Lipid Metabolism                   1
Fatty Acids        CH3(CH2)nCH2CO2H           O                           OCH3(CH2)nCH2C-OH    H-O-R   CH3(CH2)nCH2C-OH   ...
Fatty Acids as Stored Energy• Fatty acids are the body’s principal  form of stored energy• Carbon almost completely reduce...
Dietary Fatty Acids• Comprise 30-60% of caloric intake in  average American diet• Triacylglycerols, phospholipids,  sterol...
Digestion of Dietary      Triacylglycerols• Occurs in duodenum• Facilitated by    • Bile salts (emulsification)    • Alkal...
Epithelial Cell (Intestinal Wall)                      MAG Glycerol Fatty Acids   Intestinal lumen                        ...
Fat Storage• Mainly as triacylglycerols  (triglycerides) in adipose cells• Constitute 84% of stored energy    • Protein - ...
Processing of Lipid Reserves: Overview   1. Lipid Mobilization:      In adipose tissue TAGs hydrolyzed to          fatty a...
Release of Fatty Acids from     Triacylglycerols             O         CH 2OC-R1             CH 2OH             O       Li...
Hormone(Adrenalin, Glucagon, ACTH)                                     Lipolysis                        Receptor (7TM)    ...
Adenylyl cyclase        Phosphodiesterase         ATP                c-AMP                       AMP Enhanced by glucagon ...
Acylglycerol Lipases                                               Diacylglycerol (DAG)                        Triacylglyc...
Fate of Glycerol         PyruvateIn Liver:                               Glycolysis    OH               Dihydroxyacetone  ...
Beta Oxidation• Cleavage of fatty acids to acetate in  tissues• Occurs in mitochondria[O]   [O]   [O]   [O]   [O]   [O]   ...
Steps in Beta Oxidation• Fatty Acid Activation by Esterification  with CoASH• Membrane Transport of Fatty Acyl CoA  Esters...
Fatty Acid Activation by  Esterification with CoASH                       AcylCoACoASH + RCO2H + ATP            RCOSCoA + ...
Membrane Transport ofFatty Acyl CoA Esters                        +                    O        RCOSCoA + (CH3)3N         ...
TranslocaseCarnitine acyltransferase I                                     Carnitine acyltransferase II                   ...
Beta Oxidation        Reaction Sequence                   Acyl CoA         H H       Dehydrogenase      H  R-CH2 -C-C-COSC...
Complete Beta Oxidation        of Palmitoyl CoACH3CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA          ...
Energetics of Complete Oxidation of Fatty Acids                                         High Energy Phosphate             ...
Complete Oxidation Fatty Acids: 9 kcal/gCarbohydrates: 4 kcal/g Protein:     4 kcal/g                          22
Beta Oxidation of Odd           Carbon Fatty Acids        CH3CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA            ...
Beta Oxidation of      Unsaturated Fatty Acids                       H H            CH 3(CH2)7-C=C-CH2(CH2)6COSCoA        ...
Ketogenesis: Formation of            Ketone Bodies                    Thiolase    2 CH3COSCoA               CH3COCH2COSCoA...
Ketogenesis: Formation  of Ketone Bodies (Cont’d.)          OH                           HMG CoAHO2C-CH2-C-CH2COSCoA      ...
Ketone Bodies As Energy Sources                 In liver -Hydroxybutyrate           Acetoacetate          Succinyl CoA  A...
Ketones in Diabetes MellitusIn presence of insulin:   • Enhanced glucose uptake by tissues   • Decreased mobilization of l...
Ketones in Diabetes MellitusBiochemical consequences of decreasedinsulin production:  •   Glucose not taken up by liver   ...
Metabolic Acidosis in Untreated Diabetes Mellitus          CH3COCH2CO2H pKa = 3.6              Acetoacetic Acid           ...
Fatty Acid Biosynthesis                          31
Fatty Acid Synthesis vs.             Degradation                 Synthesis                   DegradationIntermediates   Li...
Fatty Acid Biosynthesis• Occurs in cytosol• Starts with acetyl CoA    • Problem:         » Most acetyl CoA produced in mit...
Citrate As Carrier of Acetate Groups               Cytosol                           Mitochondria     Glucose            P...
Fatty Acid Biosynthesis:  Formation of Malonyl CoA                                 Acetyl CoA                             ...
Fatty Acid Biosynthesis:Role of Acyl Carrier Proteins                    Acetyl                 Transferase CH3COSCoA     ...
Fatty Acid Biosynthesis:Formation of Acetoacetyl ACP   CH3CO-S-ACP + -O2CCH2CO-S-ACP                     -Ketoacyl ACP   ...
Fatty Acid Biosynthesis:  Formation of Butyryl ACP                       -Ketoacyl ACP            OH                     ...
Fatty Acid Biosynthesis:    Sources of NADPHPentose Phosphate Pathway:                          NADPH       CO2-          ...
Fatty Acid Biosynthesis:        Chain ElongationCH3CH2CH2CO-S-ACP        -O CCH CO-S-ACP                    +      2   2  ...
