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Glycolysis and its other side process
- 2. Glycolysis • What is glycolysis? – sequence of reactions that converts one molecule of glucose to two molecules of pyruvate with the formation of two ATP molecules – anaerobic
- 3. Glycolysis • Why is glucose such a commonly used fuel? – tends to exist in ring form, very stable, doesn’t generally glycosylate proteins – formed from formaldehyde under prebiotic conditions
- 4. Glycolysis • What are the possible fates of glucose?
- 5. • What’s the difference between a facultative anaerobe and an obligate anaerobe? • Can you give an example of habitat- dependent anaerobiosis? • What about activity-dependent anaerobiosis? Glycolysis
- 6. Glycolysis • All the intermediates in glycolysis have either 3 or 6 carbon atoms • All of the reactions fall into one of 5 categories – phosphoryl transfer – phosphoryl shift – isomerization – dehydration – aldol cleavage
- 7. Glycolysis • Entire reaction sequence may be divided into three stages – glucose is trapped and destabilized – six carbon molecule is split into two three carbon molecules – ATP is generated
- 8. Glycolysis – Stage 1 • glucose converted to glucose-6-PO4 • ATP is needed • catalyzed by hexokinase or glucokinase • induced fit ∀ ∆G01 = -4.0 kcal/mole
- 9. Glycolysis – Stage 1 • phosphoglucoisomerase • aldose is converted to ketose ∀ ∆G01 =+0.4 kcal/mole
- 10. Glycolysis – Stage 1 • rate limiting enzyme – allosteric – inhibited by high ATP, citric acid, long-chain fatty acids – stimulated by ADP or AMP ∆G01 = - 3.4 kcal/mole
- 11. Glycolysis
- 12. Glycolysis – Stage 2 • six carbon molecule split into 2- 3 carbon molecules – aldose and ketose ∀ ∆G01 =+ 5.73 kcal/mole
- 13. Glycolysis – Stage 3 • At equilibrium most mixture exists as dihydroxyacetone phosphate ∀ ∆G01 =+ 1.83 kcal/mole
- 15. Glycolysis – Stage 3 • redox reaction • energy from redox used to form acyl phosphate ∀ ∆G01 = +1.5 kcal/mole
- 16. Glycolysis – Stage 3 • Consists of two coupled processes
- 17. Glycolysis – Stage 3 • formation of ATP – substrate level phosphorylation
- 18. Glycolysis – Stage 3 • phosphoryl shift – uses 2,3 bisphosphoglycerate ∆G01 = +1.1 kcal/mole • dehydration ∆G01 = +.44 kcal/mole • phosphoryl transfer ∆G01 = -7.5 kcal/mole
- 19. Glycolysis
- 20. Fate of Pyruvate
- 21. Alcoholic Fermentation • Which organisms carry out this process? – yeast – other microorganisms • PDC requires thiamine pyrophosphate as coenzyme • NAD+ is regenerated
- 22. Lactic Acid Fermentation • Occurs in muscle cells, microorganisms • Regenerates NAD+
- 23. NAD+ and Dehydrogenases • Various dehydrogenases have a similar binding domain for NAD+ showing their common origin – Rossman fold
- 24. Glycolysis • How can fructose be used for energy?
- 25. Glycolysis • To use galactose it must be converted to glucose-6-PO4
- 26. Glycolysis
- 27. Glycolysis • What causes lactose intolerance?
