Metabolism of carbohydrate

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Cellular respiration - การหายใจระดับเซลล์
(เมตาบอลิสมของคาร์โบไฮเดรต)
ทนพ.สุวิทย์ คล่องทะเล

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Metabolism of carbohydrate

  1. 1. สรุป Cellular respiration ทนพ. ส ุวิทย์ คล่องทะเล (P’ Zeez) Suwit Klongthalay
  2. 2. ความรู้ค่เปรียบด้วย ู กาลัง กายแฮ สุจริตคือเกราะบัง ศาสตร์พ้อง ปัญญาประดุจดัง อาวุธ กุมสติต่างโล่ป้อง อาจแกล้วกลางสนาม พระราชนิพนธ์ในพระบาทสมเด็จพระจุลจอมเกล้าเจ้าอยู่หว พ.ศ. ๒๔๑๘ ั 2
  3. 3. Energy flow and chemical recycling in ecosystems 3
  4. 4. Stages of Metabolism • Digestion – breakdown of food; nutrients are transported to tissues • Anabolism and formation of catabolic intermediates where nutrients are: o Built into lipids, proteins, and glycogen or o Broken down by catabolic pathways to pyruvic acid and acetyl CoA. • Oxidative breakdown – nutrients are catabolized to carbon dioxide, water, and ATP
  5. 5. Concept of Metabolism Catabolism Anabolism 5
  6. 6. Metabolism 6
  7. 7. Catabolic Pathways and Production of ATP  The breakdown of organic molecules is exergonic  Fermentation is a partial degradation of sugars that occurs without O2 Aerobic respiration consumes organic molecules and O2 and  yields ATP Anaerobic respiration is similar to aerobic respiration but  consumes compounds other than O2 7
  8. 8. Carbohydrate Metabolism  Since all carbohydrates are transformed into glucose, it is essentially glucose metabolism  Oxidation of glucose is shown by the overall reaction: C6H12O6 + 6O2  6H2O + 6CO2 + Energy (ATP + heat)  Glucose is catabolized in three pathways o Glycolysis o Krebs cycle o The electron transport chain and oxidative phosphorylation
  9. 9. Oxidation and reduction reactions Oxidation o has occurred if molecule has lost hydrogen from carbon  o has occurred if molecule gains an oxygen or if the number of carbon bonds to oxygen increases Reduction: Molecule has fewer bonds to O or gains hydrogen to carbon  9
  10. 10. The Principle of Redox 10
  11. 11. Fate of Glucose Fructose Sucrose Glucose 11
  12. 12. Overview of Catabolic Pathway
  13. 13. Glycolysis  10 sequential oxidation reactions  Start from hexose and end with pyruvate (C3 compound)  Divided into 2 phases : Preparatory and Payoff phase o Glucose is oxidized into pyruvic acid  o NAD+ is reduced to NADH + H+  o  It loses 2 pairs of hydrogen It accepts 2 pairs of hydrogen lost by glucose ATP is synthesized by substrate-level phosphorylation Pyruvic acid: end-product of glycolysis o Moves on to the Krebs cycle in an aerobic pathway o Is reduced to lactic acid in an anaerobic environment 13
  14. 14. ATP • Not stored but used up rapidly and resynthesized • Phosphoanhydride bonds are energy rich – release energy when broken 1 kcal = 4.18 kJ 14
  15. 15. ATP hydrolysis 15
  16. 16. Electron carrier 16
  17. 17. 17
  18. 18. Glycolysis   18 Investment phase o Glucose is activated by phosphorylation  “Priming reactions” – need to invest energy to get more out o Uses 2 ATP’s per glucose o Glucose is converted to TWO molecules of glyceraldehyde 3phosphate (G3P) Dividend phase o Each G3P  pyruvate o Get 4 ATP’s out o Net gain of 2 ATP’s
  19. 19. Glycolysis : Prep. phase G6P can form glycogen or other Aldolase cleaves glu molecule into 2 molecules Sum Glu + 2 ATP  2 G3P +2 ADP + 2 Pi 19
  20. 20. Glycolysis : Payoff phase Substrate level phosphorylation 20
  21. 21. Glycolysis Overall reaction Glucose + 2 ADP + 2 NAD+ + 2 Pi 2 Pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O 21