Fatty Acid Biosynthesis:   Chain Elongation (Cont’d)           H                  NADPH   NADP+                           ...
Fatty Acid Biosynthesis:       Fatty Acid Synthase            in Animals•   Consists of a single polypeptide containing   ...
Orlistat: A Fatty AcidSynthase (FAS) Inhibitor    Anti-obesity (Inhibits    pancreatic lipase in git)    Inhibits thioeste...
Further Processing of Fatty     Acids: Elongation                                       In mitochondria and               ...
Further Processing of FattyAcids: Elongation (Cont’d)                        OH     CH3(CH2)13CH2CCH2COSCoA            - H...
Further Processing of Fatty   Acids: Unsaturation         CH3(CH2)13CH2CH2CH2COSCoA       Stearoyl CoA                    ...
Further Processing of Fatty      Acids: Polyunsaturation                                            9                   CH...
Formation of Arachidonate      in Mammals                                           CO2H        Linoleic acid       As CoA...
Omega-3 Fatty Acids                                                        CO2H  -3 double bond         Eicosapentaenoic ...
Metabolite Regulation of FattyAcid Synthesis and BreakdownGlucose             Citrate                            Stimulate...
Hormonal Regulation of Fatty Acid Synthesis and Breakdown                Adenylyl cyclase             Phosphodiesterase   ...
Synthesis of Phosphatidate                     CH 2OH             CH 2O2C-R1            CH 2OHDihydroxyacetone     Phospha...
Synthesis of                 Glycerophospholipids                                                NH 2  CH 2O2C-R1         ...
Respiratory Distress            SyndromeMost frequently seen in premature infantsAlso called hyaline membrane diseaseFailu...
Synthesis of Glycero-        phospholipids (Cont’d)    CH 2O2C-R1           CH 2O2C-R1                         CH 2O2C-R1 ...
Synthesis of Glycero-        phospholipids (Cont’d)  CH 2O2C-R1           CH 2O2C-R1                      CH 2O2C-R4  CHO2...
Synthesis of Glycero-  phospholipids (Cont’d) CH 2OH             CH 2-O-CH=CHR1 C=O                CHO2C-R2         O     ...
Synthesis of Sphingolipids                                               +    CH3(CH2)14COSCoA +              HOCH 2 CHNH3...
Synthesis of Sphingolipids         (Cont’d) CH 2O2C-R1                                         OH                         ...
Synthesis of Gangliosides                                    OH                    trans      CH3(CH2)12CH=CH-CH-CH-CH2OH ...
Lipid Storage Diseases   (Gangliosidoses)                         61
Tay-Sachs Disease   GM2 (a ganglioside):      Ceramide - O - Glucose - Galactose - N-Acetylgalactose                      ...
Other GangliosidosesGaucher’s disease:  Ceramide - O - Glucose                   -glucosidaseFabry’s disease: Ceramide - ...
Synthesis of Eicosanoids   CH 2O2C-R   CHO2C                                     In cell membrane          O         +   C...
Synthesis of Eicosanoids:       PLA2 ActivationVarious stimuli:               Activation ofHormones, autacoids, etc.      ...
Synthesis of Eicosanoids:           Prostaglandin Synthesis                                      Prostaglandin            ...
Cyclooxygenase (COX) Inhibitors   Nonsteroidal antiinflammatory drugs:           CO2 H                              CO2 H ...
COX-2 Selective Inhibitors                              F 3C              O                  O              N             ...
Prostaglandins                                        O                                                      CO2H         ...
Prostacyclin and Thromboxanes                                                                                   OHO       ...
Leukotriene Biosynthesis                                                     OOH                    Leukotrienes are      ...
Leukotriene Biosynthesis        (Cont’d)                   CO2H                                                           ...
Leukotriene Biosynthesis        Inhibition                S           OH                        CH-N-CONH 2               ...
Cholesterol Biosynthesis:       Formation of Mevalonate   Liver is primary site of cholesterol biosynthesis               ...
Cholesterol Biosynthesis:   Processing of Mevalonate        OH                              OH-O C-CH -C-CH CH OH         ...
Cholesterol Biosynthesis:       Isoprenoid CondensationDimethylallyl          Tailpyrophosphate                           ...
Isoprenoids• Widely distributed in nature• Generally contain multiple of 5 carbons:    • Monoterpene; 10 carbons    • Sesq...
Conversion of Squalene to Cholesterol                                                                                Squal...
Inhibition of Cholesterol Biosynthesis HO             HMGCoA                                    HO        CO2 -   reductas...
Transformations of        Cholesterol: Bile Salts                                              HO               CH3       ...
Transformations of    Cholesterol: Steroid Hormones                                                                       ...
