Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Fig 10.5 • Overview of catabolic pathways Prentice Hall c2002 Chapter 11 1 Fig 11.1 • Catabolism of glucose via glycolysis and the citric acid cycle NADH NADH, FADH2 Prentice Hall c2002 Chapter 11 2 Net reaction of glycolysis Converts: 1 glucose 2 pyruvate + • 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 Prentice Hall c2002 Chapter 11 3 Glycolysis can be divided into two stages • Hexose stage: 2 ATP are consumed per glucose • Triose stage: 4 ATP are produced per glucose Net: 2 ATP produced per glucose x2 Prentice Hall c2002 Chapter 11 4 Table 11.1 Prentice Hall c2002 Chapter 11 5 Fig 11.2 1 Transfer of a phosphoryl group from ATP to glucose enzyme: hexokinase 2 Isomerization of glucose 6-phosphate to fructose 6-phosphate enzyme: glucose 6-phosphate isomerase Prentice Hall c2002 Chapter 11 6 3 Transfer of a second phosphoryl group from ATP to fructose 6-phosphate enzyme: phosphofructokinase-1 4 Carbon 3 – Carbon 4 bond cleavage, yielding two triose phosphates enzyme: aldolase Prentice Hall c2002 Chapter 11 7 Prentice Hall c2002 Chapter 11 8 Prentice Hall c2002 Chapter 11 9 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- Prentice Hall c2002 Chapter 11 10 Fig 11.3 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 Prentice Hall c2002 Fig 11.4 Chapter 11 11 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 regulatory point for glycolysis in most cells (PFK-1 is the first committed step of glycolysis) Prentice Hall c2002 Chapter 11 12 4. Aldolase • Aldolase cleaves the hexose fructose 1,6-bisphosphate into two triose phosphates: glyceraldehyde 3phosphate and dihydroxyacetone phosphate Prentice Hall c2002 Chapter 11 13 5. Triose Phosphate Isomerase • Conversion of dihydroxyacetone phosphate into glyceraldehyde 3-phosphate Prentice Hall c2002 Chapter 11 14 Fig 11.6 Fate of carbon atoms from hexose stage to triose stage Prentice Hall c2002 Chapter 11 15 6. Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) • Conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate (1,3BPG) • Molecule of NAD+ is reduced to NADH Prentice Hall c2002 Chapter 11 16 Fig 11.7 • Mechanism of Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) Prentice Hall c2002 Chapter 11 17 Fig 11.7 (continued) (3) (2) Prentice Hall c2002 Chapter 11 18 Fig 11.7 (continued) Prentice Hall c2002 Chapter 11 19 Box 11.2 Arsenate (AsO43-) poisoning • Arsenate can replace Pi as a substrate for glyceraldehyde 3-phosphate dehydrogenase • Arseno analog which forms is unstable Prentice Hall c2002 Chapter 11 20 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 Prentice Hall c2002 Chapter 11 21 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 Prentice Hall c2002 Chapter 11 22 9. Enolase: 2-phosphoglycerate to phosphoenolpyruvate (PEP) • Elimination of water (dehydration) yields PEP • PEP has a very high phosphoryl group transfer potential because it exists in its unstable enol form Prentice Hall c2002 Chapter 11 23 10. Pyruvate Kinase • Metabolically irreversible reaction Prentice Hall c2002 Chapter 11 24 Fates of pyruvate • For centuries, bakeries and breweries have exploited the conversion of glucose to ethanol and CO2 by glycolysis in yeast Prentice Hall c2002 Chapter 11 25 Metabolism of Pyruvate 1. Aerobic conditions: pyruvate is oxidized to acetyl CoA, which enters the citric acid cycle for further oxidation 2. Anaerobic conditions (microorganisms): pyruvate is converted to ethanol 3. Anaerobic conditions (muscles, red blood cells): pyruvate is converted to lactate Prentice Hall c2002 Chapter 11 26 Fig 11.10 • Three major fates of pyruvate Prentice Hall c2002 Chapter 11 27 Fig 11.11 • Two enzymes required: (1) Pyruvate decarboxylase (2) Alcohol dehydrogenase • Anaerobic conversion of pyruvate to ethanol (yeast - anaerobic) Prentice Hall c2002 Chapter 11 28 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 3phosphate 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) Prentice Hall c2002 Chapter 11 29 Reduction of pyruvate to lactate Glucose + 2 Pi2- + 2 ADP3- 2 Lactate- + 2 ATP4- + 2 H2O Prentice Hall c2002 Chapter 11 30 Metabolically Irreversible Steps of Glycolysis • Enzymes not reversible: Reaction 1 - hexokinase Reaction 3 - phosphofructokinase Reaction 10 - pyruvate kinase • These steps are metabolically irreversible, and these enzymes are regulated • All other steps of glycolysis are near equilibrium in cells and not regulated Prentice Hall c2002 Chapter 11 31 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. Prentice Hall c2002 Chapter 11 32 Glucose transport into the cell Fig 11.13 Prentice Hall c2002 Chapter 11 33 Fig 11.14 Regulation of glucose transport • Glucose uptake into skeletal and heart muscle and adipocytes by GLUT 4 is stimulated by insulin Prentice Hall c2002 Chapter 11 34 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. Prentice Hall c2002 Chapter 11 35 Regulation of Phosphofructokinase-1 (PFK-1) • ATP is a substrate and an allosteric inhibitor 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 Prentice Hall c2002 Chapter 11 36 Fig 11.16 Regulation of Phosphofructokinase-1 by ATP and AMP • AMP relieves ATP inhibition of PFK-1 Prentice Hall c2002 Chapter 11 37 Regulation of PFK-1 by Fructose 2,6bisphosphate (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 Prentice Hall c2002 Chapter 11 38 Formation and hydrolysis of Fructose 2,6-bisphosphate Prentice Hall c2002 Chapter 11 39 Fig. 11.18 • Effect of glucagon on liver glycolysis Prentice Hall c2002 Chapter 11 40 Regulation of Pyruvate Kinase (PK) • Pyruvate Kinase is allosterically activated by Fructose 1,6bisphosphate, and inhibited by ATP • The hormone glucagon stimulates protein kinase A, which phosphorylates Pyruvate Kinase, converting it to a less active form. Prentice Hall c2002 Chapter 11 41 Other Sugars Can Enter Glycolysis • Glucose is the main metabolic fuel 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 Prentice Hall c2002 Chapter 11 42 Fructose Is Converted to Glyceraldehyde 3-Phosphate Fig 11.21 Prentice Hall c2002 Chapter 11 43 Galactose is Converted to Glucose 1-Phosphate Prentice Hall c2002 Fig 11.22 Chapter 11 44 Mannose is Converted to Fructose 6-Phosphate Prentice Hall c2002 Chapter 11 45 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 Prentice Hall c2002 Chapter 11 46 Fig 11.24 • Formation of 2,3BPG in red blood cells Prentice Hall c2002 Chapter 11 47 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 Prentice Hall c2002 Chapter 11 48