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Prof. Roshada Hashim roshadahashim@gmail

Prof. Roshada Hashim roshadahashim@gmail.com. GLYCOLYSIS. General features of Glycolysis Anaerobic degradation of hexose sugar Conversion of a 6-carbon molecule (glucose, fructose) to a 3-carbon molecule ( dihydroxyacetone phosphate, glyceraldehyde 3-phosphate; pyruvate

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Prof. Roshada Hashim roshadahashim@gmail

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  1. Prof. Roshada Hashimroshadahashim@gmail.com

  2. GLYCOLYSIS

  3. General features of Glycolysis • Anaerobic degradation of hexose sugar • Conversion of a 6-carbon molecule (glucose, fructose) to a 3-carbon molecule ( dihydroxyacetone phosphate, glyceraldehyde 3-phosphate; pyruvate • One 6-carbon molecule will give two 3-carbon molecules • All the intermediates are phosphorylated; -vely charged at pH 7 • Pi bonded by either an ester or anhydride bond • 2 phases: activation phase and energy production phase www.lowcarbluxury.com/newsletter/lclnewsvol03...

  4. 10 steps in glycolysis • First 5 steps is the preparation or activation • of glucose • Uses 2 molecules of ATP • 6-carbon degraded to 2 3-carbon molecules

  5. Step 1: Phosphorylation. Glucose converted to glucose 6 phosphate • Coupling reaction • Glucose Glucose 6-P G°’ = 13.8kJ/mol (3.3kcal/mol) • ATP + H2O ADP + Pi G°’ = -30.5kJ/mol (-7.3kcal/mol) • Glucose + ATP Glucose 6-P +ADP G°’ = -16.7kJ/mol (-4.0kcal/mol) • Reaction catalysed by hexokinase (remember kinase – ATP dependent enzyme • Substrate can be any hexose sugar (fructose, mannose, glucose) • Glucose 6-P inhibits hexokinase • Keq for this reaction is high (2000) rxn is reversible but this does not happen in the cell b’coz: • a. Hexokinase affinity for glucose and ATP is higher than for ADP and G 6-P.  hexokinase tends to be saturated with glucose and ATP • b. Hexokinase is inhibited by G 6-P

  6. Hexokinase is an allosteric enzyme: Activator: ADP Inhibitor: ATP and Glucose 6-Phosphate

  7. Liver glucokinase requires a higher glucose concentration to achieve saturation Glucokinase: lowers blood glucose

  8. Step 2: Isomerization. Glucose 6 phosphate to fructose 6-phosphate Glucose 6-P Fructose 6-P G°’ = 1.67kJ/mol (0.4kcal/mol) • The enzyme that catalyses the reaction is glucose phosphate isomerase • Acid-base catalysis: Lys and His in the active site: Lys acts as the acid and His as the base

  9. Step 3: Phosphorylation of fructose 6-phosphate to Fructose 1,6bisphosphate (-3.4 kcal/mol) • Endergonic reaction of phosphorylation of fructose 6-P is coupled with the hydrolysis of ATP. 2nd ATP; 2nd activation step • This is the step which commits glucose to glycolysis (G 6-P and F 6-P involved in other pathways. The only way for F 1,6 bisP to be metabolised is via glycolysis • Highly exergonic & irreversible • PFK – key regulatory enzyme in glycolysis; ALLOSTERIC ENZYME • ATP: negative modulator

  10. www.rpi.edu/.../MBWeb/mb1/part2/gluconeo.htm

  11. Step 4: Cleavage of Fructose 1,6bisphosphate to glyceraldehyde 3-P & dihydroxyacetone phosphate (5.7 kcal/mol) • The last of the activations step • Cleavage takes place between carbon-3 and carbon-4 • Rxn moves towards triose sugar formation although G’ is positive

