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The Energy of Oxidations in the Cycle is Efficiently Conserved. ATP generation from NADH or FADH 2 by oxidative phosphorylation NADH : 2.5 ATP FADH 2 : 1.5 ATP. 4 Oxidation steps Conserved in NDAH and FADH 2. Released energy.
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The Energy of Oxidations in the Cycle is Efficiently Conserved • ATP generation from NADH or FADH2 by oxidative phosphorylation • NADH : 2.5 ATP • FADH2 : 1.5 ATP • 4 Oxidation steps • Conserved in NDAH and FADH2 Released energy
The Energy of Oxidations in the Cycle is Efficiently Conserved • ATP generation from 1 glucose • Total : 30-32 ATP • 32 X 30.5 kJ/mol = 976 kJ/mol • 34% of the maximum of ~2,840 kJ/mol available from the complete oxidation of glucose • 65% efficiency within cells considering DG of ATP hydrolysis
Roles of citric acid cycle • Oxidation of acetyl group • Hub of intermediary metabolism • Entry of 4- or 5-C products from catabolic process “fuel” • Providing precursors for biosynthesis Incomplete citric acid cycle in anaerobic bacteria Production of biosynthetic precursors
Citric acid Cycle for Biosynthesis Amphibolic pathway
Anaplerotic Reactions Replenish Citric Acid Cycle Intermediates • Anaplerotic Reactions • Generation of OAA or malate from pyruvate or PEP • Constant maintenance of citric acid cycle intermediates • Pyruvate carboxylase in liver and kidney • Allosteric stimulation by acetyl-CoA • Biotin cofactor • PEP carboxylase in plant, yeast, bacteria • Activation by Fru 1,6-bisphosphate
Biological Tethers • Flexible tethers • Movement of reaction intermediates from one to another active sites (w/o dissociation) • Lipoate • Biotin • High affinity with avidin in egg white • Biotin-avidin interaction Useful researche tools in biochemistry and cell biology • Pantothenate
16.3 Regulation of the Citric Acid Cycle - Avoiding wasteful overproduction - Keeping the cell in stable steady state
Regulation of the Citric Acid Cycle Regulation of the Citric Acid Cycle 1. Pyruvate dehydrogenase complex rxn 2. Citrate synthase rxn 3. Isocitrate dehydrogenase rxn 4. a-Ketoglutarate dehydrogenase rxn Three factors for the rate of flux through the cycle 1. Substrate availability 2. Inhibition by accumulating products 3. Allosteric feedback inhibition Regulation mechanisms 1. Allosteric regulation 2. Covalent modification
Regulation of the Citric Acid Cycle • Regulation of PDH Complex in Mammals • Allosteric regulation • High ratio of [ATP]/[ADP], [NADH]/[NAD+], • [acetyl-CoA]/[CoA] • Allosteric inhibition • Covalent modification • (by regulatory kinase & phophatase) • Reversible -lation on Ser in E1 • High [ATP] allosteric activation of • specific kinase inactivation of E1 by • -lation
Regulation of the Citric Acid Cycle • Regulation of 3 exergonic steps • Citrate synthase • Isocitrate dehydrogenase • a-Ketoglutarate dehydrogenase complex • Substrate availability • ; OAA, acetyl-CoA, NAD+ • Feedback inhibition • ; succinyl-CoA, citrate, ATP • Ca2+ in muscle tissue • ; allosteric activation
“Substrate Channeling Through Multienzyme Complexes May Occur in the Citric Acid Cycle” Metabolons Multienzyme complexes ensuring efficient passage of the product of one enzyme reaction to the next enzyme substrate channeling In citric acid cycle Associated together as supramolecular complexes Association with the inner mitochondrial membrane
Glyoxylate Cycle • Conversion of acetate to carbohydrate • In organisms other than vertebrates • Net conversion of acetate to succinate or other 4-C intermediates of citric acid cycle • 2 Acetyl-CoA + NAD+ + 2 H2O • succinate + 2 CoA + NADH + H+ • Enzymes specific for glyoxylate cycle • Isocitrate lyase • Malate synthase • Not in vertebrates
Glyoxylate Cycle in Germinating Seeds • Glyoxysome (in plant) • Specialized peroxisome • Organelles containing enzymes for glyoxylate cycle & fatty acid degradation • Developed in lipid-rich seeds during germination
Regulation of Citric Acid Cycle and Glyoxylate Cycle • Regulation of isocitrate dehydrogenase - Isocitrate (sharing common intermediate) - Covalent modification Reversible -lation (specific kinase or phosphatase) • Intermediates of citric acid cycle and glycolysis, AMP, ADP • Allosteric regulation • Activation of isocitrate dehydrogenase via inactivation of specific kinase activation of citric acid cycle • Inactivation of isocitrate lyase inhibition of glyoxylate cycle