary transport vehicle for cholesterol synthesized in the liver .•The primary lipid and apolipoprotein contained in LDL is CE and Apo B100.4. High Density Lipoprotein (HDL)➢Highest in density due to high protein/lipid ratio➢HDL are often referred to as the “good cholesterol”because they function to take Ch from peripheral tissues back to the liver and help to lower total serum Ch.HDL receptorbile saltssphericaldisc-shapedHDLs contain the LCAT, which catalyzes synthesis of CE using fatty acids cleaved from the membrane lipid lecithin and Ch. The apo AⅠon the surface of HDL is the activator for LCAT.TYPE TRANSPORTS FROM TOChylomicronVLDL IDL and LDLHDL Albumin-FFATG Intestines OtherTissuesTG Liver OtherTissues CholesterolLiver orHDLOtherTissues Cholesterol TissuesLiver, IDLor LDLFatty Acids AdiposetissuesOtherTissuesSpecific transport functionsChapter 6 Biological Oxidation⏹key words⏹Biological oxidation⏹Respiratory chain⏹Oxidative phosphorylation⏹P/O ratioDefinition of Biological OxidationThe oxidation taking place in organism is termed biological oxidation. It mainly refers to the oxidative degradation of carbohydrates, fats, and amino acids to CO2, H2O and energy.Some of the energy is used for the generation of ATP from ADP and Pi, and the other is released as heat energy.GlycogenFats H 2O + CO 2 +energy Proteins (light and heat)burning O 2Glycogen glucose Fats fatty acids acetyl CoA CO 2Proteins amino acidsNADH+ FADH 2H 2O + ATPTACstage1 stage2 stage3 The energy released through catabolism is captured as ATP , the rest is released as heat.•Oxidative phosphorylation is the process in which ATP is generated as a result of electron flow from NADH or FADH2to O2via a series of membrane-bound electron carriers, called thee lectron transfer chain or respiratory chain (reducing O2to H2O at the end).I.Respiratory chain(electron transfer chain)Definition: The mitochondrial respiratory chain consists of a series of enzymes with prosthetic groups capable of accepting and donating either one or two electrons,most of which are membrane-bonded proteins. Each component of the chain can accept electrons from the preceding carrier and transfer them to the following one,in a specific sequence.The products are H2O and ATP.Enzyme complex Ⅰ:NADH-ubiquinone reductase Function:NADH complex Ⅰe ubiquinoneComposition:39 kinds of peptide chains( iron-sulfur protein, flavoprotein)Prosthetic group:FMN, Fe-SFlow of Electrons:NADH→FMN→Fe -S→CoQEnzyme complex Ⅱ:Succinate-ubiquinonereductase Function:succinate complex Ⅱe ubiquinone Composition:4 kinds of peptide chain(iron-sulfur protein, flavoprotein)Prosthetic group:iron porphyrin, Fe-S, FADFlow of Electrons:succinate →FAD→Fe -S→CoQEnzyme complex Ⅲ:ubiquinone-cytochrome creductase Function:CoQ complex Ⅲe Cyt cComposition:10 kinds of peptide chains(Cytb562,Cytb566, Cytc1,iron-sulfur protein)Prosthetic group:iron porphyrin, Fe-SFlow of Electrons:CoQ→Cytb 562, b 566→Fe -S→Cytc 1→CytcCoQH 22Cyt b(Fe 3+) 2Fe 2+-S Cyt c 1(Fe 3+) Cyt c (Fe 2+)CoQ 2Cyt b(Fe 2+) 2Fe 3+-S Cyt c 1(Fe 2+) Cyt c (Fe 3+)2H +Cytb562,Cytb566Enzyme complex Ⅳ:Cytochrome c oxidase Function:Cyt c Complex ⅣeO 2Composition:13 kinds of peptide chains (Cytaa3)Prosthetic group:iron porphyrin, 2CuFlow of Electrons:Cytc→Cu A →Cyta→ Cyta 3→Cu B →O 2FMN:Fe-SFAD:Fe-SCyt b,c1Fe-SCoQ CytcCytaa3½O2H2ONADHSuccinateComplexⅠComplexⅡComplex ⅢComplex ⅣThere are two respiratory chains:1. NADH oxidation respiratory chain2. Succinate oxidation respiratory chainThere are two respiratory chain:NADH oxidation respiration chainNADH →Ⅰ(FMN, Fe-S)→CoQ →Ⅲ(Cyt b 562, b 566, Fe-S , Cyt c 1)→Cyt c →Ⅳ(Cyt aa 3)→O 2Succinate oxidation respiration chainSuccinate →Ⅱ(FAD, Fe-S)→CoQ →Ⅲ(Cyt b 562, b 566 , Fe-S, Cyt c 1)→Cyt c →Ⅳ(Cyt aa 3)→O 2Ⅱ. Oxidative PhosphorylationDefinition:The process of the phosphorylation of ADP to ATP coupled to electron transfer from a substrate to molecular oxygen is termed oxidative phosphorylation.。