  12. Amino acids participating in the active site: Lys, Cys (thiol grp acts as a base) and His • Aldol cleavage

  13. Step 5: Isomerization of Dihydroxyacetone phosphate to glyceraldehyde 3-P ( 1.8kcal/mol) • 2nd glyceraldehyde 3-phosphate formed from this rxn • G under physiological conditions is slightly positive: 2.41kJ/mol or 0.58kcal/mol • Reaction favours formation of glyeraldehyde 3-phosphate because G forsubsequent reactions in glycolysis are very negative and drives the rxn forward. (Overall G for glycolysis is negative)

  14. glucose C1 and C6 becomes glyceraldehyde 3-phosphate C3 glucose C2 and C5 becomes glyceraldehyde 3-phosphate C2 glucose C3 and C4 becomes glyceraldehyde 3-phosphate C1 courses.cm.utexas.edu/.../Lecture-Ch14-1.html

  15. 2nd phase of glycolysis: production of energy • Involves 5 steps • Production of ATP

  16. Step 6: Oxidation of Glyceraldehyde 3-P to 1,3 bisphosphoglycerate (1.5kcal/mol) • Involves 2 sets of reactions: i) Electron transfer rxn, from Glyceraldehyde 3-P to NAD+ • ii) The addition of a phosphate • 2. G 3-P to 3-Phosphoglycerate G’ = -43.1kJ/mol (-10.3kcal/mol) (oxdn) • 3-PG to 1,3 bisPG G’ = 49.3kJ/mol ( 11.8kcal/mol) (phosln) • Overall G’ = 6.2kJ/mol (1.5kcal/mol)

  17. 3 2 1 Oxidation of glyceraldehyde 3-phosphate to a carboxylic acid EXERGONIC Electron transfer from G3-P to NAD+ ENDERGONIC 3-phophoglycerate

  18. Step 7: Conversion of 1,3 bisphosphoglycerate to 3-phosphoglycerate • A phosphate grp is transferred frm 1,3bPG to ADP • First ATP formed in glycolysis • Substrate-level phosphorylation Question: If the G’ for the hydrolysis of 1,3bPG = -49.3kJ/mol and the G’the hydrolysis of ATP is – 30.5kJ/mol, what is the G’ for the formation of 3-phosphoglycerate and ATP? (-4.5kcal/mol)

  19. Step 8: Conversion of 3-PG to 2-PG Step 9: Dehydration of 2-PG to phosphoenolpyruvate (PEP) (0.4 kcal/mol) (1.1 kcal/mol)

  20. Step 10: Transfer of phosphate grp. from phosphoenolpyruvate (PEP) to ADP • PEP high energy compd. with high phosphate-grp transfer potential • Another example of substrate level phosphorylation • Pyruvate kinase is an allosteric enzyme • Pyruvate kinase is inhibited by high levels of ATP (-7.5 kcal/mol)

  21. Conversion of pyruvate to lactate in the muscle • Rxn is catalysed by lactate dehydrogenase • NAD+ is the co-factor • Rxn highly exergonic: G’ =25.1kJ/mol (6kcal/mol) • Lactate can be recycled in the liver to form pyruvate and glucose by gluconeogenesis

  22. www.biologie.uni-hamburg.de/b-online/e19/19d.htm

  23. Overall conversion of glucose to 2 moles of pyruvate: G’ = -73.3 kJ/mol (-17.5kcal/mol)

  24. Regulation of glycolysis • Hexokinase • Phosphofructokinase • Pyruvate kinase www.nd.edu/~aseriann/glyreg.html

  25. www-medlib.med.utah.edu/NetBiochem/tabletit.htm

  26. ATP production and Efficiency of Glycolysis Glucose + 2 ADP + 2Pi 2 Lactate + 2 ATP G’ = -184.5kJ/mol(-44.1 kcal/mol) But in glycolysis only 2 ATPs are formed when glucose is oxidised to lactate. To form the ATP molecules would require : 161.1kJ/mol(-14.6 kcal/mol) 2ADP + 2Pi 2ATP G’ = 61.1kJ/mol(-14.6 kcal/mol)  % of energy conserved is 61.1/184.5 x 100 = 33.1%

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