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Chapter 14 Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway

Chapter 14 Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway. Glucose. Roles of glucose Fuel (Glucose  CO 2 + H 2 O ; ∆ G = ~ -2,840 kJ/mol) Precursor for other molecules. Utilization of glucose in animals and plant Synthesis of structural polymers Storage

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Chapter 14 Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway

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  1. Chapter 14 Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway

  2. Glucose • Roles of glucose • Fuel (Glucose  CO2 + H2O ; ∆G = ~ -2,840 kJ/mol) • Precursor for other molecules • Utilization of glucose in animals and plant • Synthesis of structural polymers • Storage • Glycogen, starch, or sucrose • Oxidation via glycolysis • Pyruvate for ATP and metabolic intermediate generations • Oxidation via pentose phosphate pathway • Ribose 5-P for nucleic acid synthesis • NADPH for reductive biosynthesis • Generation of glucose • Photosynthesis : from CO2 • Gluconeogenesis (reversing glycolysis) : from 3-C or 4-C precursors

  3. 14.1 Glycolysis Glycolysis Glucose 2 x Pyruvate 2 ATP & 2 NADH Fermentation the anaerobic degradation of glucose ATP production

  4. An Overview: Glycolysis • Two phases of glycolysis (10 steps) • Preparatory phase : 5 steps • From Glc to 2 glyceraldehyde 3-P • Consumption of 2 ATP molecules • Payoff phase : 5 steps • Generation of pyruvate • Generation of 4 ATP from high-energy phosphate compounds • 1,3-bisphosphoglycerate, phosphoenylpyruvate • Generation of 2 NADH

  5. Preparatory Phase

  6. Payoff Phase

  7. Fates of Pyruvate • Aerobic conditions • Oxidative decarboxylation of pyruvate • Generation of acetyl-CoA • Citric acid cycle • Complete oxidation of acetyl-CoA CO2 • Electron-transfer reactions in mitochondria • e- transfer to O2 to generate H2O • Generation of ATP • Fermentation : anaerobic conditions (hypoxia) • Lactic acid fermentation • Reduction of pyruvate to lactate  NAD+ regeneration for glycolysis • Vigorously contracting muscle • Ethanol (alcohol) fermentation • Conversion of pyruvate to EtOH and CO2 • Microorganisms (yeast)

  8. Fate of Pyruvate • Anabolic fates of pyruvate • Source of C skeleton (Ala or FA synthesis)

  9. ATP & NADH formation coupled to glycolysis • Overall equation for glycolysis • Glc + 2 NAD+ 2 pyruvate + 2NADH + 2H+ • DG’1o = -146 kJ/mol • 2ADP + 2Pi  2ATP + 2H2O • DG’2o = 2(30.5) = 61.0 kJ/mol • Glc + 2NAD+ + 2ADP + 2Pi  2 pyruvate + 2NADH + 2H+ + 2ATP + 2H2O • DG’so = DG’1o + DG’2o = -85 kJ/mol • 60% efficiency in conversion of the released energy into ATP • Importance of phosphorylated intermediates • No export of phosphorylated compounds • Conservation of metabolic energy in phosphate esters • Binding energy of phosphate group • Lower DG‡ & increase reaction specificity • Many glycolytic enzymes are specific for Mg2+ complexed with phosphate groups

  10. Glycolysis : Step 1 • 1. Phosphorylation of Glc • Hexokinase • Substrates; D-glc & MgATP2-(ease nucleophilc attack by –OH of glc) • Induced fit • Soluble & cytosolic protein

  11. Glycolysis : Step 2 • 2. Glc 6-P  Fru 6-P (isomerization) • Phosphohexose isomerase (phosphoglucose isomerase) • Reversible reaction (small DG’o)

  12. Glycolysis : Step 3 • 3. Phosphorylation of Fru 6-P to Fru 1,6-bisP • Phosphofructokinase-1 (PFK-1) • Irreversible, committed step in glycolysis • Activation under low [ATP] or high [ADP and AMP] • Phosphoryl group donor • ATP • PPi : some bacteria and protist, all plants

  13. Glycolysi : Step 4 • 4. Cleavage of Fru 1,6-bisP • Dihydroxyacetone P & glyceraldehyde 3-P • Aldolase (fructose 1,6-bisphosphate aldolase) • Class I : animals and plant • Class II : fungi and bacteria, Zn2+ at the active site • Reversible in cells because of lower concentrations of reactant

  14. Class I Aldolase Reaction

  15. Glycolysis : Step 5 • 5. Interconversion of the triose phosphates • Dihydroxyacetone P  glyceraldehyde 3-P • Triose phosphate isomerase

  16. Glycolysis : Step 6 • 6. Oxidation of glyceraldehyde 3-P to 1,3-bisphosphoglycerate • Glyceraldehyde 3-P dehydrogenase • NAD+ is the acceptor for hydride ion released from the aldehyde group • Formation of acyl phosphate • Carboxylic acid anhydride with phosphoric acid • High DG’o of hydrolysis

