1 The Citric Acid Cycle (Tricarboxylic Acid Cyle) 1. The link between gycolysis and citric acid cycle 2. TCA cycle oxidizes 2 –C units 3. Entry and metabolism controlled 4. Source of precursors 5. Glyoxylate cycle enables plants and bacteria to grow on acetate

2 Glucose Metabolism Under Aerobic and Anaerobic Conditions

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4 Citric Acid Cycle takes place in the Matrix of the Mitochondria (Eukaryotic cells, under aerobic conditions)

5 Citric Acid Cycle is the first step in Cellular Respiration

6 The link between Glycolysis and Citric Acid Cycle Pyruvate dehydrogenase complex (E. coli)

7 The conversion from Pyruvate -> Acetyl-CoA -> goes in 3 steps: And requires: 1.The 3 enzymes of the complex 2.5 co-enzymes (thiamine pyrophosphate TPP, lipoic acid, FAD, CoA, and NAD +

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9 Reaction mechanism of the conversion Pyruvate -> Acetyl-CoA Carbanion of TPP Oxidized form Reduced form

10 Reaction mechanism of the conversion Pyruvate -> Acetyl-CoA Reduced form Oxidized formReduced form Oxidation + 2e -

11 Pyruvate dehydrogenase complex

12 The Citric Acid Cycle Isomerization Oxidative Decarboxylation Oxidation (Regeneration of Oxaloacetate) Oxidation + Decaroboxylation Generation of electrons

13 1. Citric Synthase forms citrate from oxaloacetate and acetyl-CoA Aldol Condensation

14 2. Citrate is isomerized into Isocitrate Aconitase Hydroxy group is not located correct for decarboxylation reaction -> Isomerization

15 3. Isocitrate is Oxidized and Decarboxylated to α-Ketoglutarate

16 4. Oxidative Decarboxylation of α-Ketoglutarate gives Succinyl-CoA Mechanism analog to decarboxylation of pyruvate

17 5. GTP is generated from Succinyl-CoA Energy-rich thioester Synthetase

18 6. Oxaloacetate is regenerated by Oxidation of Succinate This metabolic motif -> also found in fatty acid Synthesis + degradation, degradation of some AA Methylene group (CH 2 ) -> carbonyl group (C=O) 1.Oxidation 2.Hydration 3.Oxidation

19 3 NADH -> 6e - 1 FADH 2 -> 2e > 8e -

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21 Regulation of the Pyruvate dehydrogenase complex Regulation by Allosterie + Phosphorylation

22 Regulation of the Pyruvate dehydrogenase complex

23 Control of the Citric Acid Cycle

24 The Citric Acid Cycle is a Source of Precursors ”Fast refill” of oxaloacate by carboxylation of pyruvate (in mammals)

25 Pathway Integration Pathways active during exercise after a night’s rest Rate of citric acid cycle increases during exercise -> requiring the “refill” of oxaloacetate + acetyl CoA Oxaloacetate -> from pyruvate Acetyl CoA -> from pyruvate + fatty acids

26 Blocking of Pyruvate -> Acetyl-CoA Reaction By Poisoning with Hg and As By Vitamin B1 (thiamine) deficiency – Beriberi TPP (thiamine) is co-factor in reaction Relieves the inhibition -> forms complex -> excreted

27 The Glyoxylate Cycle Enables Plant and Bacteria to grow on Acetate It bypasses the decarboxylation steps of citric acid cycle Enzymes that allow conversion from acetate into succinate are in blue boxes - Intake of 2 acetyl groups/cycle - production of succinate -> glucose - regeneration of oxaloacetate from glyoxylate Plant cell

28 Regulation of the glyoxylate cycle