  22. 22. Fluoride can inhibit Enolase Dental carries Common pathogen: Streptococcus mutans Produce lactic acid mineral content of teeth is sensitive to increases in acidity from the production of lactic acid 2PG can't access to active site of enzyme 22
  23. 23. Entry of glycogen, starch, disaccharides, and hexoses into the preparatory stage of glycolysis 23
  24. 24. Three fates of pyruvate   24 Aerobic conditions o conversion to acetyl CoA (pyruvate dehydrogenase) for use in TCA cycle and oxidative phosphorylation for ATP production Anaerobic conditions o Lactate (animal muscles) o Ethanol (plant, yeast, some bacteria)
  25. 25. Anaerobic Glycolysis  NAD+ is regenerated from NADH by the reduction of pyruvate to lactate  Occur in vigorous muscle contraction  Increase NADH/NAD+ ratio : inhibit PDH 25
  26. 26. Anaerobic Glycolysis  Yeast (baker's yeast: Saccharomyces cerevisiae) and other microorganisms ferment glucose to ethanol and CO2  Increase NADH/NAD+ ratio : inhibit PDH 26
  27. 27. 27
  28. 28. Acetyl-CoA production  Glycolysis-derived pyruvate enters mitochondria through pyruvate transporter  Pyruvate is oxidized by pyruvate dehydrogenase (PDH) 28
  29. 29. Acetyl-CoA production Pyruvate dehydrogenase complex 29
  30. 30. TCA Cycle (Citric Acid Cycle)  Oxidize pyruvate  Occurs in mitochondria  Cyclic reaction  C-atom reduced C6  C5  C4  Decarboxylation/ Dehydrogenation  End products are CO2 and NADH, FADH2 30
  31. 31. TCA Cycle (Citric Acid Cycle) 31
  32. 32. TCA Cycle Serves Two Purposes   Oxidize Acetyl-CoA to CO2 to produce energy o ATP (GTP) o Reducing power of NADH and FADH2 o The cycle is involved in the aerobic catabolism of carbohydrates, lipids and amino acids Supply precursors for biosynthesis of carbohydrates, lipids, amino acids, nucleotides and porphyrins 2 Acetyl-CoA + 6NAD+ + 2FAD+ + 2GDP 4CO2 + 6NADH + 2FADH2 + 2GTP 32
  33. 33. Regulation of TCA cycle Indicator molecule of High energy state i.e. ATP, NADH, citrate, acetyl CoA Inhibit TCA activity 33 Indicator molecule of Low energy state i.e. AMP, ADP, NAD+ stimulate TCA activity
  34. 34. 34
  35. 35. Protein complexes in ETC  Complexes I, II, III, IV  Electrons are transferred to molecular oxygen that is then reduced to water  Electrons move through the complexes in order  Electrons from NADH enter at Complex I  Electrons from FADH2 enter at Complex II  In each reaction, an electron donor is oxidized and an electron acceptor is reduced 35
  36. 36. Protein complex in ETC 36
  37. 37. Oxidation and reduction reactions   Reduction potential E0 : measure in volts of how easily the compound is reduced (how easily it gains electrons) Transfer of electrons from reducing agent (that which is oxidized) to an oxidizing agent (that which is reduced) 37
  38. 38. Electron Transport Chain 38
  39. 39. Electrons flow downhill – spontaneously moving from molecules that are strong electron DONORS to strong electron ACCEPTORS = move from high energy state to low energy state 39
  40. 40. 40
  41. 41. Electron Transport Chain 41
  42. 42. Complex I : NADH dehydrogenase  Two electrons are transferred from NADH to Q bound at the binding site near matrix  Q + 2e + 2H+  QH2; leave complex I 42
  43. 43. Complex II : Succinate dehydrogenase  Two electron from succinate are transferred, through FAD and Fe-S in complex II, to Q bound near the matrix surface  Q + 2e + 2H+  QH2; leave complex II 43
