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Chapt. 22 Glycolysis

Chapt. 22 Glycolysis. Ch. 22 Glycolysis Student Learning Outcomes : Explain how glucose is universal fuel, oxidized in every tissue to form ATP Describe the major steps of glycolysis Explain decision point for pyruvate utilization depending on oxygen Describe major enzymes regulated

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Chapt. 22 Glycolysis

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  1. Chapt. 22 Glycolysis • Ch. 22 Glycolysis • Student Learning Outcomes: • Explain how glucose is universal fuel, oxidized in every tissue to form ATP • Describe the major steps of glycolysis • Explain decision point for pyruvate utilization depending on oxygen • Describe major enzymes regulated • Explain lactic acidemia and causes

  2. Glycolysis overview • Overview of Glycolysis, TCA cycle, electron transport chain: • Starts 1 glucose phosphorylated • 2 ATP to start process • Oxidation to 2 pyruvates • yields 2 NADH, 4 ATP • Aerobic conditions: pyruvate to TCA cycle, complete oxidation • NADH from cytoplasm into mitochondria • to ETC (waste some) • Complete oxidation total 30-32 ATP Fig. 1*

  3. Anaerobic glycolysis • In absence of oxygen, anaerobic glycolysis: • Recycles NADH to permit glycolysis continue • Reduces pyruvate to lactate • Only 2 ATP per glucose • May cause lactic acidemia Fig. 2

  4. Glycolysis phases • Glycolysis phases: • Preparation: • Glucose phosphorylated • Cleaved to 2 triose phosphates • Costs 2 ATP • ATP-generating phase: • Triose phosphates oxidized more • Produces 2 NADH • Produces 4 ATP Fig. 3

  5. Glycolysis step 1 • 1. Glucose is phosphorylated by Hexokinase with ATP: • Commitment step • G6-P not cross plasma membrane • Irreversible • Many pathway choices • Glycogen synthesis needs G1-P • Many tissue-specific isozymes of hexokinases Fig. 4

  6. Glycolysis phase I • 2 ATP convert Glucose to Fructose 1,6 bis-P; • Fructose 1,6-bis-P split to 2 trioses • Glyceraldehyde 3-P (and DHAP isomerized) • Key enzymes: • Hexokinase • PFK-1 • Commits to glycolysis • Regulated step Fig. 5 top

  7. Glycolysis phase II • Oxidation, substrate level phosphorylation yield • 2 NADH, 4 ATP from 1 Glyceraldehyde 3-P • Key enzymes: • Glyceraldehyde 3-P dehydrogenase • High-energy bond • Pyruvate kinase: • Regulated step Fig. 5 lower

  8. **Alternatie fates of pyruvate • Fate of pyruvate depends on availability of oxygen: • Much more ATP from complete oxidation of glucose • Aerobic: shuttles carry NADH into mitochondria; pyruvate can be oxidized to Acetyl CoA and enter TCA • Anaerobic: pyruvate reduced by NADH to lactate, NAD+, H+ Fig. 6*

  9. Aerobic: Glycerol 3-P shuttle carries NADH • Aerobic: Glycerol 3-P shuttle carries e- from NADH into mitochondrion; regenerates cytosol NAD+ • Glycerol 3-P diffuses across • outer memberane, donates e- • to inner membrane FAD enzyme • Loses some energy • FAD(2H) not NADH Bacteria not need shuttle since only 1 compartment Fig. 5 top Fig. 7

  10. Anaerobic: • Anaerobic glycolysis: NADH reduces pyruvate to lactate, regenerates NAD+ to continue glycolysis • 1 glucose + 2 ADP + 2 Pi -> 2 lactate + 2 ATP + 2 H2O + 2 H+ • Lactate and H+ transported to blood; can have lactic acidosis • Red blood cell, muscle, eye, other tissues • To maintain cell: • Run faster • More enzymes • Use lot glucose Fig. 9

  11. Fate of lactate • Fate of lactate: • Used to make glucose (liver) – Cori cycle • Reoxidized to pyruvate (liver, heart, skeletal muscle) • lactate + NAD+ -> pyruvate + NADH • Lactate dehydrogenase (LDH) favors lactate, but if NADH used in ETC (or gluconeogenesis), then other direction • Heart can use lactate -> pyruvate for energy • Isoforms of LDH: M4 muscle; H4 heart; mixed others) Fig. 10

  12. II. Other functions of glycolysis • Glycolysis generates precursors for other paths: • 5-C sugars for NTPs • Amino acids • Fatty acids, glycerol • Liver is major site of • biosynthesis Fig. 11

  13. III. Glycolysis is regulated • Glycolysis is regulated by need for ATP: • Hexokinase • Tissue specific isoforms • Inhibited by G-6-P • Except for liver • PFK-1 • Pyruvate kinase • Pyruvate dehydrogenase • (PDH or PDC) Fig. 12

  14. Levels of ATP, ADP, AMP • Levels of AMP in cytosol good indicator of rate ATP utilization • 2 ADP <-> AMP + ATP • reaction of adenylate kinase • Hydrolysis ATP -> ADP • increases ADP, AMP • ATP present highest conc: • Small dec ATP -> large AMP Fig. 13

  15. Regulation of PFK-1 • Regulation of PFK-1: • Rate-limiting step, tetramer • 6 binding sites: • 2 substrates: ATP, Fructose 6-P • 4 allosteric: inhibit ATP • Activate by AMP • Activate by fructose 2,6 bis-P (product when excess glucose in blood) Fig. 14

  16. Regulation of glycolysis enzymes • Regulation of pyruvate kinase: • R form (RBC), L (liver); M1/M2 muscle, others • Liver enz allosteric inhibition by compound in fasting; • also inhibited by PO4 from Protein Kinase A • Regulation of PDH (PDC): • By PO4to inactivate • Rate of ATP utilization • NADH/NAD+ ratio Fig. 12

  17. Lactic Acidemia Fig. 15 • Lactic acidosis: • Excess lactic acid in blood > 5mM • pH < 7.2 • From increased • NADH/NAD+ • Many causes -> • Excess alcohol • Hypoxia

  18. Key concepts • Glycolysis is universal pathway by which glucose is oxidized and cleaved to pyruvate • Enzymes are in cytosol • Generates 2 molecules of ATP (substrate-level phosphorylation) and 2 NADH • Pyruvate can enter mitochondria for complete oxidation to CO2 in TCA + electron transport chain • Anaerobic glycolysis reduces pyruvate to lactate, and recycles (wastes) NADH -> NAD+ • Key enzymes of glycolysis are regulated: hexokinase, PFK-1, pyruvate kinase, PDH C

  19. Review question • Which of the following statements correctly describes an aspect of glycolysis? • ATP is formed by oxidative phosphorylation • Two molecules of ATP are used in the beginning of the pathway • Pyruvatekinase is the rate-limiting enzyme • One molecule of pyruvate and 3 olecules of CO2 are formed from the oxidation of 1 glucose • The reactions take place in the matrix of the mitochondria

  20. Glyceraldehyde 3-P dehydrogenase • Glyceraldehyde 3-P dehydrogenase uses covalent linkage of substrate to S of cys to form ~P: • Covalent link to S of Cys; NAD+ nearby • Oxidation forms NADH + H+; ~S bond • NADH leaves, new NAD+ • Pi attacks thioester • Enzyme reforemd Fig. 17

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