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11 lipidmetabolism

  1. 1. Lipid Metabolism 1
  2. 2. Fatty Acids CH3(CH2)nCH2CO2H O OCH3(CH2)nCH2C-OH H-O-R CH3(CH2)nCH2C-OH H-S-R O O CH3(CH2)nCH2C-O-R CH3(CH2)nCH2C-S-R Ester Thioester 2
  3. 3. Fatty Acids as Stored Energy• Fatty acids are the body’s principal form of stored energy• Carbon almost completely reduced as CH2• Very closely packed in storage tissues - not hydrated as sugars are 3
  4. 4. Dietary Fatty Acids• Comprise 30-60% of caloric intake in average American diet• Triacylglycerols, phospholipids, sterol esters• Principal sources: dairy products, meats 4
  5. 5. Digestion of Dietary Triacylglycerols• Occurs in duodenum• Facilitated by • Bile salts (emulsification) • Alkaline medium (pancreatic juice) Blocked by Orlistat (“Fat Blocker”) - Xenical/Alli Pancreatic OH Intestinal lipases lipases Glycerol + OH Fatty Acids TAG MAG 5
  6. 6. Epithelial Cell (Intestinal Wall) MAG Glycerol Fatty Acids Intestinal lumen Lipoprotein TAG Lymphatics Chylomicrons Adipose TissueBlood (bound to albumin) And Muscle 6
  7. 7. Fat Storage• Mainly as triacylglycerols (triglycerides) in adipose cells• Constitute 84% of stored energy • Protein - 15% • Carbohydrate (glucose or glycogen) - <1% 7
  8. 8. Processing of Lipid Reserves: Overview 1. Lipid Mobilization: In adipose tissue TAGs hydrolyzed to fatty acids plus glycerol 2. Transport of Fatty Acids in Blood To Tissues 3. Activation of Fatty Acids as CoA Ester 4. Transport into Mitochondria 5. Metabolism to Acetyl CoA 8
  9. 9. Release of Fatty Acids from Triacylglycerols O CH 2OC-R1 CH 2OH O Lipases CHOC-R2 CHOH O CH 2OC-R3 CH 2OH Triacylglycerol Glycerol + O O O HOC-R1 HOC-R2 HOC-R3
  10. 10. Hormone(Adrenalin, Glucagon, ACTH) Lipolysis Receptor (7TM) Activates Adenylyl Cyclase ATP c-AMPInsulin Activates lipaseblocks thisstep Triacylglycerols Glycerol + Fatty acids Blood Adipose Cell 10
  11. 11. Adenylyl cyclase Phosphodiesterase ATP c-AMP AMP Enhanced by glucagon Enhanced by insulinInactive Kinase Activated Kinase P Inactive Lipase Activated Lipase (Hormone-sensitive Phosphatase Lipase)Insulin favors formationof the inactive lipase Triacyl- Glycerol + glycerol Fatty Acids 11
  12. 12. Acylglycerol Lipases Diacylglycerol (DAG) Triacylglycerol Lipase OHTriacylglycerol (TAG) Diacylglycerol Lipase OH OH Monoacylglycerol Lipase OH Monoacylglycerol OH OH (MAG) Glycerol 12
  13. 13. Fate of Glycerol PyruvateIn Liver: Glycolysis OH Dihydroxyacetone OH Phosphate OH Gluconeogenesis Glycerol Glucose 13
  14. 14. Beta Oxidation• Cleavage of fatty acids to acetate in tissues• Occurs in mitochondria[O] [O] [O] [O] [O] [O] [O] [O] CO2H 9 CH3COSCoA 14
  15. 15. Steps in Beta Oxidation• Fatty Acid Activation by Esterification with CoASH• Membrane Transport of Fatty Acyl CoA Esters• Carbon Backbone Reaction Sequence • Dehydrogenation • Hydration • Dehydrogenation • Carbon-Carbon Cleavage (Thiolase Reaction) 15
  16. 16. Fatty Acid Activation by Esterification with CoASH AcylCoACoASH + RCO2H + ATP RCOSCoA + AMP + PPi Synthetase Pyrophos- phatase Occurs in outer mitochondrial membrane for long chain fatty acids 2 Pi G0’(KJ/mole) ATP AMP + PPi -32.3 CoASH + RCO2H RCOSCoA +31.5 PPi 2 Pi -33.6 -34.4 16
  17. 17. Membrane Transport ofFatty Acyl CoA Esters + O RCOSCoA + (CH3)3N O- OHCarnitine Carnitine Carnitineacyltransferase II acyltransferase I(matrix side of (outer part of mitochondrialinner mitochondrial inner membrane)membrane) + O (CH3)3N O- O2CR O-Acylcarnitine Transported across inner mitochondrial membrane by translocase 17