  44. 44. Complex III : Ubiquinone-Cyt c Oxidoreductase  Complex III – integral membrane protein containing 2 binding site for quinone molecules o near intermembrane space specific for QH2 o near matrix surface specific for oxidized ubiquinone  QH2 diffuses from Cpx I/II and docks on Cpx III at the binding site near intermembrane space  2H+ are released into intermembrane space  One electron is transferred, through Cyt c1, to Cyt c  Cyt c carry 1 electron at a time  leave Cpx III  Another electron is transferred, through Cyt b, to oxidized Q near the matrix surface  become ubisemiquinone carrying 1 electron  After releasing 2 electrons, QH2  fully oxidized & leave binding site 44
  45. 45. Complex III : Ubiquinone-Cyt c Oxidoreductase  The second QH2 comes in docking at the binding site near the intermembrane space and repeat the process again  Electron that goes through Cyt b reduces the ubisemiquinone still binding at the pocket near the matrix surface. The ubisemiquinone now become fully reduced, taking up 2 protons from the matrix and leaving the binding site  From the overall process o 2 QH2 are oxidized by the Cpx III, 4 protons are deposited into intermembrane space, 2 reduced Cyt c and 1 QH2 are generated 2 QH2 + 2 Cyt c (oxidized)  2 Cyt c (reduced) + 1 QH2 + 4H+ QH2 + 2 Cyt c (oxidized)  2 Cyt c (reduced) + 4H+ 45
  46. 46. Q cycle 46
  47. 47. Complex IV : Cyt c oxidase  Integral membrane protein containing a binding site for reduced Cyt c on the intermembrane space side  Cyt c transfer its electron, trough Cyt a and Cyt a3, to the CuB center  Per 1 electron transfer from Cyt c to the CuB center, 1 H+ is translocated from matrix to intermembrane space  CuB center can accommodate 4 electrons at a time  After 4 Cyt c are oxidized 4 H+ are deposited into intermembrane space  The CuB center, after having 4 electrons, reduces O2 to become H2O 47
  48. 48. 48
  49. 49. Oxidative phosphorylation 49
  50. 50. ATP Synthase F1 F0 50
  51. 51. The P:O Ratio    Translocation of 3H+ required by ATP synthase for each ATP produced 1 H+ needed for transport of Pi, ADP and ATP Net: 4H+ transported for each ATP synthesized 51
  52. 52. Malate-Aspartate shuttle 52 Liver, Kidney, Heart
  53. 53. Glycerol 3-phosphate shuttle cG3PDH Skeletal muscle & brain mG3PDH 53
  54. 54. Glucose degradation via glycolysis, TCA cycle, and oxidative phosphorylation 54
  55. 55. ATP production 5 or 3 23 26 or 28 30 or 32 55 Campbell Biology, 8th ed.
  56. 56. ATP production 56 Campbell Biology, 9th ed.
  57. 57. 57
  58. 58. Anaerobic respiration  In the absence of O2, glycolysis couples with fermentation or anaerobic respiration to produce ATP  uses ETC with an electron acceptor other than O2 o sulfate (SO42-), nitrate (NO3-), sulfur (S), fumarate o terminal electron acceptors have smaller reduction potentials than O2  less energy is released per oxidized molecule  used mainly by prokaryotes  anaerobic organisms  Fermentation uses phosphorylation instead of an electron transport chain to generate ATP 58
  59. 59. Example of respiration Type Lifestyle Electron acceptor Products Eo' [V] Example organisms Aerobic respiration Obligate and facultative aerobes O2 H2O + CO2 +0.82 eukaryotes and aerobic prokaryotes Nitrate reduction Facultative aerobes nitrate (NO3−) nitrite (NO2–) +0.40 E.coli Fumarate respiration Facultative aerobes fumarate succinate +0.03 E.coli Sulfate respiration Obligate anaerobes sulfate (SO42−) sulfide (HS−) -0.22 Desulfobacter latus Sulfur respiration Facultative aerobes and obligate anaerobes sulfur (S0) sulfide (HS−) -0.27 Desulfuromonadal es 59
  60. 60. Summary for cellular respiration 60
  61. 61. Pyruvate Kinase Deficiency 61
