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  1. GLYCOLYSIS Manoj Sigdel
  2. GLYCOLYSIS It is defined as a sequence of reactions converting glucose to pyruvate or lactate, with the production of ATP. Greek: glykys = sweet; lysis = splitting
  3. SALIENT FEATURES OF GLYCOLYSIS • takes place in all cells of the body • the enzymes of this pathway are present in cytosol of cells • in absence of oxygen -anaerobic glycolysis takes place , lactate is the end product. • in presence of oxygen -aerobic glycolysis, pyruvate is the end product. •it is also known as Embden-Meyerhof (e.m.) pathway. ( Gustav Embden; Otto Meyerhof; - elucided the whole pathway in muscle. )
  4. • glycolysis is the major pathway for ATP synthesis in tissues lacking mitochondria. • glycolysis is very essential for brain. • the intermediates of glycolysis is used in formation of non-essential amino acids and glycerol.
  5. • The sequence of reactions of glycolysis can be divided into three distinct phases 1) Energy investment phase or priming stage (reactions 1,2 and 3) 2) Splitting phase (reaction 4) 3) Energy generation phase
  6. Hexokinase Phosphofructokinase glucose Glycolysis ATP ADP glucose-6-phosphate Phosphoglucose Isomerase fructose-6-phosphate ATP ADP fructose-1,6-bisphosphate Aldolase glyceraldehyde-3-phosphate + dihydroxyacetone-phosphate Triosephosphate Isomerase Glycolysis continued Mg++ Mg++ Mg++ H O OH H OH H OH CH2OH H OH H H O OH H OH H OH CH2OPO3 2 H OH H 2 3 4 5 6 1 1 6 5 4 3 2 ATP ADP Mg2+ glucose glucose-6-phosphate Hexokinase H O OH H OH H OH CH2OPO3 2 H OH H 1 6 5 4 3 2 CH2OPO3 2 OH CH2OH H OH H H HO O 6 5 4 3 2 1 glucose-6-phosphate fructose-6-phosphate Phosphoglucose Isomerase
  7. Glyceraldehyde-3-phosphate Dehydrogenase Phosphoglycerate Kinase Enolase Pyruvate Kinase glyceraldehyde-3-phosphate NAD+ + Pi NADH + H+ 1,3-bisphosphoglycerate ADP ATP 3-phosphoglycerate Phosphoglycerate Mutase 2-phosphoglycerate H2O phosphoenolpyruvate ADP ATP pyruvate Mg++ Mg++ Mg++
  8. Phosphofructo kinase reaction is the rate-limiting step of glycolysis. This is an irreversible and regulatory step in glycolysis. PFK is an allosteric enzyme, the activity of which is controlled by several allosteric molecules. Phosphoglycerate kinase step is the good example of substrate level of phosphorylation since ATP is synthesized without ETC. It is reversible, a rare example of kinase reactions Enolase is inhibited by Fluoride
  9. ENERGY PRODUCTION AND UTILIZATION  2 ATP invested  4 ATP produced (2 from each of two 3C fragments from glucose)  Net production of 2 ~P bonds of ATP per glucose. Glycolysis - total pathway, glucose + 2 NAD+ + 2 ADP + 2 Pi  2 pyruvate + 2 NADH + 2 ATP In aerobic organisms:  pyruvate produced in Glycolysis is oxidized to CO2 via Krebs Cycle  NADH produced in Glycolysis & Krebs Cycle is reoxidized via the respiratory chain, with production of much additional ATP.
  10. Glycolysis, glucose + 2 NAD+ + 2 ADP + 2 Pi  2 pyruvate + 2 NADH + 2 ATP Fermentation, from glucose to lactate: glucose + 2 ADP + 2 Pi  2 lactate + 2 ATP Anaerobic catabolism of glucose yields only 2 “high energy” bonds of ATP.
  11. C C CH3 O O O C HC CH3 O OH O NADH + H+ NAD+ Lactate Dehydrogenase pyruvate lactate E.g., Lactate Dehydrogenase catalyzes reduction of the keto in pyruvate to a hydroxyl, yielding lactate, as NADH is oxidized to NAD+.
  12. REGULATION OF GLYCOLYSIS Glycolysis pathway is regulated by control of 3 enzymes : 1) Hexokinase 2) Phosphofructokinase 3) Pyruvate Kinase.
  13. 1) Hexokinase is inhibited by product glucose-6- phosphate:  by competition  by allosteric interaction  Has low KM (0.1mM)  Glucokinase ( a variant of Hexokinase) is found in liver. Glucokinase has a high KM (10mM) for glucose. It is active only at high [glucose].
  14. 2) Phosphofructokinase is usually the rate-limiting step of the glycolysis pathway. phosphofructokinase is allosterically inhibited by ATP, citrate, H+ it is allosteric activated by fructose 2,6 bisphosphate, AMP, Pi 3) Pyruvate Kinase, the last step Glycolysis Inhibited by ATP Activated by F1,6-BP
  15. Feeder Pathways for Glycolysis • Many carbohydrates besides glucose meet their catabolic fate in glycolysis, after being transformed into one of the glycolytic intermediates. • The most significant are the storage polysaccharides glycogen and starch; the disaccharides maltose, lactose, trehalose, and sucrose; and the monosaccharides fructose, mannose, and galactose
  16. Fig: Feeder pathways of glycolysis
  17. Glycogen and Starch Are Degraded by Phosphorolysis • Glycogen in animal tissues and in microorganisms (and starch in plants) can be mobilized for use within the same cell by a phosphorolytic reaction catalyzed by glycogen phosphorylase (starch phosphorylase in plants).
  18. Fructose • D-Fructose, present in free form in many fruits and formed by hydrolysis of sucrose in the small intestine of vertebrates, is phosphorylated by hexokinase • This is a major pathway of fructose entry into glycolysis in the muscles and kidney.
  19. • In the liver, however, fructose enters by a different pathway. The liver enzyme fructokinase catalyzes the phosphorylation of fructose at C-1 rather than C-6 • The fructose 1-phosphate is then cleaved to glyceraldehyde and dihydroxyacetone phosphate by fructose 1-phosphate aldolase
  20. Galactose • The conversion proceeds through a sugar- nucleotide derivative, UDPgalactose, which is formed when galactose 1-phosphate displaces glucose 1-phosphate from UDP- glucose. • UDP-galactose is then converted by UDP- glucose 4-epimerase to UDP-glucose, in a reaction that involves oxidation of C-4 (pink) by NAD, then reduction of C-4 by NADH; the result is inversion of the configuration at C-4. • The UDPglucose is recycled through another round of the same reaction. The net effect of this cycle is the conversion of galactose 1- phosphate to glucose 1-phosphate; there is no net production or consumption of UDP- galactose or UDP-glucose. Fig: Conversion of galactose to glucose 1-phosphate.
  21. Pasteur effect • The inhibition of glycolysis by oxygen (aerobic condition) is known as Pasteur effect. • Discovered by Louis Pasteur while studying fermentation in yeast. • He observed that when anaerobic yeast cultures were exposed to air, the utilization of glucose decreased by 7 fold. • The levels of glycolytic intermediates from fructose 1,6 bisphosphate onward decrease while the earlier intermediates accumulate • This is due to inhibition of Phosphofructokinase • The inhibitory effect of citrate and ATP on phosphofructokinase explains the Pasteur effect
  22. Crabtree effect • The phenomenon of inhibition of oxygen consumption by the addition of glucose to tissues having high aerobic glycolysis is known as Crabtree effect. • It is due to increased competition of glycolysis for inorganic phosphate (Pi) and NAD+ which limits their availability for phosphorylation and oxidation
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