University:
Glendale Community College
Course:
BIO160 | Introduction to Human Anatomy and Physiology
Academic year:

2020
Views:

55

Pages:

19
Author:

helkoktcj

Section 9.2: Reactions of the CAC §Eight reactions in two stages: Stage 1. Liberation of two CO2 from acetyl-CoA, 1-4 1. Introduction of two carbons as acetyl-CoA-forming citrate 2. Citrate isomerization 3. Isocitrate is oxidized to form NADH and CO2 4. a-Ketoglutarate is oxidized; forms NADH and CO2 §Reactions 3 and 4 are oxidative decarboxylation reactions §Products: succinyl-CoA, 2 NADH, 2CO2, H+ Stage 2. Regeneration of oxaloacetate. 5 – 8 5. Cleavage of Succinyl-CoA leads to substrate-level phosphorylation 6. Succinate is oxidized to form fumarate and FADH2 7. Fumarate is hydrated and forms L-malate 8. Malate is oxidized to form oxaloacetate and a third NADH § Products: L-oxaloacetate, CoASH, FADH2, NADH, H+, ATP or GTP Section 9.2: Reactions of the CAC § § § § Condensation reaction – new C-C bond Catalyzed by citrate synthase Exergonic – releases energy from hydrolysis of thioester Inhibited - NADH, ATP, succinyl-CoA Section 9.2: Reactions of the CAC § Rearrangement – OH- moved C2 to C3 § Catalyzed by aconitase, requires Fe2+ Section 9.2: Reactions of the CAC § Decarboxylation – 6C to 5C molecule § Catalyzed by isocitrate dehydrogenase § Allosteric enzyme § § § Inhibited: ATP, NADH § Activated: ADP, NAD+ Step 1: isocitrate oxidized to oxalosuccinate, NADH produced Step 2: oxalosuccinate decarboxylated Section 9.2: Reactions of the CAC § 2nd oxidation – 5C to 4C molecule § Catalyzed by a-ketoglutarate dehydrogenase complex § Requires: CoA, thiamine pyrophosphate, lipoic acid, FAD, NAD+ § Inhibited: Succinyl-CoA, NADH, ATP, GTP End of 1st Stage: 2NADH, 2 CO2, ATP Section 9.2: Reactions of the CAC § Catalyzed by succinyl-CoA synthetase § Hydrolysis – succinyl-CoA to succinate & CoASH, releases energy § Phosphorylation – GDP to GTP § Slightly exergonic – substrate-level phosphorylation (GTP to ATP) § Catalyzed by nucleosidediphosphate kinase Nucleosidediphosphate kinase Section 9.2: Reactions of the CAC § 3rd oxidation – FAD linked § Catalyzed – succinate dehydrogenase § Electron acceptor: FAD § FAD reduced to FADH2 Section 9.2: Reactions of the CAC § Hydration – water added § Catalyzed – succinate dehydrogenase Section 9.2: Reactions of the CAC § Final oxidation § Catalyzed – succinate dehydrogenase § 3rd NAD+ reduced to NADH Section 9.2: Reactions of the CAC Section 9.2: Citric Acid Cycle §Amphibolic Citric Acid Cycle §Involved in both anabolic & catabolic processes §Anabolic – intermediates are precurors to biosynthetic pathways §OAA – gluconeogenesis substrate; precursor for lysine, threonine, isoleuine, methionine §a-ketoglutarate – precursor for glutamate, glutamine, proline, arginine §Succinyl-CoA – synthesis of porphyrins; heme & chlorophyll §Excess citrate – transported to cytoplasm; forms OAA & acetyl-CoA Figure 9.13 Amphibolic Citric Acid Cycle Section 9.2: Citric Acid Cycle §Amphibolic Citric Acid Cycle §Anaplerotic reactions contribute intermediates into the cycle §Oxaloacetate from pyruvate or aspartate §Succinyl-CoA from fatty acids Figure 9.13 Amphibolic Citric Acid Cycle Section 9.2: CAC Regulation Pyruvate dehydrogenase – controls access to CAC § Inihibited: ATP, NADH § Feedback inhibition: final product inhibits initial reaction §Citrate synthase §Inhibited: ATP, NADH, succinyl-CoA §Substrate inhibition by citrate §Isocitrate dehydrogenase §Activated: ADP, NAD+ §Inhibited: ATP, NADH §a-Ketoglutarate dehydrogenase a-ketoglutarate dehydrogenase Figure 9.14 Control of Citric Acid Cycle §Activated: ADP, NAD+ §Inhibited: ATP, NADH, succinylCoA Section 9.2: Citric Acid Cycle §Calcium regulation: cytoplasmic [Ca2+] increase is followed rapidly by [Ca2+] increase in the matrix §Cytoplasmic increase - increases ATP production by stimulating enzymes that regulate the pace of the citric acid cycle §Stimulates PDHC activity §Activates isocitrate dehydrogenase, a-ketoglutarate dehydrogenase directly §Signal driven response in matrix - matches energy demand with energy production Section 9.2: Citric Acid Cycle Figure 9.15 Citrate Metabolism Section 9.2: Citric Acid Cycle Figure 9.15 Citrate Metabolism Section 9.2: Citric Acid Cycle §Plants, some fungi, algae, protozoans, bacteria §Modified citric acid cycle §Five reactions – 2C cmpds 1. Citrate synthesis 2. Isocitrate synthesis 3. Split isocitrate to glyoxylate & succinate isocitratelyase 4. Malate formation malate synthases 5. Oxaloacetate formation malate dehydrogenase Figure 9.16 The Glyoxylate Cycle Section 9.2: Citric Acid Cycle §Citric Acid Cycle and Human Disease §Most common diseases are severe forms of encephalopathy §Encephalopathies have been linked to mutations in a-ketoglutarate dehydrogenase, succinate dehydrogenase, fumarase, and succinyl-CoA synthetase Biochemistry in Perspective §Carcinogenesis: The Warburg Effect and Metabolic Reprogramming §Emerging research reveals that “aerobic” glycolysis is closely associated with altered cell signaling pathways that cause a reprograming of metabolic pathways. §Aerobic Glycolysis is a process in tumor cells in which there is rapid glycolysis-generated ATP synthesis that occurs even when O2 is present. §Loss of glycolysis regulation is one facet of carcinogenesis, the set of mechanisms whereby normal cells gradually transform into cancerous cells.