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Glycolysis

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A metabolic pathway. The breakdown of glucose by enzymes, releasing energy and pyruvic acid.

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Glycolysis

  1. 1. Glycolysis A Metabolic Pathway Gobinda Panigrahi M. Sc Part-I (2015-16) P. G. DEPARTMENT OF BOTANY BERHAMPUR UNIVERSITY, BHANJA BIHAR, BERHAMPUR- 760007 GANJAM, ODISHA, INDIA e-mail-
  2. 2. GENERAL INFORMATION  The word GLYCOLYSIS is combination of GLYCOSE means GLUCOSE and LYSIS means DEGRADATION, which together means the degradation of glucose.  Glycolysis is the metabolic pathway that converts glucose (C6H12O6), into pyruvate (CH3COCOO- + H+ ).  The free energy released in this process is used to form the high energy compounds ATP (ADENOSINE TRI PHOSPHATE) and NADH (reduced NICOTINAMIDE ADENINE DINUCLEOTIDE).  Glycolysis is a determined sequence of ten enzyme catalyzed reactions.
  3. 3.  Glycolysis is an oxygen independent metabolic pathway, meaning that it doesn’t use molecular oxygen (i.e. atmospheric oxygen) for any of its reactions.  However the products of glycolysis (pyruvate and NADH+H+) are sometimes disposed of using atmospheric oxygen.  When molecular oxygen is used in the disposal of the products of glycolysis the process is usually referred to as aerobic, whereas if the disposal uses no oxygen the process is said to be anaerobic.
  4. 4.  Thus, glycolysis occurs, with variations, in nearly all organisms, both aerobic and anaerobic.  The wide occurrence of glycolysis indicates that it is one of the most ancient metabolic pathways.  Indeed, the reactions that constitute glycolysis and its parallel pathway, the pentose phosphate pathway, occur metal-catalyzed under the oxygen free conditions of the archean oceans, also in the absence of oxygen.
  5. 5.  Glycolysis could thus have originated from chemical constraints of the prebiotic world.  Glycolysis occurs in most organisms in the cytosol of the cell.  The most common type of glycolysis is the Embden-Meyerhof-Parnas (EMP pathway), which was discovered by Gustav Embden, Otto Meyerhof, and Jacob Karol Parnas.
  6. 6. Sequence of reactions The entire glycolytic pathway can be separated into two phases:  The Preparatory Phase – constituted by the reactions in which ATP is consumed and is hence also known as the investment phase.  The Pay Off Phase – constituted by the reactions in which ATP is produced.
  7. 7. Preparatory Phase  The first five steps are regarded as the preparatory phase, since they consume energy to convert the glucose into two three-carbon sugar phosphates. A. Glucose → glucose-6-phosphate (G6P), first ATP utilization Enzyme: hexokinase (HK) Reaction: Transfer phosphoryl group ∆G0’= -20.9 kJ/mol; ∆G = -27.2 kJ/mol (physiological condition)
  8. 8. Reaction mechanism  C6 – OH group of glucose nucleophilic attacks on the у-phosphate of an Mg2+ - ATP complex
  9. 9. B. Glucose 6 –phosphate (G6P) to Fructose 6 –phosphate (F6P) Enzyme: Phosphoglucose isomerase (PGI) Reaction: Isomerization of an aldose to ketose ∆G0’ = +2.2 kJ/mol; ∆G = -1.4 kJ/mol
  10. 10. Reaction mechanism The reaction requires ring opening, followed by isomerization, and subsequent ring closure. 1. An acid (ε-amino group of Lys) donates a proton to O5 to open the ring. 2. A base (carboxylate of Glu) abstracts the acidic proton from C2. 3. The proton is replaced on C1. 4. The proton on O5 is returned to the acid (Lys) and the O5 nucleophilic attacks on C2 to close the ring.
  11. 11. C. Fructose 6-phosphate (F6P) to Fructose-1,6-bisphosphate (FBP), Second ATP Utilization Enzyme: Phosphofructokinase (PFK) Reaction: Transfer phosphoryl group ∆G0’= -17.2 kJ/mol ∆G = -25.9 kJ/mol Reaction mechanism Similar to the hexokinase reaction.
