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Refer to chapter 16, Stryer, 5e & chapter 14, Lehninger, 4e

The biosynthesis of cell constituents IV: glycolysis & fermentation. Objectives Maintaining the redox balance: diverse fates of pyruvate. Ethanol and lactate fermentation. Tight regulation of the glycolytic pathway. Glycolysis and cancer. Refer to chapter 16, Stryer, 5e &

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Refer to chapter 16, Stryer, 5e & chapter 14, Lehninger, 4e

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  1. The biosynthesis of cell constituents IV: glycolysis & fermentation • Objectives • Maintaining the redox balance: diverse fates of pyruvate. • Ethanol and lactate fermentation. • Tight regulation of the glycolytic pathway. • Glycolysis and cancer. Refer to chapter 16, Stryer, 5e & chapter 14, Lehninger, 4e Lecture 19, Michael Schweizer

  2. Diverse fates of pyruvate

  3. Location of redox balance steps: generation and consumption of NADH within the glycolytic pathway.

  4. Fermentation DG0’= -25.1 kJ mol-1 Anaerobes lack a respiratory chain for reoxidizing NADH. They must reoxidize NADH.NAD+ is needed for Glyceraldehyde-3-P Dehydrogenase of glycolysis. Skeletal muscles function anaerobically in exercise, when aerobic metabolism cannot keep up with energy needs. Pyruvate is converted to lactate, regenerating NAD+ needed for glycolysis, the main source of ATP under anaerobic conditions.

  5. Athletes, alligators and coelacanths: glycolysis at limiting concentrations of O2.

  6. Fermentation Some anaerobic organisms metabolize pyruvate to ethanol, which is excreted as a waste product. The above pathway regenerates NAD+, needed for continuation of glycolysis.

  7. Thiamine pyrophosphate (TPP) is the coenzyme of vitamin B1 (thiamine). The reactive carbon atom in the thiazolium ring is shown in red. In the reaction catalyzed by pyruvate decarboxylase are carried transiently on TPP in the form of an active ‘acetaldehyde’ group which is subsequently released as acetaldehyde

  8. Active site of alcohol dehydrogenase.

  9. Scanning electron micrograph of Lactobacillus. This genus of bacteria ferments glucose into lactic acid and is widely used in the food industry. Lactobacillus is also a component of the human bacterial flora of the urogenetical tract where, because of its acidic environment, it prevents growth of harmful bacteria.

  10. Industrial scale fermentation

  11. Regulation of Glycolysis Three glycolytic enzymes catalyze spontaneous reactions: Hexokinase, Phosphofructokinase, Pyruvate Kinase. Control of these enzymes determines the rate of the glycolytic pathway.

  12. Regulation of the glycolytic pathway HexokinaseI is controlled by the concentration of the inhibitory reaction product glucose-6-phosphate. Cells trap glucose by phosphorylating it, preventing exit on glucose carriers. Product inhibition of Hexokinase I ensures that cells will not continue to accumulate glucose from the blood, if [glucose-6-phosphate] within the cell is ample. Glucokinase, a variant of Hexokinase I (hexokinase IV) found in liver, has a high Km for glucose. It is active only at high [glucose]. Glucokinase is not subject to product inhibition by glucose-6-phosphate. Liver will take up & phosphorylate glucose even when liver [glucose-6-phosphate] is high.

  13. Control of Phosphofructokinase Phosphofructokinase is usually the rate-limiting step of the glycolysis pathway. Phosphofructokinase catalyzes: fructose-6-P + ATP  fructose-1,6-bisP + ADP. Phosphofructokinase is allosterically inhibited byATP. • At low concentration, ATP binds only at the active site. • At high concentration, ATP binds also at a low-affinity regulatory site, promoting the tense conformation.

  14. The tense conformation of PFK, at high [ATP], has lower affinity for the other substrate, fructose-6-P. Sigmoidal dependence of reaction rate on [fructose-6-P] is seen. AMP, present at significant levels only when there is extensive ATP hydrolysis, antagonizes effects of high ATP. ADP + ADP ATP +AMP

  15. Regulators affecting PFK-1 activity.

  16. Structure of phosphofructokinase in the liver (a tetramer of four identical subunits).

  17. Regulation of pyruvate kinase.

  18. Inhibition of the Glycolysis enzyme Phosphofructokinase when [ATP] is high prevents breakdown of glucose in a pathway whose main role is to make ATP. It is more useful to the cell to store glucose as glycogen when ATP is plentiful.

  19. Alternative fates of glycolytic intermediates in biosynthethic pathways.

  20. Many adults are intolerant of milk because they are deficient in lactase.

  21. Alteration in gene expression in tumours due to hypoxia.

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