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Overview of catabolic pathways

Overview of catabolic pathways. Catabolism of glucose via glycolysis and the citric acid cycle . NADH. NADH, FADH 2. Converts: 1 glucose 2 pyruvate. Net reaction of glycolysis. +. Two molecules of ATP are produced Two molecules of NAD + are reduced to NADH.

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Overview of catabolic pathways

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  1. Overview of catabolic pathways

  2. Catabolism of glucose via glycolysis and the citric acid cycle NADH NADH, FADH2

  3. Converts: 1 glucose2 pyruvate Net reaction of glycolysis + • Two molecules of ATP are produced • Two molecules of NAD+ are reduced to NADH Glucose + 2 ADP + 2 NAD+ + 2 Pi 2 Pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O

  4. Glycolysis can be divided into two stages • Hexosestage: 2 ATP are consumed per glucose • Triosestage: 4 ATP are produced per glucose • Net: 2 ATP produced per glucose x2

  5. Fig 11.2 Transfer of a phosphorylgroup from ATP to glucose enzyme: hexokinase 1 Isomerization of glucose 6-phosphateto fructose 6-phosphate enzyme: glucose 6-phosphate isomerase 2

  6. Transfer of a secondphosphoryl group from ATP to fructose 6-phosphate enzyme: phosphofructokinase-1 3 Carbon 3 – Carbon 4bond cleavage, yielding twotriose phosphates enzyme: aldolase 4

  7. Enzyme 1. Hexokinase • Transfers the g-phosphoryl of ATP to glucose C-6 oxygen to generate glucose 6-phosphate • Mechanism: attack of C-6 hydroxyl oxygen of glucose on the g-phosphorous of MgATP2- displacing MgADP- Fig 11.3

  8. 2. Glucose 6-Phosphate Isomerase • Converts glucose 6-phosphate (an aldose) to fructose 6-phosphate (a ketose) • Enzyme converts glucose 6-phosphate to open chain form in the active site Fig 11.4

  9. 3. Phosphofructokinase-1 (PFK-1) • Catalyzes transfer of a phosphoryl group from ATP to the C-1 hydroxyl group of fructose 6-phosphate to form fructose 1,6-bisphosphate (F1,6BP) • PFK-1 is metabolically irreversible and a critical regulatorypoint for glycolysis in most cells (PFK-1 is the first committed step of glycolysis)

  10. 4. Aldolase • Aldolase cleaves the hexose fructose 1,6-bisphosphate into two triose phosphates: glyceraldehyde 3-phosphate and dihydroxyacetone phosphate

  11. 5. Triose Phosphate Isomerase • Conversion of dihydroxyacetone phosphate into glyceraldehyde 3-phosphate

  12. Fig 11.6 Fate of carbon atoms from hexose stage to triose stage

  13. 6. Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) • Conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate (1,3BPG) • Molecule of NAD+ is reduced to NADH

  14. Box 11.2 Arsenate (AsO43-) poisoning • Arsenate can replace Pi as a substrate for glyceraldehyde 3-phosphate dehydrogenase • Arseno analog which forms is unstable

  15. 7. Phosphoglycerate Kinase • Uses uses the high-energy phosphate of 1,3-bisphosphoglycerate to form ATP from ADP • Transfer of phosphoryl group from the energy-rich 1,3-bisphosphoglycerate to ADP yields ATP and 3-phosphoglycerate

  16. 8. Phosphoglycerate Mutase • Catalyzes transfer of a phosphoryl group from one part of a substrate molecule to another • Reaction occurs without input of ATP energy

  17. 9. Enolase: 2-phosphoglycerate to phosphoenolpyruvate (PEP) • Elimination of water (dehydration) yields PEP • PEP has a veryhigh phosphoryl group transfer potential because it exists in its unstable enol form

  18. 10. Pyruvate Kinase • Metabolically irreversible reaction

  19. Fates of pyruvate • For centuries, bakeries and breweries have exploited the conversion of glucose to ethanol and CO2 by glycolysis in yeast

  20. Metabolism of Pyruvate 1. Aerobicconditions: pyruvate is oxidized to acetyl CoA, which enters the citric acid cycle for further oxidation 2. Anaerobicconditions (microorganisms): pyruvate is converted to ethanol 3. Anaerobicconditions (muscles, redbloodcells): pyruvate is converted to lactate