  12. 12. D. Fructose-1,6-bisphosphate to two trioses, Glyceraldehyde-3-phosphate (GAP) and Dihydroxyacetone phosphate (DHAP) Enzyme: Aldolase Reaction: Aldol cleavage ∆G0’= +22.8 kJ/mol ∆G= -5.9 kJ/mol
  13. 13. E. Dihydroxyacetone phosphate to Glyceraldehyde-3-phosphate (GAP) Enzyme: Triose phosphate isomerase (TIM) Reaction: Isomerization (aldose to ketose) ∆G0’= +7.9 kJ/mol ∆G= +4.4 kJ/mol
  14. 14. Reaction mechanism 1. Glu-165 interacts with the proton on C2 of GAP, and the proton of His-95 interacts with C1=O to form GAP:TIM Michaelis complex. 2. at the first transition state, these two protons participate in the low-barrier hydrogen bonds (very short hydrogen bonds). 3.the protons are moved to the carbonyl oxygen of Glu-165 and to the carbonyl oxygen of GAP. 4. At the second transition state, Glu-165 donates the proton to C1 of GAP, and GAP donates the proton of O2-H to His-95 through the low-barrier hydrogen bonds. 5. After the proton transfer, DHAP:TIM Michaelis complex is formed.
  15. 15. Pay-off Phase  The second half of glycolysis is known as the pay-off phase, characterized by a net gain of the energy-rich molecules ATP and NADH.  Since glucose leads to two triose sugars in the preparatory phase, each reaction in the pay- off phase occurs twice per glucose molecule.  This yields 2 NADH molecules and 4 ATP molecules, leading to a net gain of 2 NADH molecules and 2 ATP molecules from the glycolytic pathway per glucose.
  16. 16. F. Glyceraldehyde 3-phosphate (GAP) to 1,3-Bisphosphoglycerate (1,3-BPG), First “High Energy” Intermediate Formation Enzyme: Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) Reaction: Oxidation and Phosphorylation ∆G0’= +6.7 kJ/mol ∆G= -1.1 kJ/mol
  17. 17. Reaction mechanism The active site has the essential sulfhydryl group (-SH), a base residue (-B:) and cofactor NAD+. 1. GAP binds to the enzyme. 2. The base amino acid residue abstracts the proton from –SH, and thus the activated –S- attacks on the carbonyl carbon to form thiohemiacetal intermediates. 3. By transferring the proton to NAD+ , the thiohemiacetal becomes an acyl thioester. 4. NADH is replaced with another NAD+ . 5. A phosphate ion enters into the active site and its nucleophilic attack on the carbonyl carbon of acyl thioester forms 1,3- bisphosphoglycerate. The –S receives a proton from the base amino acid residue, and mthe product is released.
  18. 18. G. 1,3-Bisphosphoglycerate (1,3-BPG) to 3-Phosphoglycerate (3PG), First ATP Generation Enzyme: Phosphoglycerate kinase (PGK) Reaction: Phosphorylation ∆G0’= -18.8 kJ/mol ∆G = ~0 kJ/mol
  19. 19. Reaction mechanism nucleophilic attack of the terminal phosphoryl oxygen of ADP on the C1 phosphorus atom of 1,3- BPG forms the reaction product.
  20. 20. H. 3-Phosphoglycerate (3PG) to 2-Phosphoglycerate (2PG) Enzyme: Phosphoglycerate mutase (PGM) Reaction: Intramolecular phosphoryl group transfer ∆G0’= +4.7 kJ/mol ∆G = -0.6 kJ/mol
  21. 21. Reaction mechanism 1. 3PG binds to the phosphorylated enzyme ( E-His-PO3 - ) 2. The PO3 – is transferred to the substrate to form 2,3- BPG:E complex. 3. The PO3 – attached on the O3 is transferred to the enzyme, and 2PG is released.
