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GLYCOLYSIS, GLUCONEOGENESIS, AND THE PENTOSE PHOSPHATE PATHWAY

GLYCOLYSIS, GLUCONEOGENESIS, AND THE PENTOSE PHOSPHATE PATHWAY. Lehninger Ch. 14 BIO 322 Recitation 1 / Spring 2013. OUTLINE. Glycolysis Fates of Pyruvate Regulation of Glycolysis (Chapter 15) Gluconeogenesis Pentose Phosphate Pathway. Fates of Glucose. Glycolysis.

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GLYCOLYSIS, GLUCONEOGENESIS, AND THE PENTOSE PHOSPHATE PATHWAY

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  1. GLYCOLYSIS, GLUCONEOGENESIS,AND THE PENTOSE PHOSPHATEPATHWAY Lehninger Ch. 14 BIO 322 Recitation 1 / Spring 2013

  2. OUTLINE • Glycolysis • Fates of Pyruvate • Regulation of Glycolysis (Chapter 15) • Gluconeogenesis • Pentose Phosphate Pathway

  3. Fates of Glucose

  4. Glycolysis • D-Glucose (6C) 2 molecules of Pyruvate (3C) • ATP, NADH conserve some released energy • In some mammalian tissues/cell types sole source of energy • Ten steps: 5 in preparatory phase & 5 in payoff phase

  5. First 5 steps – Prepatory Phase • 2 ATP invested , raising the free energy content of intermediates • Metobolized hexoses converted to common product G3P. One molecule of glucose yields to two molecules of G3P. • Last 5 steps – Payoff Phase • 4 ATP produced, Net yield 2 ATP • Energy Conserved via 2 NADH per glucose molecule. • Three types of chemical transformation: • Degradation of glucose carbon skeleton to yield pyruvate. • ADP into ATP • NAD+ - NADH ‘Lysis’ step Triose Phosphates Phosphorylation without ATP

  6. Fates of Pyruvate • Under STD conditions, glycolysis is irreversible, completed by a large net decrease in free energy • At cellular conditions, energy recovered as ATP with an efficiency of more than %60 • Most of the energy is still in pyruvate and can be extracted by oxidative reactions in • Citric Acid Cycle (Ch. 16) • Oxidative Phosphorylation (Ch. 19)

  7. STEP 1: Phosphorylation of Glucose • Glucose Phosphorylation at C-6 • Irreversible step • Hexokinase • Requires Mg (True Substrate Mg+ATP) • Mg shields negative charges of phosphoryl groups of ATP • Mg makes terminal phosphorus easier target for nucleophilic attack • Soluble, cytosolic Protein • Hepatocytes – an extra hexokinase called hexokinase IV or glucokinase – different from other hexokinase in kinetic and regulatory properties

  8. STEP 3: Phosphorylation of Fructose 6-Phosphate to Fructose 1,6-Bisphosphate • Irreversible under celluar conditions • Commited Step, since G6P and F6P has other fates, but F16BP is targeted for glycolysis. • Major regulatory point in glycolysis. • PFK-1 activity increased, when ATP is low or ADP and AMP are in excess • PFK-1 inhibited by ATP, activated by F26BP (product of PFK-2) – Next week in regulation

  9. STEP 10: Transfer of the Phosphoryl Group from Phosphoenolpyruvate to ADP • PEP + ADP –> Pyruvate + ATP • Pyruvate kinase • Mg, K, Mn • Substrate Level Phosphorylation • At pH 7, keto form dominates (non-enzymatic process) • Due to keto form, large negative standard free energy change (-31,4) – large driving force pushing reaction forward to ATP synthesis • PEP hydrolysis (-61.9), ATP formation (-30,5) • Irreversible and important site of regulation

  10. Glycogen phosphorylase (alpha 1-4) at non-reducing end until alpha 1-6 branch point. (debranching enzyme) • Starch by alpha-amylase (mouth), by pancreatic alpha amylase – maltose (1,4), dextrin (1,6)

