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Transcript
Cell Biology Chapter 14 Glycolysis Oxidation without Oxygen Glycolytic Pathway o Simplest mechanism to get most free energy out of glucose and other catabolic substrates. Net yield 2 ATP/glucose o Glucose partially oxidized without use of oxygen: Energy of oxidation drives ATP production from ADP and P i o 10 Steps: Glucose Pyruvate: Final product after completion of the pathway either lactate or ethanol, in the absence of aerobic metabolism via TCA cycle and ETS o In the case of aerobic metabolism: Pyruvate carbon dioxide + water: Carbon is completely oxidized, full energy given to ATP production Net yield up to 38 ATP/glucose Initiation and Activation o Start with non-oxidizable 6-C sugar glucose which is split into 2 oxidizable 3-C compounds in GLY-4 o Two 3-C molecules oxidized in GLY-6, reducing NAD o ATP generation follows in GLY-7 and GLY-10 o Initially glucose must be phosphorylated so that it carries 2 phosphate groups, 1 for each 3-C intermediate to transfer to ADP to make ATP o Energy added makes it possible to split glucose GLY-1: First Phosphorylation o Glycolysis splits the sugar: Want a phosphate on both termini so both halves of sugar can be used for energy generation Glucose Glucose-6-phosphate o Energy is added in the form of ATP, yielding ADP as it transfers a phosphate group to the sugar o Free energy not favorable to putting phosphate group on free OH group of C-6 due to loss of resonance energy: ΔG°’ = +4.0 kcal/mole. Reaction driven forward by energy of ATP hydrolysis, ΔG°’ = -7.3 kcal/mol, ΔG° difference of -3.3 kcal/mol makes reaction favorable o Catalyzed by hexokinase GLY-2: Aldohexose Ketohexose o No similar free OH for addition on C-1, so cell must convert the aldosugar to a ketosugar o An isomerase converts Glucose-6-phosphate Fructose-6-phosphate o Now there is a readily phosphorylatable free OH group on C-1 GLY-4: Splitting the Sugar o With high energy phosphate groups on either end, sugar is energized and ready to be split o Fructose-1,6-biphosphate higher in energy than glucose because cell has used 2 ATP to activate it o Aldolase splits fructose-1,6-biphosphate into dihydroxyacetone phosphate and glyceraldehydes-3-phosphate o 6-C sugar split into two 3-C sugars at cost of 2 ATP o Glyceraldehyde-3-phosphate can be directly oxidized, but dihydroxyacetone phosphate cannot be oxidized directly GLY-5: Interconversion o Dihydroxyacetone phosphate, though not directly oxidizable, readily converted into glyceraldehydes-3-phosphate, which is oxidizable o Triose isomerase rearranges dihydroxyacetone phosphate bonds, converting it to glyceraldehydes-3-phosphate o Summary: 1 glucose + 2 ATP 2 glyceraldehyde-3-phosphate + 2 ADP GLY-6: Oxidation o Oxidation of glyceraldehydes-3-phosphate very exergonic: Inorganic catalysis releases considerable heat o Cell instead couples this energy to reducing NAD coenzyme to NADH(H+) in GLY-6, and ATP production in GLY-7 o In presence of oxygen this energy carried by NADH9H+) can be used to produce ATP via ETS and oxidative phosphorylation o In absence of oxygen, cell performs fermentation and energy in NADH9H+) lost to lactate/ethanol production, but NAD regenerated for more glycolysis o Glyceraldehyde-3-phosphate oxidized into 1,3-biphosphoglycerate, reducing NAD. Phosphate added at same time, capturing remaining energy of oxidative event. o 1st energy capture: NAD NADH(H+) o 2nd energy capture: High energy phosphate bond created on C1’s of glyceraldehydes3-phosphates to generate 1.3-biphosphoglycerates o Diphosphorylated intermediate has an extremely high energy bond: ΔG°’ of breaking this phosphoanhydride bond is -11.8 kcal/mol o Energy transferred from oxidation of glyceraldehydes-3-phosphate to NAD by moving electrons, forming NADH(H+) o Reaction catalyzed by glyceraldehydes-3-phosphate dehydrogenase GLY-7: 1st ATP Production o High energy bond in each 1,3-biphosphoglycerate yield phosphate group to ADP, forming 3-phophoglycerate and ATP via substrate level phosphorylation o Even in ATP expenditure and production: Per glucose 2 ATP’s used, 2 ATP’s generated o Still have two 3-C compounds each with one phosphate group, but these are low in energy: This is a problem because… o ATP from ADP and phosphate required higher energy o Phosphoglycerokinase catalyzes reaction GLY-8: Intramolecular Energy Rearrangement o Intramolecular rearrangement of energy to convert low energy ester bond to high energy phophoenol bond. To do this the phosphate group must be moved from C-3 to C-2, converting 3-phosphoglycerate into 2phosphoglycerate o Enzyme catalyzing reaction: Phosphoglyceromutase GLY-9: High Energy Enol Produced o Water removed, introducing double bond between C-2 and C-3, making molecule an enol. 2-phophoglycerate converted to phosphoenolpyruvate by enolase. o Phosphate group on C-2 with double bond now very high energy, but no free energy expended: Just rearranged intramolecularly st o 1 Law of Thermodynamics obeyed: Energy neither created nor destroyed. It has however been moved. o Phosphate group on C-2 “locks” double bond in place; molecule would be much more stable as a ketone, transferring those electrons to double bond on C-2 oxygen, but with phosphate attached to that oxygen transfer cannot take place. Considerable free energy to derived removing that phosphate and transferring it to another molecule: ADP GLY-10: Net ATP Gain o High energy phosphate available for transfer to ADP for net ATP gain o PEP is converted to pyruvate yielding another ATP per molecule of PEP, 2 per glucose for a net yield of 2 ATP o Catalyzed by pyruvate kinase o 1 Glucose + 2 NAD + 2 ADP + 2 P i 2 Pyruvate + 2 NADH(H+) + 2 ATP + 2 H20 NAD Regeneration and Fermentation o If oxygen available, pyruvate fed into TCA cycle where it generates some ATP and more NADH(H+) and FADH2 are used to generate ATP by oxidative phosphorylation and chemiosmotic coupling via ETS. Oxidized to carbon dioxide. o If there is no oxygen available or cannot be used another way to regenerate NAD coenzyme has to be employed: Pyruvate converted into lactate or ethanol by which means NAD regenerated for more glycolysis. This type of metabolism is called fermentation. Gluconeogenesis o Lactate and pyruvate can be regenerated into glucose: Many parts of the pathway use the same enzymes, others different, for high-energy steps o Balance between glycolysis and gluconeogenesis: Allosteric and hormonal regulation of several enzymes by substrates and products o Typically glycolysis and gluconeogenesis not operating simultaneously in cell: Energetically wasteful and undesirable because of the Second Law of Thermodynamics: Futile cycle Futile Cycle in Brown Fat Cells o Usually having glycolysis and gluconeogenesis running simultaneously is a wasteful and futile cycle o 2nd Law of Thermodynamics states with each transformation energy lost to entropy, or randomness in the system, shows up as random molecular motion we measure as heat o In the case of brown fat cells heat is the desired product Brown fat, in humans usually only found in infants, has been found in necks of Laplanders where they are exposed to extreme cold: Here desired product is heat generated by futile cycle of glycolysis and gluconeogenesis