  17. Glyceraldehyde 3-P dehydrogenase

  18. Glycolysis : Step 7 • 7. Phosphoryl transfer from 1,3-bisphosphoglycerate to ADP • 3-phosphoglycerase kinase • Substrate-level phosphorylation of ADP to generate ATP • c.f. Respiration-linked phosphorylation • Coupling of step 6 (endergonic) and step 7 (exergonic) • Glyceraldehyde 3-P + ADP + Pi + NAD+ 3-phosphoglycerate + ATP + NADH + H+ • DG’o = -12.5 kJ/mol • Coupling through 1,3-bisphophoglycerate (common intermediate)  Removal of 1,3-bisphosphoglycerate in step 7  strong negativeDG of step 6

  19. Glycolysis : Step 8 • 8. 3-phosphoglycerate to 2-phosphoglycerate • Phosphoglycerate mutase • Mg2+ • Two step reaction with 2,3-BPG intermediate

  20. Glycolysis : Step 9 • Dehydration of 2-phosphoglycerate to phosphoenolpyruvate (PEP) • Enolase • Free energy for hydrolysis • 2-phosphoglycerate : -17.6 kJ/mol • PEP : -61.9 kJ/mol

  21. Glycolysis : Step 10 • Transfer of phosphoryl group from PEP to ADP • Pyruvate kinase • Substrate-level phosphorylation • Tautomerization from enol to keto forms of pyruvate • Irreversible • Important site for regulation

  22. Overall Balance in Glycolysis Glucose + 2ATP + 2NAD+ + 4ADP + Pi 2Pyruvate + 2ADP + 2NADH + 2H+ + 4ATP + 2H2O Multienzyme complex Substrate channeling Tight regulation Rate of glycolysis: anaerobic condition (2ATP) aerobic condition (30-32) ATP consumption NADH regeneration Allosteric regulation of enzymes; Hexokinase, PFK-1, pyruvate kinase Hormone regulations; glucagon, insulin, epinephrine Changes in gene expression for the enzymes

  23. 14.2 Feeder Pathways for Glycolysis

  24. Entry of Carbohydrates into Glycolysis

  25. Degradation of Glycogen and Starch by Phosphorolysis • Glycogen phosphorylase • (Glc)n + Pi Glc 1-P + (Glc)n-1 • Debranching enzyme • Breakdown of (a16) branch • Phosphoglucomutase • Glc 1-P  Glc 6-P • Bisphosphate intermediate

  26. Digestion of Dietary Polysaccharides and Disaccharides • Digestion of starch and glycogen • a-amylase in saliva • Hydrolysis of starch to oligosaccharides • Pancreatic a-amylase •  maltose and maltotriose, limit dextrin • Hydrolysis of intestinal dextrins and disaccharides • Dextrinase • Maltase • Lactase • Sucrase • Trehalase • Transport of monosaccharide into the epithelial cells • c.f. lactase intolerance • Lacking lactase activity in the intestine • Converted to toxic product by bacteria • Increase in osmolarity  increase in water retention in the intestine

  27. Entry of Other monosaccharides into Glycolytic Pathway • Fructose • In muscle and kidney • Hexokinase • Fru + ATP  Fru 6-P + ADP • In liver • Fructokinase • Fru + ATP  Fru 1-P + ADP • Fructose 1-P aldolase Triose phosphate isomerase Glyceraldehyde 3-P Triose kinase

  28. Entry of Other monosaccharides into Glycolytic Pathway • Galactose • Glactokinase; Gal  Glc 1-P • Galatosemia • Defects in the enzymatic pathway • Mannose • Hexokinase • Man + ATP  Man 6-P + ADP • Phosphomannose isomerase • Man 6-P  Fru 6-P

  29. 14.3 Fates of Pyruvate under Anaerobic Conditions: Fermentation

  30. Pyruvate fates • Hypoxic conditions • Rigorously contracting muscle • Submerged plant tissues • Solid tumors • Lactic acid bacteria Failure to regenerate NAD+ Fermentation is the way of NAD+ regeneration

  31. Lactic Acid Fermentation • Lactate dehydrogenase • Regeneration of NAD+ • Reduction of pyruvate to lactate • Fermentation • No oxygen consumption • No net change in NAD+ or NADH concentrations • Extraction of 2 ATP

  32. Ethanol Fermentation • Two step process • Pyruvate decarboxylase • Irreversible decarboxylation of pyruvate • Brewer’s and baker’s yeast & organisms doing ethanol fermentation • CO2 for brewing or baking • Mg2+ & thiamine pyrophosphate (TPP) • Alcohol dehydrogenase • Acetaldehyde + NADH + H+ EtOH + NAD+ • Humanalcohol dehydrogenase • Used for ethanol metabolism in liver