  18. 18. TranslocaseCarnitine acyltransferase I Carnitine acyltransferase II 18 Source: http://cellbio.utmb.edu/cellbio/mitochondria_1.htm
  19. 19. Beta Oxidation Reaction Sequence Acyl CoA H H Dehydrogenase H R-CH2 -C-C-COSCoA R-CH2 -C=C-COSCoA H H FAD FADH2 H trans- 2 -enoyl CoA H2 O Enoyl CoA Hydratase -Ketoacyl CoA L--Hydroxyacyl CoA H H H Dehydrogenase R-CH2 -C-C-COSCoA R-CH2 -C-C-COSCoA OH NADH NAD + HO H L--Hydroxyacyl CoA + H+CoASH Thiolase (-ketothiolase) Occurs in Mitochondria R-CH2 -C-SCoA CH 3 -C-SCoA + O O Repeat Sequence 19
  20. 20. Complete Beta Oxidation of Palmitoyl CoACH3CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA 7 Cycles + 8 CH3COSCoA + 7 FADH2 + 7 NADH + 7 H 20
  21. 21. Energetics of Complete Oxidation of Fatty Acids High Energy Phosphate Bonds GeneratedPalmitic Acid Palmitoyl CoA -2 TCA CycleCH3COSCoA CO2 + H2O 108 Net 106106 High Energy Phosphate Bonds G0’ = 3,233 KJ/MoleFor Palmitic Acid CO2: EfficiencyG0’ = - 9,790 KJ/Mole of -Oxidation = 33% 21
  22. 22. Complete Oxidation Fatty Acids: 9 kcal/gCarbohydrates: 4 kcal/g Protein: 4 kcal/g 22
  23. 23. Beta Oxidation of Odd Carbon Fatty Acids CH3CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA 5 Cycles 5 CH3COSCoA + CH3CH2COSCoA Propionyl CoA Propionyl CoA Carboxylase TCA Cycle ATP/CO2 CO2 H CO2 H Mutase EpimeraseHO 2CCH2CH2COSCoA CH 3 -C-H H-C-CH3 Succinyl CoA Vit. B12 COSCoA COSCoA L-Methylmalonyl D-Methylmalonyl CoA CoA 23
  24. 24. Beta Oxidation of Unsaturated Fatty Acids H H CH 3(CH2)7-C=C-CH2(CH2)6COSCoA Oleoyl CoA Beta Oxidation (3 Cycles) H H H IsomeraseCH 3(CH2)7-C=C-CH2COSCoA CH 3 (CH2 )7 -CH2 -C=C-COSCoA cis- 3 trans-2 H Continuation of Beta Oxidation 24
  25. 25. Ketogenesis: Formation of Ketone Bodies Thiolase 2 CH3COSCoA CH3COCH2COSCoA CH3COSCoA Acetoacetyl CoA HMG CoA Synthase Several Cholesterol steps OH (in cytosol) See Slide 78 HO2C-CH2-C-CH2COSCoA CH3(in liver: mitochon- drial matrix) Ketogenesis -Hydroxy--methylglutaryl CoA (HMG CoA) 25
  26. 26. Ketogenesis: Formation of Ketone Bodies (Cont’d.) OH HMG CoAHO2C-CH2-C-CH2COSCoA lyase CH3COCH2CO2 CH3 - CH3COSCoA Acetoacetate + HMG CoA NADH + H Dehydrogenase - CO2 + NAD OH CH3COCH3 CH3CHCH2CO2 Acetone -Hydroxybutyrate (volatile)Ketone bodies are important sourcesof energy, especially in starvation 26
  27. 27. Ketone Bodies As Energy Sources In liver -Hydroxybutyrate Acetoacetate Succinyl CoA Acetoacetate is major energy source in cardiac muscle and renal cortex; also in brain in -Ketoacyl CoA transferase starvation and diabetes Not found in liver Thiolase Succinate2 Acetyl CoA Acetoacetyl CoA Combines with oxaloacetate TCA Cycle 27
  28. 28. Ketones in Diabetes MellitusIn presence of insulin: • Enhanced glucose uptake by tissues • Decreased mobilization of lipids by adipocytesIn absence of insulin: • Decreased glucose uptake by tissues • Increased mobilization of lipids by adipocytes 28
  29. 29. Ketones in Diabetes MellitusBiochemical consequences of decreasedinsulin production: • Glucose not taken up by liver • Decreased oxaloacetate to combine with acetyl CoA to enter TCA • Adipocytes release fatty acids into blood • Increased production of ketone bodies in liver 29
  30. 30. Metabolic Acidosis in Untreated Diabetes Mellitus CH3COCH2CO2H pKa = 3.6 Acetoacetic Acid OH CH3CHCH2CO2H pKa = 4.7 -Hydroxybutyric acid Concentration of acetoacetic acid can result in metabolicacidosis (pH 7.1) affinity of Hb for O2. 30
