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Chapt. 22 Glycolysis Glycolysis overview 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 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 Fig. 1* cycle, complete oxidation • NADH from cytoplasm into mitochondria to ETC (waste some) • Complete oxidation total 30-32 ATP • Explain lactic acidemia and causes Anaerobic glycolysis Glycolysis phases In absence of oxygen, anaerobic glycolysis: Glycolysis phases: • Recycles NADH to permit glycolysis continue • Preparation: • Glucose phosphorylated • Cleaved to 2 triose phosphates • Costs 2 ATP • Reduces pyruvate to lactate • Only 2 ATP per glucose • May cause lactic acidemia Fig. 2 • ATP-generating phase: • Triose phosphates oxidized more • Produces 2 NADH • Produces 4 ATP Fig. 3 1 Glycolysis step 1 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) 1. Glucose is phosphorylated by Hexokinase with ATP: • Commitment step • G6-P not cross plasma membrane Fig. 4 • Irreversible • Many pathway choices • Glycogen synthesis needs G1-P • Many tissue-specific isozymes of hexokinases Key enzymes: • Hexokinase • PFK-1 • • Commits to glycolysis Regulated step Fig. 5 top Glycolysis phase II **Alternatie fates of pyruvate Oxidation, substrate level phosphorylation yield 2 NADH, 4 ATP from 1 Glyceraldehyde 3-P Fate of pyruvate depends on availability of oxygen: Key enzymes: Glyceraldehyde 3-P dehydrogenase • High-energy bond • 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+ Pyruvate kinase: • Regulated step Fig. 5 lower Fig. 6* 2 Aerobic: Glycerol 3-P shuttle carries NADH Anaerobic: Aerobic: Glycerol 3-P shuttle carries e- from NADH into mitochondrion; regenerates cytosol NAD+ Anaerobic glycolysis: NADH reduces pyruvate to lactate, regenerates NAD+ to continue glycolysis • Glycerol 3-P diffuses across outer memberane, donates eto inner membrane FAD enzyme 1 glucose + 2 ADP + 2 Pi -> 2 lactate + 2 ATP + 2 H2O + 2 H+ • Loses some energy • FAD(2H) not NADH • Red blood cell, muscle, eye, other tissues • To maintain cell: • Run faster • More enzymes • Use lot glucose Bacteria not need shuttle since only 1 compartment • Lactate and H+ transported to blood; can have lactic acidosis Fig. 9 Fig. Fig. 5 top7 Fate of lactate II. Other functions of glycolysis Fate of lactate: • Used to make glucose (liver) – Cori cycle • Reoxidized to pyruvate (liver, heart, skeletal muscle) Glycolysis generates precursors for other paths: • • • • 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 • 5-C sugars for NTPs • Amino acids • Fatty acids, glycerol • Liver is major site of biosynthesis Fig. 11 3 III. Glycolysis is regulated Levels of ATP, ADP, AMP Levels of AMP in cytosol good indicator of rate ATP utilization Glycolysis is regulated by need for ATP: • Hexokinase • • • 2 ADP <-> AMP + ATP reaction of adenylate kinase Tissue specific isoforms Inhibited by G-6-P Except for liver • Hydrolysis ATP -> ADP increases ADP, AMP • PFK-1 • Pyruvate kinase • Pyruvate dehydrogenase • (PDH or PDC) Fig. 13 • ATP present highest conc: • Small dec ATP -> large AMP Fig. 12 Regulation of PFK-1 Regulation of glycolysis enzymes Regulation of PFK-1: • Rate-limiting step, tetramer • 6 binding sites: • • Regulation of pyruvate kinase: 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 • 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 PO4 to inactivate • Rate of ATP utilization • NADH/NAD+ ratio Fig. 12 4 Lactic Acidemia Lactic acidosis: Key concepts Fig. 15 • 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+ • Excess lactic acid in blood > 5mM • pH < 7.2 • From increased NADH/NAD+ Many causes -> • Excess alcohol • Hypoxia • • Key enzymes of glycolysis are regulated: hexokinase, PFK-1, pyruvate kinase, PDH C Review question Which of the following statements correctly describes an aspect of glycolysis? a. ATP is formed by oxidative phosphorylation b. Two molecules of ATP are used in the beginning of the pathway 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 c. Pyruvate kinase is the rate-limiting enzyme d. One molecule of pyruvate and 3 olecules of CO2 are formed from the oxidation of 1 glucose e. The reactions take place in the matrix of the mitochondria Fig. 17 5