  11. Fermentation • Lactic Acid Fermentation • Hypoxic conditions; • NADH generated by glycolysis cannot be reoxidixed by oxygen • Glycolysis would stop due to lack NAD+  no electron acceptor for the oxidation of G3P. • Regeneration required in an other way. • NAD+ regenerated from NADH by reduction of pyruvate to lactate via lactate dehydrogenase. (Exergonic) • No net change in NAD+ or NADH (erythrocytes-no mitochondria- produce lactate even under aerobic conditions) • Lactate from muscle or erythrocytes to blood, targeted to liver, converted back to glucose – back to muscle (Cori cycle)

  12. Ethanol Fermentation • Pyruvate carboxylase (Mg, Thiamine pyrophosphate (coenzyme)) • Irreversible • Present in brewers`and baker`s yeast • Carbon dioxide • Absent in vertebrate tissues and in organisms that carry lactic acid fermentation. • 2. Alcohol dehydrogenase (Zn) • -is present in many organisms that metabolize ethanol, including humans. • -human liver, oxidation of ethanol with reduction in NAD+/NADH ratio • TPP : Derived from vitamin B1 • Deficiency  beriberi Cleavage of bonds adjacent to carbonyl group.

  13. Gluconeogenesis • Brain – 120 g of glucose, more than half of the glucose stored as glycogen in muscle and liver. • Source: Lactate, pyruvate, glycerol, certain AA (3C) • In mammals - takes place in the liver and renal cortex • 7/10 identical rxns to glycolysis • Hexokinase, PFK-1 and Pyruvate Kinase • All have large negative free energy change • Irreversible • Whereas others have free energy change near to zero. • In gluconeogenesis 3 separate set of enyzmes catalyze exergonic reactions.  Both irreversible processes.

  14. Bypass of Irreversible Steps • Conversion of Pyruvate to PEP • Pyruvate Carboxylase: • Pyruvate to oxaloacetate by pyruvate carboxylase (mitoch enzyme, coenzyme biotin -carries HCO3-) • First regulatory enzyme, requires Acetyl-CoA as positive regulator (accumulation is a sign of FA availability as fuel) • No mitoch transporter for oxaloacetate, malate dehydrogenase reduces it to malate for export to cytosol. (malate leaves mitoch via specific transporter, back to oxaloacetate in cytosol) • PEP Carboxykinase: • Oxaloacetate to PEP by PEP carboxykinase (Mg dependent, GTP as the phophoryl donor) • Pyruvate  cytosol to mitochondria for conversion •  Or can be generated from alanine within mitochondria by transamination • Overall actual free energy change -25 kj/mol due to high PEP consumption in other rxns  The reaction must be effectively irreversible.

  15. Produced and consumed NADH in balance • Lactate as glucogenic precursor • Lactate to pyruvate in cytosol by lactate dehydrogenase • Pyruvate to oxaloacetate by pyruvate carboxylase • Mitochondrial isozyme of PEP carboxykinase • PEP transported out.

  16. Pentose Phosphate Pathway of Glucose Oxidation • G6P into pentose phosphates • Oxidative pathway • NADP elecctron acceptor  NADPH • Rapidly dividing cells such as bone marrow, skin, intestinal mucosa use pentoses to make RNA, DNA, ATP, NADH, FADH2, CoA • Other tissues – product is just NADPH • Needed for reductive biosynthesis • To prevent oxidative damage by maintaining high NADPH/NADP+ • Glucose 6-Phosphate dehydrogenrase oxidizes glucose 6-phosphate • 6-phosphogluconate oxidized and decarboxylated • NADP+ electron acceptor

  17. Nonoxidative Pathway • In tissues require primarly NADPH, the pentose phophates produced in oxidative phase are recyled into G6P.

  18. Glucose 6-phosphate Glycolysis PPP • High [NADP+]  PPP • Low [NADP+]  Glycolysis

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