- 28. Glycolysis • What is galactosemia? – inability to metabolize galactose – missing galactose 1-phosphate uridyl transferase • liver disease • development of cataracts • CNS malfunction
- 29. Control of Glycolysis • Of what value is glycolysis for cells? – provides energy in form of ATP – provides building blocks for synthetic reactions • Where are most control points found? – enzymes that catalyze irreversible reactions • hexokinase • phosphofructokinase • pyruvate kinase
- 30. Phosphofructokinase • Most important control point in mammalian glycolytic pathway – allosteric enzyme • activated by AMP and fructose 2,6 bisphosphate • inhibited by high levels of ATP, citrate, fatty acids
- 32. Hexokinase • Hexokinase is inhibited by its product glucose-6-PO4 – glucose remains in blood • Glucokinase, an isozyme of hexokinase is not inhibited by glucose-6-PO4 – found in liver – has lower affinity for glucose
- 33. Pyruvate Kinase • Pyruvate kinase exists as isozymes – L form – predominates in liver – M form – mostly in muscle and brain • PK is an allosteric enzyme – activated by fructose 1,6 bisphosphate – inhibited by ATP, alanine • L form of PK influenced by covalent modification – inhibited by phosphorylation
- 34. Pyruvate Kinase
- 35. Glucose Transport • What is the role of glucose transporters in animal cells? – facilitate movement of glucose across cell membrane • What kind of molecule is a transporter and where is it located? – small protein embedded in plasma membrane
- 36. Glucose Transport • mammalian glucose transporter
- 38. Glycolysis and Cancer • Why are rapidly growing tumor cells dependent upon glycolysis? – insufficient oxygen supply • What is the function of HIF-1? – hypoxia-inducible transcription factor stimulates synthesis of many glycolytic enzymes and GLUT-1 and 3 – also stimulates vascular endothelial growth factor
- 39. Gluconeogenesis • What is gluconeogenesis? – synthesis of glucose from non-carbohydrate precursors • Why is this an important pathway? • What are some of the major precursors? – lactate, amino acids, glycerol • Where does this process occur? – liver, kidney
- 40. Gluconeogenesis • If gluconeogenesis involves the conversion of pyruvate to glucose why is it not simply the reverse of glycolysis? – glycolysis contains several irreversible reactions • Which reactions in glycolysis are irreversible? – phosphoenolpyruvate to pyruvate – fructose 6-phosphate to fructose 1,6- bisphosphate – glucose to glucose 6-phosphate
- 41. Gluconeogenesis • What is the first reaction? CH3 CCO2 - O CH2 CCO2 - O CO2 - + CO2 + ATP + ADP + Pi Pyruvate Oxaloacetate biotin pyruvate carboxylase
- 42. Gluconeogenesis • Why is pyruvate carboxylase of special interest? – structural properties • contains ATP-grasp domain at N-terminal end • contains biotin-binding domain at C-terminal end
- 43. Gluconeogenesis • What is the role of biotin in this reaction? – prosthetic group lined to ε-amino group of lysine residue – carrier of activated carbon dioxide
- 44. Gluconeogenesis • Pyruvate carboxylase is an allosteric enzyme – activated by acetyl CoA – needed to form carboxybiotin
- 45. Gluconeogenesis • Carboxylation of pyruvate occurs in the mitocondria but next step in reaction sequence occurs in cytosol
- 46. Gluconeogenesis Decarboxylation of oxaloacetate is coupled with phosphorylation by GTP enzyme is phosphoenolpyruvate carboxykinase CH2 = CCO2 - OPO3 2 - CH2 CCO2 - O CO2 - + CO2 + GTP Phosphoenol pyruvate Oxaloacetate + GDP
- 47. Gluconeogenesis • Which other steps in glycolysis are irreversible? – conversion of fructose 1,6-bisphosphate to fructose 6-phosphate – conversion of glucose 6-phosphate to glucose
- 48. Gluconeogenesis Fructose-6-phosphate C CH2 OP O3 2 - O HHO OHH OHH CH2 OH Fructose-1,6-bisphosphate C CH2 OP O3 2 - O HHO OHH OHH CH2 OP O3 2 - fructose-1,6-bis- phosphatase H2 O P i ∆G° = -16.7 kJ mol-1 – fructose-1,6-bisphosphatase is an allosteric enzyme, inhibited by AMP and activated by ATP
- 49. Gluconeogenesis • Enzyme that catalyzes last reaction not found in all tissues – liver and kidney cortex
- 50. Gluconeogenesis • Is gluconeogenesis an energetically favorable reaction in the cell? • What drives this reaction? • Are glycolysis and gluconeogenesis active at the same time?
- 51. Regulation of Glycolysis and Gluconeogenesis • What are some of the factors that ensure the reciprocal regulation of these processes? – allosteric regulators of key enzymes – energy charge – fructose 2,6-bisphosphate – hormones
- 52. Regulation of Glycolysis and Gluconeogenesis
- 53. Regulation of Glycolysis and Gluconeogenesis • fructose 2,6-bisphosphate stimulates PFK and inhibits fructose 1,6-bisphosphase – controlled by insulin and glucagon and reflects the nutritional status of the cell
- 54. Regulation of Glycolysis and Gluconeogenesis • How do hormones influence the enzymes associated with these processes? – influence gene expression • change transcription rate • influence degradation of m-RNA – insulin →PFK, PK – glucagon →PEPCK, fructose 1,6-bisphosphatase
- 55. Regulation of Glycolysis and Gluconeogenesis • What are substrate cycles and why are they important? – can amplify metabolic signals – can generate heat
- 56. Regulation of Glycolysis and Gluconeogenesis • What is the Cori cycle and why is it important?
- 57. Regulation of Glycolysis and Gluconeogenesis