  21. Fig 11.10 • Fates of pyruvate

  22. Fig 11.11 • Two enzymes required: • (1) Pyruvate decarboxylase • (2) Alcohol dehydrogenase • Anaerobic conversion of pyruvate to ethanol (yeast - anaerobic)

  23. Reduction of Pyruvate to Lactate (muscles - anaerobic) • Muscles lack pyruvate dehydrogenase and cannot produce ethanol from pyruvate • Muscle lactate dehydrogenase converts pyruvate to lactate • This reaction regenerates NAD+ for use by glyceraldehyde 3-phosphate dehydrogenase in glycolysis • Lactate formed in skeletal muscles during exercise is transported to the liver • Liver lactate dehydrogenase can reconvert lactate to pyruvate • Lactic acidosis can result from insufficient oxygen (an increase in lactic acid and decrease in blood pH)

  24. Glucose + 2 Pi2- + 2 ADP3- 2 Lactate- + 2 ATP4- + 2 H2O Reduction of pyruvate to lactate

  25. Metabolically Irreversible Steps of Glycolysis • Enzymes not reversible: Reaction 1 - hexokinase Reaction 3 - phosphofructokinase Reaction 10 - pyruvate kinase • These steps are metabolicallyirreversible, and these enzymes are regulated • All other steps of glycolysis are near equilibrium in cells and not regulated

  26. Regulation of Glycolysis • 1. When ATP is needed, glycolysis is activated • Inhibition of phosphofructokinase-1 is relieved. • Pyruvate kinase is activated. • 2. When ATP levels are sufficient, glycolysis activity decreases • Phosphofructokinase-1 is inhibited. • Hexokinase is inhibited.

  27. Glucose transportinto the cell Fig 11.13

  28. Fig 11.14 Regulation of glucose transport • Glucose uptake into skeletal and heart muscle and adipocytes by GLUT 4 is stimulatedbyinsulin

  29. Regulation of Hexokinase • Hexokinase reaction is metabolically irreversible • Glucose 6-phosphate (product) levels increase when glycolysis is inhibited at sites further along in the pathway • Glucose 6-phosphate inhibits hexokinase.

  30. Regulation of Phosphofructokinase-1 (PFK-1) • ATP is a substrate and an allostericinhibitor of PFK-1 • High concentrations of ADP and AMP allosterically activate PFK-1 by relieving the ATP inhibition. • Elevated levels of citrate (indicate ample substrates for citric acid cycle) also inhibit Phospofructokinase-1

  31. Regulation of PFK-1 by Fructose 2,6-bisphosphate (F2,6BP) • Fructose 2,6-bisphosphate is formed from Fructose 6-phosphate by the enzyme phosphofructokinase-2 (PFK-2) • Fig 11.17 Fructose 2,6-bisphosphate

  32. Formation and hydrolysis of Fructose 2,6-bisphosphate Chapter 11

  33. Fig. 11.18 • Effect of glucagon on liver glycolysis Chapter 11

  34. Regulation of Pyruvate Kinase (PK) • Pyruvate Kinase is allosterically activated by Fructose 1,6-bisphosphate, and inhibited by ATP • The hormone glucagon stimulates protein kinase A, which phosphorylates Pyruvate Kinase, converting it to a lessactive form. Chapter 11

  35. Other Sugars Can Enter Glycolysis • Glucose is the mainmetabolicfuel in most organisms • Other sugars convert to glycolytic intermediates • Fructose and sucrose (contains fructose) are major sweeteners in many foods and beverages • Galactose from milk lactose (a disaccharide) • Mannose from dietary polysaccharides, glycoproteins Chapter 11

  36. Fructose Is Converted to Glyceraldehyde 3-Phosphate

  37. Galactose is Converted to Glucose 1-Phosphate Fig 11.22

  38. Mannose is Converted to Fructose 6-Phosphate

  39. Formation of 2,3-Bisphosphoglycerate in Red Blood Cells • 2,3-Bisphosphoglycerate (2,3BPG) allosterically regulates hemoglobin oxygenation (red blood cells) • Erythrocytes contain bisphosphoglycerate mutase which forms 2,3BPG from 1,3BPG • In red blood cells about 20% of the glycolytic flux is diverted for the production of the important oxygen regulator 2,3BPG Chapter 11

  40. Fig 11.24 • Formation of 2,3BPG in red blood cells

  41. Feedback inhibition • Product of a pathway controls the rate of its own synthesis by inhibiting an enzyme catalyzing an early step Feed-forward activation • Metabolite early in the pathway activates an enzyme further down the pathway Chapter 11

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