  31. 31. Fatty Acid Biosynthesis 31
  32. 32. Fatty Acid Synthesis vs. Degradation Synthesis DegradationIntermediates Linked to SH in Linked to CoASH Proteins (Acyl Carrier Proteins)Site Cytosol MitochondriaEnzymes Components of Separate Polypeptides Single PeptideRedox NADP+ / NADPH NAD+ / NADHCoenzymes 32
  33. 33. Fatty Acid Biosynthesis• Occurs in cytosol• Starts with acetyl CoA • Problem: » Most acetyl CoA produced in mitochondria » Acetyl CoA unable to traverse mitochondrial membrane 33
  34. 34. Citrate As Carrier of Acetate Groups Cytosol Mitochondria Glucose Pyruvate Pyruvate Pyruvate Acetyl CoA Dehydrogenase Malic enzyme Malate Malate Oxalo- dehydrogenase acetate CitrateAcetyl CoA OxaloacetateATP-Citrate Lyase Note: Acetyl CoA Citrate cannot be converted to glucose Mitochondrial membrane 34
  35. 35. Fatty Acid Biosynthesis: Formation of Malonyl CoA Acetyl CoA Carboxylase Malonyl CoACH3COSCoA + ATP + HCO3- -O CCH COSCoA 2 2 + ADP + Pi + H+• Committed step in fatty acid synthesis• Reaction is irreversible• Regulation of acetyl CoA carboxylase activity: by palmitoyl CoA by citrate by insulin by epinephrine and glucagon• Malonyl CoA inhibits carnitine acyl transferase I • Blocks beta oxidation 35
  36. 36. Fatty Acid Biosynthesis:Role of Acyl Carrier Proteins Acetyl Transferase CH3COSCoA CH3CO-S-ACP Acetyl ACP Malonyl Transferase-O CCH COSCoA -O CCH CO-S-ACP 2 2 2 2 Malonyl ACP ACP = Acyl carrier protein 36
  37. 37. Fatty Acid Biosynthesis:Formation of Acetoacetyl ACP CH3CO-S-ACP + -O2CCH2CO-S-ACP -Ketoacyl ACP Synthetase CH3COCH2CO-S-ACP + CO2 Acetoacetyl ACP 37
  38. 38. Fatty Acid Biosynthesis: Formation of Butyryl ACP -Ketoacyl ACP OH reductase CH3COCH2CO-S-ACP CH3CCH2CO-S-ACP Acetoacetyl ACP NADPH NADP + H +H + -D-Hydroxybutyryl ACP -Hydroxyacyl ACP - H2O dehydratase NADP+ NADPH H + H+CH3CH2CH2CO-S-ACP CH3C=C-CO-S-ACP 2,3-trans- Butyryl ACP Enoyl ACP Crotonyl ACP H reductase 38
  39. 39. Fatty Acid Biosynthesis: Sources of NADPHPentose Phosphate Pathway: NADPH CO2- NADPH CHO NADP+ + H+ NADP+ + H+ OH OH OH O HO HO OH OH OH OH OH OH OP OP OP CO2 Ribulose-5- Glucose-6- 6-Phospho- phosphate phosphate gluconate NADPHMalic Enzyme: NADP+ + H+ O HO-CH-CO2- CH3CCO2- Malate Malic Pyruvate - CH2CO2 Enzyme CO2 39
  40. 40. Fatty Acid Biosynthesis: Chain ElongationCH3CH2CH2CO-S-ACP -O CCH CO-S-ACP + 2 2 CH3CH2CH2COCH2CO-S-ACP H OHCH2CH2CH2CHCH2CO-S-ACP CH3CH2CH2C=CCO-S-ACP H 40
  41. 41. Fatty Acid Biosynthesis: Chain Elongation (Cont’d) H NADPH NADP+ + H+CH3CH2CH2C=CCO-S-ACP CH3(CH2)3CH2CO-S-ACP H 5 Cycles - CH3(CH2)13CH2CO-S-ACPCH3(CH2)13CH2CO2 Thioesterase Palmitoyl ACP Palmitate 41
  42. 42. Fatty Acid Biosynthesis: Fatty Acid Synthase in Animals• Consists of a single polypeptide containing three distinct domains• Conducts all steps in fatty acid synthesis except function of acyl CoA carboxylase 42
  43. 43. Orlistat: A Fatty AcidSynthase (FAS) Inhibitor Anti-obesity (Inhibits pancreatic lipase in git) Inhibits thioesterase domain of FAS Anti-cancer (experimental): FAS overexpressed in several tumor types; inhibition induces apoptosis 43
  44. 44. Further Processing of Fatty Acids: Elongation In mitochondria and at surface of CH3(CH2)13CH2COSCoA endoplasmic reticulum Palmitoyl CoA CH3COSCoA Thiolase CH3(CH2)13CH2COCH2COSCoA NADH + H+ Dehydrogenase NAD+ OH L- Configuration CH3(CH2)13CH2CCH2COSCoA H 44
  45. 45. Further Processing of FattyAcids: Elongation (Cont’d) OH CH3(CH2)13CH2CCH2COSCoA - H2O H Hydratase H CH3(CH2)13CH2C=CCOSCoA NADPH + H+ Dehydrogenase H NADP+ CH3(CH2)13CH2CH2CH2COSCoA Stearoyl CoA 45
