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1、University of ManitobaAdam Burgener生物化学IILectureFattyacidmetabolismwebversionStillwatersrundeep.流静水深流静水深,人静心深人静心深Wherethereislife,thereishope。有生命必有希望。有生命必有希望University of ManitobaAdam BurgenerFatty acid oxidation-energy from lipidsLong chain FA serve as main source for animals: Long chain FA serve a
2、s main source for animals: FA are oxidized and broken down to AcCoA.FA are oxidized and broken down to AcCoA.The release of electrons (NADH) drives ATP The release of electrons (NADH) drives ATP synthesis synthesis Energy EnergyThe production of AcCoA feeds the TCA cycle The production of AcCoA feed
3、s the TCA cycle Energy EnergySources of FA:Sources of FA:1. 1.DietDiet2. 2.Cell storage (lipid droplets)Cell storage (lipid droplets)3. 3.Synthesis (excess carbs, etc.)Synthesis (excess carbs, etc.)University of ManitobaAdam BurgenerFatty acid oxidation outlineLipases are produced in the pancreasLip
4、ases are produced in the pancreasUniversity of ManitobaAdam BurgenerRole of LipasesBreakdown of Triglycerides1.Triglycerides ingested water insolubleEmulsified by bile salts (detergents) in Emulsified by bile salts (detergents) in intestineintestineLipases break them down to Lipases break them down
5、to fatty acids and fatty acids and glycerolglycerol which are taken up by intestinal which are taken up by intestinal mucosamucosa2.Triglycerides stored in adipose tissueBroken down by lipases, triggered by Broken down by lipases, triggered by hormonal signals (epinephrine, glucagon)hormonal signals
6、 (epinephrine, glucagon)University of ManitobaAdam BurgenerLipasesR = fatty acid chain (CH2)nCH3University of ManitobaAdam BurgenerBreakdown of phospholipids by phospholipases Phospholipases A (1 and 2), C, and D.Phospholipases A (1 and 2), C, and D. Phospholipases important for intracellular signal
7、sPhospholipases important for intracellular signals Ex: Inositol triphosphate from Phosphotidyl inositol which is Ex: Inositol triphosphate from Phosphotidyl inositol which is involved in signalling Cainvolved in signalling Ca+ + release from ER (muscle contraction, other release from ER (muscle con
8、traction, other acitivties)acitivties) Phospholipases also present in snake venom and wasp/bee poisonsPhospholipases also present in snake venom and wasp/bee poisonsUniversity of ManitobaAdam Burgener-oxidation Sequential breakdown of fatty Sequential breakdown of fatty acids to yield AcCoAacids to
9、yield AcCoA Occurs in mitochondria (like Occurs in mitochondria (like TCA)TCA) Series of 4 basic steps that are Series of 4 basic steps that are repeated over and overrepeated over and over AcCoA produced AcCoA produced TCA cycle TCA cycle CO CO2 2 and energy and energy For a CFor a C1616 we have 7
10、rounds of we have 7 rounds of - -oxidation to yield:oxidation to yield: 8 AcCoA8 AcCoA 7 NADH7 NADH 7 FADH7 FADH2 2University of ManitobaAdam Burgener-oxidationPalmitic acid (C16):C C1515H H3131COOH + 23 0COOH + 23 02 2 16 CO 16 CO2 2 + 16 H + 16 H2 2O OGGoo = - 9773 KJ/mol = - 9773 KJ/molGlucose(CH
11、(CH2 2O)O)6 6 + 6 O + 6 O2 2 6 CO 6 CO2 2 + 6 H + 6 H2 2O O G Goo = - 2868 KJ/mol = - 2868 KJ/molPalmitic acid has many more carbons to oxidize and is much more reducedUniversity of ManitobaAdam Burgener-oxidation-transport into mitochondria The fatty acids, once taken The fatty acids, once taken up
12、 by the cell, must be up by the cell, must be transported to the transported to the mitochondriamitochondria Fatty Acyl CoA Synthetase Fatty Acyl CoA Synthetase is is bound to mitochondrial bound to mitochondrial outer membraneouter membraneUniversity of ManitobaAdam BurgenerSummary of transport1.Ac
13、tivation with CoASH by fatty acyl CoA Activation with CoASH by fatty acyl CoA synthetasesynthetase2.Transport across mitochondrial INNER membrane Transport across mitochondrial INNER membrane by linking with carnitine by carnitine acyl by linking with carnitine by carnitine acyl transferase I and tr
14、ansferase I and removalremoval by carnitine acyl by carnitine acyl transferase II.transferase II.Fatty acyl ester linkage hereUniversity of ManitobaAdam Burgener-oxidation of straight chain FA Acyl CoA dehase:Acyl CoA dehase: Has 3 isoenzymes:Has 3 isoenzymes: Long chain (12-18 C)Long chain (12-18 C
15、) Medium chain (4 -14 C)Medium chain (4 -14 C) Short chain (4-8 C)Short chain (4-8 C) This is repeated 6 more This is repeated 6 more times to yield:times to yield: 7 AcCoA7 AcCoA 7 NADH7 NADH 7 FADH7 FADH2 2 7 rounds for a C7 rounds for a C1616 Why not 8?Why not 8?-ketoacyl-CoA thiolaseUniversity o
