Central Pathways of Oxidative Metabolism PDF

CENTRAL PATHWAYS OF OXIDATIVE METABOLISM Metabolic pathways leading to acetyl-CoA formation. The pyruvate dehydrogenase complex. Citric acid cycle. Energy efficiency and regulation. Anaplerotic reactions. 1 Re...

CENTRAL PATHWAYS OF OXIDATIVE METABOLISM Metabolic pathways leading to acetyl-CoA formation. The pyruvate dehydrogenase complex. Citric acid cycle. Energy efficiency and regulation. Anaplerotic reactions. 1 Respiration 2  RESPIRATION STAGE 1 : ACETYL-COA PRODUCTION Generates some: ATP, NADH, FADH2 3 STAGE 1 : CONVERSION OF PYRUVATE TO ACETYL-COA Enzyme 1 ✓ Step 1: Decarboxylation of pyruvate to an aldehyde ✓ Step 2: Oxidation of aldehyde to a carboxylic acid ▪ Electrons reduce lipoamide and form a thioester Enzyme 2 ✓ Step 3: Formation of acetyl-CoA (product 1) Enzyme 3 ✓ Step 4: Reoxidation of the lipoamide cofactor ✓ Step 5: Regeneration of the oxidized FAD cofactor ▪ Forming NADH (product 2) 4  RESPIRATION STAGE 2 : ACETYL-CoA OXIDATION, THE CITRIC ACID CYCLE (CAC) Generates more NADH, FADH2, and one GTP 5  STAGE 2 : ACETYL-CoA OXIDATION, THE CITRIC ACID CYCLE (CAC) In eukaryotes, citric acid cycle occurs in mitochondria Glycolysis occurs in the cytoplasm Citric acid cycle occurs in the mitochondrial matrix ✓Except succinate dehydrogenase, which is located in the inner membrane Oxidative phosphorylation occurs in the inner membrane 6  STAGE 2 : ACETYL-CoA OXIDATION, THE CITRIC ACID CYCLE (CAC) Net oxidation of two carbons to CO2 Equivalent to two carbons of acetyl-CoA but NOT the exact same carbons Energy captured by electron transfer to NADH and FADH2 Generates 1 GTP, which can be converted to ATP 7  One Turn of the Citric Acid Cycle ❖ The stages of the cycle with indication of the energy elements released at each turn of the cycle: Step 1: Formation of the C-C bond to give rise to citrate Step 2: Isomerization by dehydration/rehydration Steps 3-4: 2 successive reactions of Oxidative decarboxylation to give 2 NADH Step 5: Substrate-level phosphorylation to give GTP Step 6: Dehydrogenation to give FADH2 Step 7: Hydration Step 8: Dehydrogenation to give NADH https://www.youtube.com/watch?v=UZlmm-yzWrQ 8 CAC is AMPHIBOLIC 9  ANAPLEROTIC REACTIONS Intermediates in the citric acid cycle can be used in biosynthetic pathways (removed from cycle) Must replenish the intermediates in order for the cycle, a central metabolic pathway, to continue 4-carbon intermediates are formed by carboxylation of 3-carbon precursors 10  REGULATION OF THE CITRIC ACID CYCLE Regulated at highly thermodynamically favorable and irreversible steps PDH (piruvato deshidrogenasa), citrate synthase, IDH (Isocitrato deshidrogenasa), and KDH (Cetoglutarato deshidrogenasa) General regulatory mechanism Activated by substrate availability Inhibited by product accumulation Overall products of the pathway are NADH and ATP Affect all regulated enzymes in the cycle Inhibitors: NADH and ATP Activators: NAD+ and AMP 11  SUMMARY A large multi-subunit enzyme, pyruvate dehydrogenase complex, converts pyruvate into acetyl-CoA Several cofactors are involved in reactions that harness the energy from pyruvate Citric acid cycle is an important catabolic process: it makes GTP and reduced cofactors (NADH and FADH) that could yield ATP Citric acid cycle plays important anabolic roles in the cell Organisms have multiple ways to replenish intermediates that are used in other pathways The citric acid cycle is largely regulated by availability of substrates and product inhibition (especially NADH and ATP) 12