  46. 46. Further Processing of Fatty Acids: Unsaturation CH3(CH2)13CH2CH2CH2COSCoA Stearoyl CoA O2 Stearoyl CoA Desaturase CH3(CH2)7C=C(CH2)7COSCoA + H2O Oleoyl CoA H HThis reaction occurs in eukaryotesEndoplasmic reticulum membrane 46
  47. 47. Further Processing of Fatty Acids: Polyunsaturation 9 CH3(CH2)7C=C(CH2)7CO2H Oleic acid H H (18:19) Plants: Further unsaturation Animals: Further unsaturation occurs primarily in this region occurs primarily in this region 12 9 CO2H Linoleic acid (18:29, 12) Essential dietaryfatty acids in mammals 15 12 9 CO2H Linolenic acid (18:39, 12, 15) 47
  48. 48. Formation of Arachidonate in Mammals CO2H Linoleic acid As CoA ester: 1) Elongation 2) Desaturation x 2 14 11 8 5 CO2H Arachidonic acid (20:45, 8, 11, 14) (Eicosa-5,-8,11,14-tetraenoic acid) Prostaglandins 48
  49. 49. Omega-3 Fatty Acids CO2H -3 double bond Eicosapentaenoic acid (20:55, 8, 11, 14, 17) CO 2H Docahexaenoic acid (22:64, 7, 10, 13, 16, 19)• Found in fish oils, esp. cold water fish• Important in: Growth regulation Modulation of inflammation Platelet activation Lipoprotein metabolism 49
  50. 50. Metabolite Regulation of FattyAcid Synthesis and BreakdownGlucose Citrate Stimulates Blocks BetaPyruvate Acetyl CoA Malonyl CoA Oxidation Inhibits Palmitoyl CoA 50
  51. 51. Hormonal Regulation of Fatty Acid Synthesis and Breakdown Adenylyl cyclase Phosphodiesterase ATP cAMP AMP Stimulates Stimulates Glucagon and Insulin epinephrine Inactivates Activates Protein Kinase lipaseInhibition of Activates triacyl- Inactivates ACC byfatty acid glycerollipase phosphorylationsynthesis 51
  52. 52. Synthesis of Phosphatidate CH 2OH CH 2O2C-R1 CH 2OHDihydroxyacetone Phosphate C=O Glycerol CHO 2C-R2 CHOH (from glycolysis) O O - - CH 2O-P-O CH 2O-P-O CH 2OH O- O- Phosphatidate (formed in endoplasmic reticulum) O CH 2O2C-R1 CH 2OC-R 1 Diacylglycerol R3COSCoA O Triacylglycerol (important in CHO 2C-R2 cell signaling) CHOC-R 2 (transported to Diacylglycerol adipocytes and acyltransferase O muscle) CH 2OH (liver) CH 2OC-R 3 52
  53. 53. Synthesis of Glycerophospholipids NH 2 CH 2O2C-R1 N CH 2O2C-R1 O N CHO2C-R2 + + Transferase R3NCH 2CH2OPOPO O CHO2C-R2 O OH OH CH 2OH CH 2O-P-O-CH2CH 2R3 R=H; CDP ethanolamine O-Diacylglycerol R=CH3; CDP choline + CDP = cytidine diphosphate R3=NH3; Phosphatidylethanolamine + R3=N(CH3)3; Phosphatidylcholine CH 2O2C-R1 + HOCH 2 CHNH3 CHO2C-R2 + CO 2 - Serine O + HOCH 2 CH 2 NH 3 CH 2O-P-O-CH2CHNH 3 Ethanolamine O- - CO2 Phosphatidylserine 53
  54. 54. Respiratory Distress SyndromeMost frequently seen in premature infantsAlso called hyaline membrane diseaseFailure to produce sufficient dipalmitoyl phosphatidylcholine,which normally is found in the extracellular fluid surroundingalveoli; decreases surface tension of fluid to prevent lungcollapseTreatment in infants born before 30 weeks includesadministration of artificial lung surfactant (e.g., Exosurf orPumactant) 54
  55. 55. Synthesis of Glycero- phospholipids (Cont’d) CH 2O2C-R1 CH 2O2C-R1 CH 2O2C-R1 CHO2C-R2 CHO2C-R2 CHO2C-R2 Phosphatidyl- O inositol O CH 2O-P-O - O- CH 2O-P-O CH 2O-CDP OH OH O- Phosphorylation OH of 4 & 5 OH groups Phosphatidate Cytidine diphosphate (CDP) HO diacylglycerol OH Phospholipase C (plasma membrane) OH OH CH 2O2C-R1 OPO3 H2Both IP3 and DAG are + CHO2C-R2 OPO3 H2important second messengers H2 O3POin cell signaling pathways OH CH 2OH Inositol-1,4,5- Diacylglycerol (DAG) triphosphate (IP3) 55