  62. 62. Pentose Phosphate pathway  To generate NADPH for reductive biosynthesis reactions (especially, FA synthesis) and anti-oxidant in RBC  To provide the cell with ribose-5phosphate for the synthesis of nucleotides and nucleic acids  Liver, adipose, tissue, adrenal cortex, testis, lactating mammary gland, RBC have high levels of PPP enzymes 62
  63. 63. NADPH  NADPH is also necessary for maintaining redox proteins in RBC 63
  64. 64. Molecular mechanism of Acute hemolysis Hemolytic anaemia Antimalarial drugs (i.e. Primaquine) 64
  65. 65. Production of glucose    Why do we need this process? o Starvation Do all tissue rely on glucose as major fuel? o Only RBC and Brain Two major pathways to release glucose o Glycogenolysis (short term supply of glucose) o Gluconeogenesis (long term supply of glucose) 65
  66. 66. Glycogenolysis 66
  67. 67. Mobilization of glycogen Glucose released as α-D-glucose-1-phosphate       Catalyzed by the enzyme glycogen phosphorylase in animals Enzyme removes glucose residues from the nonreducing ends of glycogen Acts only on α-1-4 linkages of glycogen polymer α(16) branches hydrolyzed by debranching enzymes Glucose-1-phosphate is ISOMERIZED readily to glucose-6phosphate and enters glycolysis Note that this pathway uses LESS ATP than entry of glucose into glycolysis (bypass 1st kinase reaction) 67
  68. 68. Glycogen debranching enzyme 68
  69. 69. Mobilization of glycogen 69
  70. 70. Glycogenolysis-derived glucose transportation Membrane bound enzyme   Liver : glucose is exported to blood circulation Muscle : cannot secrete glucose because muscle lack G-6-Pase 70
  71. 71. 71
  72. 72. Substrate for gluconeogenesis Cori cycle LDH Sources of lactic acid • RBCs • Fast-twitch muscle fiber 72 LDH
  73. 73. Substrate for gluconeogenesis Glycerol 73
  74. 74. Substrate for gluconeogenesis Glucogenic amino acid 74
  75. 75. Substrate for gluconeogenesis Glucose-Alanine cycle 75
  76. 76. Other pathway of Glu metabolism Pentose Phosphate pathway : Role of G6PD Provide NADPH G6PD 76
  77. 77. Glycolysis & PPP  Role of NADPH in regulating the partitioning of glucose-6-phosphate between glycolysis and the pentose phosphate pathway 77
  78. 78. Carbohydrate metabolism control Hormone system   Hypoglycemic hormone: o Insulin Hyperglycemic hormone: o Glucagon o Epinephrine (adrenal medulla) o Cortisol (adrenal cortex) o Thyroid hormone o Growth hormone o Adrenocorticotrophic hormone (anterior pituitary gland) 78
  79. 79. Carbohydrate metabolism control 79
  80. 80. Islets of Langerhans 1 million islets  1-2% of the pancreatic mass  Beta (β) cells produce insulin  Alpha (α) cells produce glucagon  Delta (δ) cells produce somatostatin (GHIH) 80 
  81. 81. Islets of Langerhans 81
  82. 82. Glucose regulation of insulin secretion endocrine system of the pancreas 82
  83. 83. Insulin Action on Cells     Liver o Stimulates glucose oxidation o Promotes glucose storage as glycogen o Inhibits glycogenolysis and gluconeogenesis Skeletal muscle o Stimulates glucose uptake (GLUT4) o Promotes glucose storage as glycogen Adipose tissue o Stimulates glucose transport into adipocytes o Promotes the conversion of glucose into triglycerides and fatty acids The net result is fuel storage 83
  84. 84. Insulin : Summary 84
  85. 85. Glucagon  A 29-aa polypeptide hormone that is a potent hyperglycemic agent  Produced by α cells in the pancreas  Its major target is the liver, where it promotes: o Glycogenolysis o Gluconeogenesis o Release of glucose to the blood from liver cells 85
  86. 86. Glucagon : Summary 86
  87. 87. Glucagon : Summary 87
  88. 88. Insulin & Glucagon Regulate Metabolism 88
  89. 89. Regulation of Blood Glucose Concentrations 89

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