16、f ManitobaAdam Burgener-oxidation of straight chain FA Energy yield:Energy yield: Activation: - 2 ATPActivation: - 2 ATP -oxidation: -oxidation: 7 NADH7 NADH 17.5 ATP 17.5 ATP 7 FADH7 FADH2 2 10.5 ATP10.5 ATP 8 AcCoA:8 AcCoA: 24 NADH24 NADH60 ATP60 ATP 8 FADH8 FADH2 212 ATP12 ATP 8 GTP8 GTP8 ATP8 AT
17、P TotalTotal106 ATP106 ATP Oxidation of palmitic acid: 9800 KJ/molOxidation of palmitic acid: 9800 KJ/mol 106 ATP: energy from phosphate bonds: 106 x 30.5 KJ/mol = 3230 106 ATP: energy from phosphate bonds: 106 x 30.5 KJ/mol = 3230 KJ/molKJ/mol Therefore efficiency is 3230/9800 x 100% = 33% Therefor
18、e efficiency is 3230/9800 x 100% = 33% Comparable to efficiency in glycolysisComparable to efficiency in glycolysisUniversity of ManitobaAdam Burgener-oxidation of straight chain FAQuestion:How much more ATP from stearic acid? (CHow much more ATP from stearic acid? (C1818) ) 1 more round 1 more roun
19、d -oxidation: 1 NADH, 1 FADH-oxidation: 1 NADH, 1 FADH2 2 1 more AcCoA: 3 NADH, 1 FADH1 more AcCoA: 3 NADH, 1 FADH2 2, 1 GTP, 1 GTP Total = 14 extra ATPTotal = 14 extra ATPUniversity of ManitobaAdam Burgener-oxidation of unsaturated FAMonounsaturated FAMonounsaturated FAUniversity of ManitobaAdam Bu
20、rgener-oxidation of unsaturated FAPolyunsaturated FA:Ex: linoleic acid (cis-Ex: linoleic acid (cis- 9 9, cis-, cis-1212) )Requires a Requires a dienoyl-CoA reductasedienoyl-CoA reductase (NADPH) (NADPH) step as well as an step as well as an enoyl CoA isomeraseenoyl CoA isomerase step step before con
21、tinuing normal before continuing normal -oxidation-oxidationUniversity of ManitobaAdam Burgener-oxidation of odd-numbered fatty acids Normal Normal -oxidation proceeds until we are left with a C-oxidation proceeds until we are left with a C3 3 chain chain Ex: CEx: C1717 will proceed for 7 rounds of
22、will proceed for 7 rounds of -oxidation.-oxidation.CO2 incorporated via BiotinUniversity of ManitobaAdam BurgenerRole of biotinBiotin is commonly used is carboxylation Biotin is commonly used is carboxylation reactions as cofactor:reactions as cofactor:ATPADPBiotinCarboxybiotinPropionyl CoA carboxyl
23、aseMethyl Malonyl CoAPropionyl CoACO2University of ManitobaAdam BurgenerStarvation fate of fatty acidsWhat happens when youre starving?Run out of glucose, glycogen stores (diabetics)Run out of glucose, glycogen stores (diabetics)Body initiates gluconeogenesisBody initiates gluconeogenesis Glucose ne
24、eded for key areas (brain, etc)Glucose needed for key areas (brain, etc)TCA cycle intermediates (such as OAA) are TCA cycle intermediates (such as OAA) are depleted to do thisdepleted to do this -oxidation initiatedAcCoA produced in -oxidation initiatedAcCoA produced in large amountslarge amountsPot
25、ential problem?University of ManitobaAdam BurgenerStarvation fate of fatty acids Excess AcCoA produced that body cannot metabolizeExcess AcCoA produced that body cannot metabolize Liver converts it to acetoacetate and Liver converts it to acetoacetate and -hydroxybutyrate and -hydroxybutyrate and re
26、leases it into bloodreleases it into blood Acetoacetate used by peripheral tissues for energyAcetoacetate used by peripheral tissues for energy Can lead to a decrease in blood pH Can lead to a decrease in blood pH acidosisacidosis (common to (common to diabetics)diabetics)University of ManitobaAdam
27、BurgenerEnergy sources for exercise Creatine: another energy carrier other than ATPCreatine: another energy carrier other than ATP Acts as a reservoir of phosphoryl groupsActs as a reservoir of phosphoryl groups When ATP is depleted by rapid exercise or exertion, creatine-When ATP is depleted by rap
28、id exercise or exertion, creatine-phosphate is used to replenish ATP stores by the reverse reactionphosphate is used to replenish ATP stores by the reverse reaction Creatine is found in many tissues (muscle, heart, brain) and is found Creatine is found in many tissues (muscle, heart, brain) and is f
29、ound at 10x the concentration of ATPat 10x the concentration of ATP Creatine is synthesized in liver (or from exogenous sources: fish and Creatine is synthesized in liver (or from exogenous sources: fish and meat) meat) mostly stored in muscle (120 to 140 g/person). mostly stored in muscle (120 to 1
30、40 g/person).University of ManitobaAdam BurgenerATP sources under maximum demand Creatine-phosphate used for explosive energy (sprints, weight lifting, etc)Creatine-phosphate used for explosive energy (sprints, weight lifting, etc) Oxidative phosphorylation lowest output of energy but longest lastingOxidative phosphorylation lowest output of energy but longest lasting ATP/Cr P highest energy output but lasts only a short timeATP/Cr P highest energy output but lasts only a short time