  56. 56. Synthesis of Glycero- phospholipids (Cont’d) CH 2O2C-R1 CH 2O2C-R1 CH 2O2C-R4 CHO2C-R2 CHO2C-R2 CHO2C-R3 O O CH 2O-CDP CH 2O-P-O-CH2CHCH 2-O-P-O-CH2 O- OH O-Cytidine diphosphate Cardiolipin: formed in inner(CDP) diacylglycerol mitochondrial membrane; plays role in oxidative phosphorylation 56
  57. 57. Synthesis of Glycero- phospholipids (Cont’d) CH 2OH CH 2-O-CH=CHR1 C=O CHO2C-R2 O O + - CH 2O-P-O CH 2O-P-O-CH2CH 2NH 3 O- O-DihydroxyacetonePhosphate Plasmalogens(from glycolysis) (Abundant in cardiac tissue and CNS) 57
  58. 58. Synthesis of Sphingolipids + CH3(CH2)14COSCoA + HOCH 2 CHNH3 Serine Palmitoyl CoA CO 2 - 3-Ketosphingosine synthase HCO3-2 CoASH CH3(CH2)14CO-CHCH2OH 2S,3-Ketosphinganine NH3+ 3 Steps OH trans CH3(CH2)12CH=CH-CH-CH-CH2OH Ceramide CH3(CH2)nCONH 58
  59. 59. Synthesis of Sphingolipids (Cont’d) CH 2O2C-R1 OH trans CHO2C-R2 CH3(CH2)12CH=CH-CH-CH-CH2OH O + CH 2O-P-O-CH2CH 2N(CH 3)3 CH3(CH2)nCONH Ceramide O- Phosphatidylcholine Diacylglycerol OH O trans + CH3(CH2)12CH=CH-CH-CH-CH2O-P-OCH2CH2N(CH3)3 Sphingomyelin CH3(CH2)nCONH O- Gangliosides Cerebrosides 59
  60. 60. Synthesis of Gangliosides OH trans CH3(CH2)12CH=CH-CH-CH-CH2OH Ceramide CH3(CH2)nCONH OH Glucose or trans galactose CH3(CH2)12CH=CH-CH-CH-CH2O-Sugar CH3(CH2)nCONH Cerebroside Ceramide - Sugar - Sugar - GalNAc - GalNAN = N-acetylneuraminate Ganglioside NAN 60GalNAc = N-acetylgalactose
  61. 61. Lipid Storage Diseases (Gangliosidoses) 61
  62. 62. Tay-Sachs Disease GM2 (a ganglioside): Ceramide - O - Glucose - Galactose - N-Acetylgalactose Hexoseaminidase A catalyzes cleavage of this glycoside linkageAutosomal recessive disorder characterized by deficiencyof hexoseaminidase A; accumulation of gangliosides in brainMost prevalent in Jews from Eastern EuropeFor further information see:http://www.marchofdimes.com/professionals/681_1227.asp 62
  63. 63. Other GangliosidosesGaucher’s disease: Ceramide - O - Glucose -glucosidaseFabry’s disease: Ceramide - O - Glucose - O - Galactose - O - Galactose -galactosidaseNieman-Pick disease: Ceramide - Phosphate - Choline sphingomyelinase 63
  64. 64. Synthesis of Eicosanoids CH 2O2C-R CHO2C In cell membrane O + CH 2O-P-O-CH2CH 2NR3 R’= H or CH3 O- Hydrolysis of sn-2 ester bond by phospholipase A2 (PLA2) - O2C Arachidonate 64
  65. 65. Synthesis of Eicosanoids: PLA2 ActivationVarious stimuli: Activation ofHormones, autacoids, etc. Membrane-bound PLA2 Receptors Activity Ca+2 Arachidonate release and eicosanoid synthesis are important mediators of tissue injury and inflammation 65
  66. 66. Synthesis of Eicosanoids: Prostaglandin Synthesis Prostaglandin endoperoxide O CO2- O CO2- synthetase O O (Cyclooxygenase) H O=O Cyclic Cyclooxygenase endoperoxide CO2- O CO2-O HydroperoxidaseO O OH O-O-H PGG2 PGH2 Hydroperoxide Prostaglandin endoperoxide synthetase (also called cyclooxygenase) possesses both cyclooxygenase and hydroperoxidase activity Two forms of cyclooxygenase: COX -1 - constitutively expressed COX -2 - inducible 66
  67. 67. Cyclooxygenase (COX) Inhibitors Nonsteroidal antiinflammatory drugs: CO2 H CO2 H COX COX HOH 2 C OCOCH3 O - CCH3 Ser-530 CH2OCOCH3Acetylsalicylic acid O (aspirin) Irreversible inhibition of COX by acetylation of the active site Actions of Aspirin: Antiinflammatory (COX-2 inhibition) GI injury (COX-1 inhibition) 67
  68. 68. COX-2 Selective Inhibitors F 3C O O N N CH3 SO2 CH3 SO2 NH 2 Rofecoxib (Vioxx) Celecoxib (Celebrex)Glucocorticoids block COX-2 expression 68
