Glycolysis - Chapter 17 Glycolysis Major pathways of...

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Unformatted text preview: Chapter 17 Glycolysis Major pathways of glucose metabolism Glycolysis Glucose + 2NAD+ + 2ADP + 2Pi 2Pyruvate + 2NADH + 2ATP + 2H2O + 4H+ Common metabolic pathway conserved throughout almost all living organisms Conversion of glucose (C6) to two pyruvate (C3) 10 enzymatic reactions The generation of 2 ATP and 2 NADH per glucose Glycolytic pathway overview Chemical strategy of glycolysis Phosphoryl transfer to the glucose Conversion of phosphorylated intermediates to "high-energy" compounds ATP synthesis coupled with the phosphate hydrolysis of the reactive substances Stage I (Reactions 1-5) - Consumption of 2 ATPs Stage II (Reaction 6-10) - Generation of 4 ATPs Recycling of NAD+ Homolactic fermentation under anaerobic condition in muscle: reduction of pyruvate to lactate by NADH Alcoholic fermentation under anaerobic condition in yeast: decarboxylation of pyruvate to CO2 and acetaldehyde (and its subsequent reduction to ethanol by NADH) Aerobic oxidation: mitochondrial oxidation of each NADH to NAD+ yields three ATPs Hexokinase (HK) Phosphoglucose isomerase (PGI) Mechanism of phosphoglucose isomerase aldose ketose Phosphofructokinase (PFK) Significant role in the control of glycolysis Aldolase Base-catalyzed retro aldol condensation Two classes of aldolase Class I (animal and plants) - Formation of the covalent enzyme-substrate Schiff base intermediate Class II (fungi, algae and some bacteria) - Metal (Zn2+ or Fe2+) stabilizes the enolate intermediate Enzymatic mechanism of Class I aldolase Triose phosphate isomerase (TIM) Transition state analog inhibitors of TIM Proposed enzymatic mechanism of TIM Flexible loop closes over the active site Protecting the enediol intermediate from hydrolysis TIM is a perfect enzyme Diffusion controlled reaction The interconversion of GAP and DHAP is at equilibrium K = [GAP]/[DHAP] = 4.73 x 10-2 As GAP is utilized in the succeeding reaction, more DHAP is converted to GAP Summary for the first stage of glycolysis Glycelaldehyde-3-phosphate dehydrogenase (GAPDH) Elucidating the enzymatic mechanism of GAPDH Enzymatic mechanism of GAPDH Phosphoglycerate kinase (PGK) :The first ATP generation Mechanism of the PGK reaction Energetics of the GAPDH-PGK reaction pair GAP + Pi + NAD+ 1,3-BPG + NADH 1,3-BPG + ADP 3PG + ATP Go'= +6.7 kJ/mol Go'= -18.8 kJ/mol GAP + Pi + NAD+ + ADP 3PG + NADH + ATP Go'= -12.1 kJ/mol Phosphoglycerate mutase (PGM) Reaction primer Reaction mechanism of PGM Synthesis and degradation of 2,3-BPG in erythrocytes Linkage between glycolysis and oxygen transport (2,3-BPG deficiency) (2,3-BPG accumulation) Enolase The mechanism of enolase Pyruvate kinase: Second ATP generation Mechanism of pyruvate kinase Summary for the second stage of glycolysis Metabolic fate of pyruvate NAD+ regeneration by homolactic fermentation in muscle Stereoselective reduction of pyruvate Recycling of lactate Alcoholic fermentation in yeast Mechanism of pyruvate decarboxylase Regeneration of NAD+ by alcohol dehydrogenase (ADH) Metabolic fate of ingested ethanol "Gasohol" Energetics of fermentation Homolactic fermentation (Energy efficiency: 31%) Glucose 2Lactate + 2H+ Go'= -196 kJ/mol (2 ATP generated: Go'= 61 kJ/mol) Alcohol fermentation (Energy efficiency: 26%) Glucose 2Ethanol + 2CO2 Go'= -235 kJ/mol (2 ATP generated: Go'= 61 kJ/mol) Glycolysis is used for rapid ATP production Number of ATP produced - Glycolysis : 2 ATP per glucose - Oxidative phosphorylation: 38 ATP per glucose The rate of ATP production by anaerobic glycolysis can be up to 100 times faster than that of oxidative phosphorylation ATP production in fast and slow-twitch muscle fibers (Predominant in muscles capable of short bursts of rapid activity) Nearly devoid of mitochondria Production of ATP almost exclusively by anaerobic fermentation (Predominant in muscles for slow and steady contracton) Rich in mitochondria Production of ATP almost exclusively through oxidative phosphorylation Control of glycolysis Nonequilibrium reactions (possible flux control points) Effectors of the nonequlibrium enzymes of glycolysis Phosphofructokinase is the major flux-controlling enzyme of glycolysis Inhibitor site ATP allosterically inhibits PFK by binding to the T state AMP, ADP and F2,6P allosterically activates PFK by binding to the R state Active site Inhibitor site Active site T R conformational change of PFK T state R state Inhibits R T transition Repulsion Salt bridge AMP overcomes the ATP inhibition of PFK Adenylate kinase catalyzes the reaction: 2ADP ATP + AMP K= [ATP][AMP] [ADP]2 = 0.44 In muscle, [ATP]50[AMP] and [ATP] 10[ADP] 10% Decrease in [ATP] result in 100% increase in [ADP] and >400% increase in [AMP] Effect on PFK is amplified Substrate cycling in the regulation of PFK Fructose-1,6bisphosphatase (FBPase) (G = -8.6 kJ/mol) PFK (G = -25.9 kJ/mol) In resting muscle In active muscle Metabolism of hexoses other than glucose The metabolism of fructose The metabolism of galactose The metabolism of mannose...
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