  33. Thiamine Phyrophosphate (TPP) as Active Aldehyde Group Carrier • TPP • Vitamin B1 derivative • Cleavage of bonds adjacent to a carbonyl group • Decarboxylation of a-keto acid • Rearrangement of an activated acetaldehyde group

  34. Role of Thiamine Pyrophosphate (TPP) in pyruvate decarboxylation • TPP • Nucleophilic carbanion of C-2 in thiazolium ring • Thiazolium ring acts as “e- sink”

  35. Fermentation in Industry • Food • Yogurt • Fermentation of carbohydrate in milk by Lactobacillus bulgaricus • Lactate  low pH & precipitation of milk proteins • Swiss cheese • Fermentation of milk by Propionibacterium freudenreichii • Propionic acid & CO2 milk protein precipitation & holes • Other fermented food • Kimchi, soy sauce • Low pH prevents growth of microorganisms • Industrial fermentation • Fermentation of readily available carbohydrate (e.g. corn starch) to make more valuable products • Ethanol, isopropanol, butanol, butanediol • Formic, acetic, propionic, butyric, succinic acids

  36. 14.4 Gluconeogenesis

  37. Gluconeogenesis • Pyruvate & related 3-/ 4-C compounds  glucose • Net reaction • 2 pyruvate + 4ATP + 2GTP + 2NADH + 2H+ + 4H2O  Glc + 4ADP + 2GDP + 6Pi +2NAD+ • In animals • Glc generation from lactate, pyruvate, glycerol, and amino acids • Mostly in liver • Cori cycle ; Lactate produced in muscle  converted to glc in liver  glycogen storage or back to muscle • In plant seedlings • Stored fats & proteins  disaccharide sucrose • In microorganisms • Glc generation from acetate, lactate, and propionate in the medium

  38. Gluconeogenesis

  39. Glycolysis vs. Gluconeogenesis • 7 shared enzymatic reactions • 3 bypass reactions; irreversible steps requiring unique enzymes • Large negative DG in glycolysis • Hexokinase vs. glc 6-phosphatase • Phosphofructokinase-1 vs. fructose 1,6-bisphosphatase • Pyruvate kinase vs. pyruvate carboxylase + PEP carboxykinase

  40. From Pyruvate to PEP Pyruvate + HCO3- + ATP  oxaloacetate + ADP + Pi • Pyruvate carboxylase • Mitochondrial enzyme with biotin coenzyme • Activation of pyruvate by CO2 transfer  oxaloacetate

  41. From Pyruvate to PEP Oxaloacetate + GTP  PEP + CO2 + GDP • PEP carboxykinase • Cytosolic and mitochondria enzyme • Overall reaction equation • Pyruvate + ATP + GTP + HCO3- • PEP + ADP + GDP + Pi + CO2, DG’o = 0.9 kJ/mol • But, DG= -25 kJ/mol

  42. Alternative paths from pyruvate to PEP • From pyruvate • Oxaloacetate + NADH + H+ malate + NAD+ (mitochondria) • Malate + NAD+ oxaloacetate + NADH + H+ (cytosol) • [NADH]/[NAD+] in cytosol : 105 times lower than in mitochondria • Way to provide NADH for gluconeogenesis in cytosol • From lactate • NADH generation by oxidation of lactate • No need to generate malate intermediate

  43. 14.5 Pentose Phosphate Pathway of Glucose Oxidation

  44. Pentose Phosphate Pathway • Oxidative phase; NADPH & Ribose 5-P • Nonoxidative phase • Recycling of Ribulose 5-P to Glc 6-P • Pentose ribose 5-phosphate • Synthesis of RNA/DNA, ATP, NADH, FADH2, coenzyme A in rapidly dividing cells (bone marrow, skin etc) • NADPH • Reductive biosynthesis • - Fatty acid (liver, adipose, lactating mammary gland) • - Steroid hormones & cholesterol (liver, adrenal glands, gonads) • Defense from oxygen radical damages • - High ratio of NADPH/NADP+ a reducing atmosphere  preventing oxidative damages of macromolecules

  45. Oxidative Pentose Phosphate Pathway

  46. Nonoxidative Pentose Phosphate Pathway • 6 Pentose phosphates  • 5 Hexose phosphates • Reductive pentose phosphate pathway • Reversal of nonoxidative Pentose Phosphate Pathway • Photosynthetic assimilation of CO2 by plant

  47. Nonoxidative Pentose Phosphate Pathway • Transketolase • Transfer of a 2-C fragment from a ketose donor to an aldose acceptor • Thiamine pyrophosphate (TPP) cofactor • Transaldolase • Transfer of a 3-C fragment • Lys : Schiff base with the carbonyl group of ketose Stabilization of carbanion intermdeidate

  48. Nonoxidative Pentose Phosphate Pathway

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