  69. 69. Prostaglandins O CO2H HO PGE2 OHO CO2- HOO CO2 H OH PGH2 O OH PGD2 HOProstaglandins exhibit a variety CO2 Hof actions on different tissues HO OH PGF2 69
  70. 70. Prostacyclin and Thromboxanes OHO CO2- Prostacyclin HO 2C OH synthaseO O PGH2 OH Prostacyclin (PGI2): Blocks platelet aggregation Thromboxane synthase OH CO2- Non-Enzymatic CO2 - O O HO O OH OH Thromboxane A2 (TxA2): Thromboxane B2 (TxB2): Promotes platelet inactive aggregation (t1/2 = 30 sec.) 70
  71. 71. Leukotriene Biosynthesis OOH Leukotrienes are CO2H CO2H 5-Lipoxygenase important mediators of inflammationArachidonic acid 5-Hydroperoxyeicosa- 6,8,11,14-tetraenoic acid (5-HPETE) 5-Lipoxygenase CO2H O OH CO2 HLeukotriene B4 (LTB4) Leukotriene A4 (LTA4) Gly Glutathione Glu Cys LTC4 synthase Cys S - Glu S CO2H - Gly CO2 H OH OH Leukotriene C4 (LTC4) Leukotriene E4 (LTE4) Cysteinyl leukotrienes 71
  72. 72. Leukotriene Biosynthesis (Cont’d) CO2H CO2H 12-Lipoxygenase HOOArachidonic acid 12-Hydroperoxyeicosa- 5,8,10,14-tetraenoic acid (12-HPETE) CO2HHO 12-Hydroxyeicosa- 5,8,10,14-tetraenoic acid (12-HETE) 72
  73. 73. Leukotriene Biosynthesis Inhibition S OH CH-N-CONH 2 CH3 Zileuton (Zyflo) An inhibitor of 5-lipoxygenase Used in the treatment of asthma 73
  74. 74. Cholesterol Biosynthesis: Formation of Mevalonate Liver is primary site of cholesterol biosynthesis Thiolase 2 CH3COSCoA CH3COCH2COSCoA CH3COSCoA Acetoacetyl CoA HMG CoA Synthase OH OH HMGCoA reductaseHO2C-CH2-C-CH2CH2OH HO2C-CH2-C-CH2COSCoA CH3 CoASH NADP + NADPH CH3 + H+ 3R-Mevalonic acid -Hydroxy--methyl- Key control step glutaryl CoA (HMG CoA) in cholesterol biosynthesis 74
  75. 75. Cholesterol Biosynthesis: Processing of Mevalonate OH OH-O C-CH -C-CH CH OH -O C-CH -C-CH CH OPOP 2 2 2 2 2 Steps 2 2 2 2 CH3 ATP CH3 Mevalonate 5-Pyrophospho- mevalonate - CO2 - H 2O CH3 Isomerase CH3-C=CH2CH2OPOP CH2=C-CH2CH2OPOP Dimethylallyl Isopentenyl CH3 pyrophosphate pyrophosphate 75
  76. 76. Cholesterol Biosynthesis: Isoprenoid CondensationDimethylallyl Tailpyrophosphate Head to tail OPOP Head Condensation Tail OPOP Head OPOP Tail Geranyl transferase H Isopentenyl Head Pyrophosphate (IPP) Geranyl Pyrophosphate (GPP) Isoprenes Geranyl Head to tail Tail to tail transferase condensation condensation of IPP and GPP of 2 FPPs Squalene OPOP synthase Squalene Head Tail Farnesyl Pyrophosphate (FPP) 76
  77. 77. Isoprenoids• Widely distributed in nature• Generally contain multiple of 5 carbons: • Monoterpene; 10 carbons • Sesquiterpene: 15 carbons • Diterpene: 20 carbons OH OHMenthol: a monoterpene Lycopene: a tetraterpene 77
  78. 78. Conversion of Squalene to Cholesterol Squalene- Squalene 2,3-epoxide monooxygenase O2 O Squalene + 2,3-Oxidosqualene H cyclase CH3 CH3 CH3 CH3 20 Steps CH3 HO LanosterolHO H3C CH3 CH3 Cholesterol Acyl-CoA: RCO2 cholesterol acyltransferase Cholesterol esters 78 (principal transport form in blood)
  79. 79. Inhibition of Cholesterol Biosynthesis HO HMGCoA HO CO2 - reductase CO2- HOCH3 COSCoA [ CH3 H C -S -CoA OH ] CH3 CO2 - OH HMG CoA Intermediate Mevalonate HO CO2- H OH Atorvastatin (Lipitor): CH2 CH2 resembles intermediate N F C6H5NHCO 79
  80. 80. Transformations of Cholesterol: Bile Salts HO CH3 CH3 CO2 - CH3 CH3HO HO OH H Cholesterol Cholic acid CH3 R = CH2SO3- Taurocholate CONHCH2R R = CO2- Glycocholate Detergents 80
  81. 81. Transformations of Cholesterol: Steroid Hormones OH O CH3 HO OH O CH3 O HOO Cholesterol CortisolProgesterone OH OH OH OHO Testosterone CH 2 Estradiol Vitamin D HO OH 81
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