GlycolysisGluconeogenesis. Glycolysis - Overview One of best characterized pathways Characterized in the first half of 20th century Glucose --> 2 pyruvates

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  • Slide 1
  • GlycolysisGluconeogenesis
  • Slide 2
  • Glycolysis - Overview One of best characterized pathways Characterized in the first half of 20th century Glucose --> 2 pyruvates + energy Strategy add phosphoryl groups to glucose convert phosphorylated intermediates into compounds with high phosphate group-transfer potentials couple the subsequent hydrolysis of reactive substances to ATP synthesis Glucose + 2NAD + + 2 ADP + 2P i --> 2NADH + 2 pyruvates + 2ATP + 2H 2 O + 4H +
  • Slide 3
  • Overview of Glycolysis The Embden-Meyerhof (Warburg) Pathway Essentially all cells carry out glycolysis Ten reactions - similar in most cells - but rates differ Two phases: First phase converts glucose to two G-3-P Second phase produces two pyruvates Products are pyruvate, ATP and NADH NADH must be recycled Three possible fates for pyruvate
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  • Glycolysis
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  • Fate of pyruvate Decarboxylation to acetaldehyde Reduction to ethanol Reduction to lactate Mitochondrial oxidation 1 NADH --> ~3 ATP
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  • Enzymes of glycolysis Catalyzed reactions and properties
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  • Glucose Glucose-6-phosphate Fructose-6- phosphate Fructose-1,6- biphosphate Glyceraldehyde-3- phosphate Hexokinase, glucokinase Phosphoglucoisomerase Phosphofructokinase Aldolase Triose phosphate isomerase Dihydroxyacetone phosphate
  • Slide 10
  • First Phase of Glycolysis The first reaction - phosphorylation of glucose Hexokinase or glucokinase This is a priming reaction - ATP is consumed here in order to get more later ATP makes the phosphorylation of glucose spontaneous
  • Slide 11
  • Hexokinase 1st step in glycolysis; G large, negative Hexokinase (and glucokinase) act to phosphorylate glucose and keep it in the cell K m for glucose is 0.1 mM; cell has 4 mM glucose So hexokinase is normally active! Glucokinase (K m glucose = 10 mM) only turns on when cell is rich in glucose Hexokinase is regulated - allosterically inhibited by (product) glucose-6-P -
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  • Hexokinase First step in glycolysis Large negative deltaG Hexokinase is regulated - allosterically inhibited by (product) glucose-6-P Corresponding reverse reaction (Gluconeogenesis) is catalyzed by a different enzyme (glucose-6- phosphatase) Is it the committed step in glycolysis ?
  • Slide 14
  • Glucose Fructose-6-P Glucose-6-P Glyceraldehyde-3-P Pyruvate ATP GlycogenRibose-5-P + NADPH Nucleic acid synthesis Reducing power Glucose-6-P dehydrogenase
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  • Rx 2: Phosphoglucoisomerase Glucose-6-P to Fructose-6-P
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  • Rx 3: Phosphofructokinase PFK is the committed step in glycolysis! The second priming reaction of glycolysis Committed step and large, neg delta G - means PFK is highly regulated ATP inhibits, AMP reverses inhibition Citrate is also an allosteric inhibitor Fructose-2,6-bisphosphate is allosteric activator PFK increases activity when energy status is low PFK decreases activity when energy status is high
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  • Glycolysis - Second Phase Metabolic energy produces 4 ATP Net ATP yield for glycolysis is two ATP Second phase involves two very high energy phosphate intermediates. 1,3 BPG Phosphoenolpyruvate
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  • Glyceraldehyde-3- phosphate 1,3-biphosphoglycerate 3-phosphoglycerate 2-phosphoglycerate phosphoenolpyruvate pyruvate Glyceraldehyde-3-phosphate dehydrogenase Phosphoglycerate kinase Phosphoglycerate mutase Enolase Pyruvate kinase
  • Slide 22
  • Rx 10: Pyruvate Kinase PEP to Pyruvate makes ATP These two ATP (from one glucose) can be viewed as the "payoff" of glycolysis Large, negative G - regulation! Allosterically activated by AMP, F-1,6-bisP Allosterically inhibited by ATP and acetyl- CoA
  • Slide 23
  • The Fate of NADH and Pyruvate Aerobic or anaerobic?? NADH is energy - two possible fates: If O 2 is available, NADH is re-oxidized in the electron transport pathway, making ATP in oxidative phosphorylation In anaerobic conditions, NADH is re-oxidized by lactate dehydrogenase (LDH), providing additional NAD + for more glycolysis
  • Slide 24
  • The Fate of NADH and Py Aerobic or anaerobic?? Pyruvate is also energy - two possible fates: aerobic: citric acid cycle anaerobic: LDH makes lactate
  • Slide 25
  • The elegant evidence of regulation! Standard state G values are scattered: + and - G in cells is revealing: Most values near zero 3 of 10 reactions have large, negative G Large negative G reactions are sites of regulation! Energetics of Glycolysis
  • Slide 26
  • Gluconeogenesis Synthesis of "new glucose" from common metabolites Humans consume 160 g of glucose per day 75% of that is in the brain Body fluids contain only 20 g of glucose Glycogen stores yield 180-200 g of glucose So the body must be able to make its own glucose
  • Slide 27
  • Comparison of glycolysis and gluconeogenesis pathways
  • Slide 28
  • Substrates for Gluconeogenesis Pyruvate, lactate, glycerol, amino acids and all TCA intermediates can be utilized Fatty acids cannot! Most fatty acids yield only acetyl-CoA Acetyl-CoA (through TCA cycle) cannot provide for net synthesis of sugars
  • Slide 29
  • Gluconeogenesis I Occurs mainly in liver and kidneys Not the mere reversal of glycolysis for 2 reasons: Energetics must change to make gluconeogenesis favorable (delta G of glycolysis = -74 kJ/mol Reciprocal regulation must turn one on and the other off - this requires something new!
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  • Energetics of Glycolysis The elegant evidence of regulation! G in cells is revealing: Most values near zero 3 of 10 reactions have large, negative G Large negative G reactions are sites of regulation! Reactions 1, 3 and 10 should be different to go into opposite direction
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  • Gluconeogenesis II Something Borrowed, Something New Seven steps of glycolysis are retained: Steps 2 and 4-9 Three steps are replaced: Steps 1, 3, and 10 (the regulated steps!) The new reactions provide for a spontaneous pathway ( G negative in the direction of sugar synthesis), and they provide new mechanisms of regulation

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