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FERMENTATION: Anaerobic Glycolysis

This article covers anaerobic glycolysis, homolactic fermentation, alcoholic fermentation, and the Krebs Cycle. Learn about the regulation and synthesis of Acetyl CoA, the Pyruvate Dehydrogenase Complex, and metabolic fate of pyruvate. Explore how cancer cells and other sugars like lactose and fructose interact with these pathways.

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FERMENTATION: Anaerobic Glycolysis

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  1. FERMENTATION: Anaerobic Glycolysis

  2. CATABOLIC FATES OF PYRUVATE

  3. HOMOLACTIC FERMENTATION • Utilized by muscles when the demand for ATP is high and oxygen availability is low. • ATP is rapidly regenerated compared to oxidative phosphorylation. • The reaction is freely reversible

  4. HOMOLACTIC FERMENTATION • Net reaction: Glucose + 2ADP+ 2Pi 2 lactate + 2ATP+ 2H2O+ 2H+ • Lactate formed can either exported from the cell or converted back to pyruvate • The lactate formed in muscles is carried by the blood to the liver, where it is converted to glucose

  5. CORI CYCLE

  6. ALCOHOLIC FERMENTATION • The NAD+ regenerated in this reaction will be utilized by GAPDH • TPP is an important cofactor of Pyruvatedecarboxylase

  7. ALCOHOLIC FERMENTATION

  8. GLYCOLYSIS AND CANCER • Utilization of glucose and glycolysis proceed faster in cancer cells • Because of hypoxia, cancer cells depend on anaerobic glycolysis for ATP production • Tumor cells also have smaller amount of mitochondria • Some tumor cells overproduce several glycolytic enzymes due to the presence of HIF-1 • HIF-1 acts at the level of mRNA synthesis to stimulate the production of at least 8 glycolytic enzymes

  9. Entry of other sugars: Lactose

  10. Entry of other sugars: Fructose

  11. SYNTHESIS OF ACETYL Co-A Pyruvatedehydrogenase complex is composed of 3 enzymes and requires 5 coenzymes

  12. PYRUVATE DEHYDROGENASE COMPLEX • E1: pyruvatedehydrogenase (30 heterodimers) • E2: dihydrolipoamidetransacetylase (20 trimers) • E3: dihydrolipoamidedehydrogenase (12 dimers) • ~10,000 kD

  13. PYRUVATE DEHYDROGENASE COMPLEX

  14. Thiamine = Vitamin B1 (ribo)Flavin = Vitamin B2 Niacin = Vitamin B3 Pantothenic Acid = Vitamin B5

  15. REGULATION OF THE COMPLEX • The eukaryotic complex contains two regulatory enzymes: a kinase that phosphorylates three serine residues in E1 and the phosphatase that removes those phosphates • The activity of the complex is controlled by allosteric inhibition and covalent modification that is in turn controlled by the energy state of the cell. • ATP is an allosteric inhibitor of the complex; AMP is an activator • E2 is inhibited by acetyl-CoA and activated by CoA-SH • E3 is inhibited by NADH and activated by NAD+

  16. REGULATION OF THE COMPLEX • Regulation also occurs by covalent modification of E1 (de/phosphorylation) • NADH and acetyl-CoA activate the pyruvatedehydrogenasekinase which phosphorylates the 3 specific serine residues in E1 rendering it inactive • Pyruvatedehydrogenasephosphatase removes the phosphate groups. This enzyme is activated by Ca2+ and Mg2+

  17. KREBS CYCLE • Aka tricarboxylic acid cycle and citric acid cycle • central oxidative pathway • Composed of 8 reactions that oxidizes acetyl CoA to 2 molecules of CO2 • Occurs in the mitochondrial matrix

  18. Citrate Synthase Reaction (First) • Claisencondensation • OAA must bind first before Acetyl-CoA (sequential mechanism) • -32.2kJ

  19. Aconitase Reaction • Forms isocitrate • Goes through alkene intermediate (cis-aconitate) • elimination then addition • 13.3kJ

  20. Isocitrate Dehydrogenase • All dehydrogenase reactions make NADH or FADH2 • Oxidative decarboxylation • -20.9kJ • Energy from increased entropy in gas formation

  21. α-ketoglutarate dehydrogenase • Same as pyruvate dehydrogenase reaction • Formation of thioester • endergonic • driven by loss of CO2 • increases entropy • exergonic • -33.5kJ

  22. Succinyl CoA synthetase • Hydrolysis of thioester • Releases CoASH • Exergonic • Coupled to synthesis of GTP • Endergonic • GTP very similar to ATP and interconverted later • -2.9kJ

  23. Succinate dehydrogenase • Dehydrogenation • Uses FAD • NAD used to oxidize oxygen-containing groups • Aldehydes • alcohols • FAD used to oxidize C-C bonds • 0kJ

  24. Fumarase • Addition of water to a double bond • -3.8kJ

  25. Malate Dehydrogenase • Oxidation of secondary alcohol to ketone • Makes NADH • Regenerates oxaloacetate for another round • 29.7 kJ

  26. REGULATION OF KREBS CYCLE • 3 rate determining enzymes: citrate synthase, isocitratedehydrogenase and alpha-ketoglutaratedehydrogenase • 3 mechanisms used by the enzymes: • Substrate availability (acetyl CoA and oxaloacetate) • Product inhibition (NADH) • Competitive feedback inhibition by intermediates (citrate and succinylCoA • ADP is an effector of isocitratedehydrogenase • Ca2+ activates pyruvatedehydrogenasephosphatase, isocitratedehydrogenase and alpha-ketoglutaratedehydrogenase

  27. Counting ATP’s: one molecule of glucose

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