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Download The citric acid cycle • Also known as the Kreb`s cycle
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The citric acid cycle • Also known as the Kreb’s cycle -named after Hans Krebs, whose work on this cycle earned him a Nobel prize in 1953 • Or TCA cycle (tricarboxylic acid) cycle (not The Citric Acid cycle) The citric acid cycle requires _____________ conditions • O2 serves as the final electron acceptor as pyruvate is completely oxidized to CO2 and H2O If ____________ conditions exist, we get < 10% of the energy generated under aerobic conditions • Can you determine what the exact amount of energy is under these conditions?? Results: 1. _____________________ Oxidation of Acetyl-CoA to CO2 produces energy Energy is generated as ATP (GTP) Energy is also found in the reducing power of NADH and FADH2 2. ______________________________ Carbohydrates, lipids, amino acids, nucleotides, porphyrins Intermediates of TCA cycle are starting points for biosynthetic reactions (exit points) Other pathways feed into the cycle (entrance points) TCA is a cyclic pathway This is different from glycolysis (which is linear). Other differences: Glycolysis occurs in the cytoplasm Glycolysis does not require oxygen (can occur under anaerobic and aerobic conditions), while TCA requires oxygen (only occurs under aerobic conditions) Chemistry C483 Fall 2009 Prof Jill Paterson 31-1 Chemistry C483 Fall 2009 Prof Jill Paterson 31-2 Let’s look at the citric acid cycle in detail. As we do, note: 1. the flow of C 2. the movement of electrons 3. the production of energy simplify further: Net: oxidation of acetyl CoA by the release of electrons if shown cycle, know: 1. type of reaction occurring 2. type of enzyme catalyzing the reaction 3. be able to follow the C atoms 4. the steps where energy is produced (and if it is ATP, NADH, FADH2) 5. the steps where CO2 is released 6. the committed step 7. regulatory steps 8. structure of citrate (tricarboxylic acid) Step 1: Citrate synthase 1. Citrate formed (condensation of oxaloacetate with acetyl CoA) 2. Aldol condensation (acetyl to keto double bond) 3. Only reaction where C-C bond is formed Rxn ATP NADH FADH2 Total Chemistry C483 Fall 2009 Prof Jill Paterson 31-3 4. ∆G = -31.5 kJ/mol (but we do not create ATP!! This favorable energy ensures the cycle moves in 1 direction. Not none of these steps are listed as reversible) 5. Synthase catalyzes this reaction (catalyzes for addition to a double bond, or elimination to form a double bond. Does not require ATP) Step 2: aconitase 1. Isomerization reaction: tertiary alcohol to secondary alcohol 2. A lyase reaction occurs to allow for isomerization (next slide). Overall, nonhydrolytic cleavage. 3. This rearrangement occurs to allow for further oxidation of the molecule. Rxn ATP NADH FADH2 Total Step 3: Isocitrate dehydrogenase • First of four oxidation/reduction steps First of four oxidative decarboxylation steps, coupled to NAD+ reduction • Irreversible • Also a non-hydrolytic cleavage reaction • Transfer of a hydride to NAD+ • First reaction where we lose electrons Chemistry C483 Fall 2009 Prof Jill Paterson 31-4 Rxn ATP NADH FADH2 Total Step 4: α-ketoglutarate dehydrogenase complex • Second oxidative decarboxylation reaction, coupled to NAD+ • Also a non-hydrolytic cleavage • Mechanism is identical to pyruvate dehydrogenase, except succinyl group is activated, not acetyl (SuccinylCoA thioester is a HIGH energy bond) • Purpose of this step is to generate the high energy succinyl CoA Rxn ATP NADH FADH2 Total Step 5: Succinyl-CoA synthetase • Energy of succinyl CoA is transferred (conserved) to GTP • SUBSTRATE LEVEL PHOSPHORYLATION: group transfer reaction • ONLY step where ATP is directly formed • All other ATP is produced by oxidative phosphorylation Oxid. Phosphor. is the oxidation of reduced cofactors (NADH, FADH2), to form ATP from ADP + Pi (see future notes) Chemistry C483 Fall 2009 Prof Jill Paterson 31-5 Rxn ATP NADH FADH2 Total Step 6: succinate dehydrogenase complex • This enzyme is located in the inner mitochondrial membrane (all other reactions are in the mitochondrial matrix) Also known as Complex II, which feeds e- directly into the electron transport chain (we will see in a bit) • Oxidation/reduction with formation of double bond • Formation of FADH2 (note we get NADH with hydroxyl and carbonyl groups, FADH2 with other reactions) • Enzyme has a Fe-S cluster (remember why??) • Only the trans isomer is formed Rxn ATP NADH FADH2 Total Chemistry C483 Fall 2009 Prof Jill Paterson 31-6 Step 7: Fumarase • Trans addition of water • Only the L-isoform forms Rxn ATP NADH FADH2 Total Step 8: Malate dehydrogenase • Oxidation of L-malate • Regenerates oxaloacetate • Reaction is at equilibrium (so reversible) Results of TCA cycle 1. Oxidation of 1 acetyl-CoA to 2 CO2 (release CO2 at steps 3 & 4) 2. 3 NAD+ are reduced to NADH with dehydrogenase reactions (steps 3, 4, & 8) 3. 1 FAD is reduced to FADH2 (Step 6) 4. 1 phosphoanhydride bond is formed making GTP (Step 5) 5. Oxaloacetate is reformed Chemistry C483 Fall 2009 Prof Jill Paterson 31-7 Energy production from 1 pyruvate (and from 1 TCA cycle): Every pyruvate generates: 1 NADH from pyruvate dehydrogenase 3 NADH from TCA cycle 1 ATP from TCA cycle 1 FADH2 from TCA cycle We will see that from oxidation of: NADH we will yield _________ FADH2 we will yield _________ Energy derived from 1 glucose molecule We see this occur in muscles when we exercise and they go into oxygen debt. The reason our muscles get sore is from lactate (lactic acid) Chemistry C483 Fall 2009 Prof Jill Paterson 31-8 Summary of energy ATP NADH + H+ FADH2 Glycolysis PDH TCA cycle Total Just like glycolysis, TCA cycle is highly regulated • Energy level of the cell regulates TCA- the goal is to keep our cellular energy constant. • If cells are high in energy (ATP, NADH), reactions are slowed. (generally products decrease rates, substrate increase) • If cells are low in energy, reactions speed up. Regulation of pyruvate dehydrogenase • Controls the level of acetyl CoA Chemistry C483 Fall 2009 Prof Jill Paterson 31-9 Regulation of pyruvate dehydrogenase This is a commitment step! Pyruvate can be converted to glucose (through gluconeogenesis), but acetylCoA cannot. Three reactions in TCA are regulated Enzyme Activators Inhibitors Others PDH Phosphorylation Citrate synthase [metabolite] Isocitrate dehydrogenase [metabolite] a-ketoglutarate dehydrogenase complex [metabolite] Chemistry C483 Fall 2009 Prof Jill Paterson 31-10