  22. 22. I. 2-Phosphoglycerate (2PG) to Phosphoenolpyruvate (PEP) Enzyme: Enolase Reaction: Dehydration ∆G0’= -3.2 kJ/mol ∆G = -2.4 kJ/mol
  23. 23. Reaction mechanism - The enzyme forms a complex with Mg2+ before the substrate is bound. - Fluoride ion (F- ) inhibits this process, since F- forms a complex with bound Mg2+ in the active site, and block the substrate binding. - A water molecule is in the active site, which hydrogen- bonds to two Glu residues. 1. The water molecule bound to the two carboxylates of Glu residues abstracts a proton at C2, and thus the carboanion is formed (rapid reaction). The abstracted proton is readily exchanged with a proton in the solvent. 2. Slow elimination of Mg2+ - stabilized OH at C3 produces a phosphoenolpyruvate (PEP) and a water molecule. R
  24. 24. J. Phosphoenolpyruvate (PEP) to Pyruvate Enzyme: Pyruvate kinase Reaction: Hydrolysis to ATP synthesis ∆G0’= -23.0 kJ/mol ∆G = -13.9 kJ/mol
  25. 25. Reaction mechanism - Monovalent (K+) and divalent (Mg2+) cations are required. 1. A nucleophilic attack of the ADP β-phosphoryl oxygen atom on the phosphorus atom of PEP forms ATP and enolpyruvate. 2. A tautomerization is taken place to form a pyruvate from a enolpyruvate.
  26. 26. Net ATP count in a glycolytic pathway
  27. 27. Regulation  Glycolysis is regulated by slowing down or speeding up certain steps in the pathway by inhibiting or activating the enzymes that are involved.  The steps that are regulated may be determined by calculating the change in free energy, ∆G, for each step.  When ∆G is negative, a reaction proceed spontaneously in the forward direction only and is considered irreversible.  When ∆G is positive, the reaction is non-spontaneous and will not proceed in the forward direction unless coupled with an energetically favorable reaction.  When ∆G is zero, the reaction is at equilibrium, can proceed in either directions and is considered reversible.  If a step is at equilibrium (∆G is zero), the enzyme catalyzing the reaction will balance the products and reactants and cannot confer directionality to the pathway.  These steps (and associated enzymes) are considered unregulated.  If a step is not at equilibrium, but spontaneous (∆G is negative), the enzyme catalyzing the reaction is not balancing the products and reactants and is considered to be regulated.
  28. 28. Importance of glycolysis  Nearly all of the energy used by living cells comes from the energy in the bonds of the sugar glucose.  Glycolysis is the first pathway used in the breakdown of glucose to extract energy.  It takes place in the cytoplasm of both prokaryotic and eukaryotic cells.  It was probably one of the earlier metabolic pathways to evolve since it is used by nearly all of the organisms on earth.  The process doesn’t use oxygen and is, therefore, anaerobic.  Glycolysis is the first of the main metabolic pathways of cellular respiration to produce energy in the form of ATP.  Overall, the process of glycolysis produces a net gain of two pyruvate molecules, two ATP molecules, and two NADH molecules for the cell to use for energy.
  29. 29. Glycolysis in disease Genetic diseases  glycolytic mutations are generally rare due to importance of the metabolic pathway, this means that the majority of occurring mutations result in an inability for the cell to respire, and therefore cause the death of the cell at an early stage.  However some mutations are seen with one notable example being Pyruvate kinase deficiency, leading to chronic hemolytic anemia. Cancer  Malignant rapidly growing tumor cells typically have glycolytic rates that are upto 200 times higher than those of their normal tissues of origin. This phenomenon was first described in 1930 by Otto Warburg and is referred to as Warburg effect.  This hypothesis claims that cancer is primarily caused by dysfunctionality in mitochondrial metabolism, rather than because of uncontrolled growth of cells.
  30. 30. Thank you all for your benign presence
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A metabolic pathway. The breakdown of glucose by enzymes, releasing energy and pyruvic acid.

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