Metabolism Gluconeogenesis/Citric Acid Cycle

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1 Metabolism Gluconeogenesis/Citric Acid Cycle BIOB111 CHEMISTRY & BIOCHEMISTRY Session 21

2 Session Plan Gluconeogenesis Cori Cycle Common Metabolic Pathway The Citric Acid Cycle Stoker 2014, p859

3 Gluconeogenesis Metabolic pathway by which glucose is synthesized from noncarbohydrate sources. Glycogen stores in muscle & liver tissue are depleted within hours of fasting or in even less time from heavy work or strenuous physical activity Without gluconeogenesis, the brain, which is dependent on glucose as a fuel, would have problems functioning if food intake were restricted for even one day. Gluconeogenesis helps to maintain normal blood glucose levels in times of inadequate dietary carbohydrate intake.

4 Gluconeogenesis The non-carbohydrate starting materials are: Pyruvate (from AA catabolism) Oxaloacetate (from AA catabolism) Lactate (from muscles & RBCs) Glycerol (from TAG hydrolysis) Certain AAs (from dietary protein hydrolysis or from muscle protein during starvation) About 90% of Gluconeogenesis takes place in the liver. Not the exact opposite process to Glycolysis. Glycolysis (10 steps) vs. Gluconeogenesis (11 steps).

5 Gluconeogenesis 7 reactions are the reverse of Glycolysis & use the same enzymes. 3 reactions are not reversible catalyzed by kinase enzymes. Reaction 1 of Glycolysis Hexokinase Reaction 3 of Glycolysis Phosphofructokinase Reaction 10 of Glycolysis Pyruvate kinase Gluconeogenesis requires different enzymes to bypass these steps. Bypass of Reaction 10 Pyruvate carboxylase & Phosphoenolpyruvate carboxykinase Bypass of Reaction 3 Fructose 1,6-bisphosphatase Bypass of Reaction 1 Glucose 6-phosphatase

Pyruvate to Phosphoenolpyruvate The last step of Glycolysis produces ATP, however the reverse process in Gluconeogenesis can t be accomplished in a single step due to large energy difference between

6 Pyruvate to Phosphoenolpyruvate The last step of Glycolysis produces ATP, however the reverse process in Gluconeogenesis can t be accomplished in a single step due to large energy difference between Pyruvate & Phosphoenolpyruvate. Hence a 2 step process is required. 1. Pyruvate forms Oxaloacetate (connection to CAC if energy is needed rather than glucose) Catalyzed by Pyruvate carboxylase (Biotin cofactor) 2. Oxaloacetate Phosphoenolpyruvate Catalyzed by Phosphoenolpyruvate carboxykinase Stoker 2014, Figure p906

8 Comparison of Glycolysis & Gluconeogenesis Phosphoenolpyruvate to Fructose-1,6-bisphosphate using the same enzymes as glycolysis (reversal of glycolysis) Stoker 2014, Figure p907

9 Gluconeogenesis Glycolysis produces 2 ATP. Gluconeogenesis requires equivalent of 6 ATP (4ATP & 2GTP). Whenever Gluconeogenesis occurs it is at the expense of other ATP-producing metabolic processes. The overall net reaction for Gluconeogenesis:

10 Regulation of Glycolycis & Gluconeogenesis Glycolysis Gluconeogenesis Enzyme Hexokinase Glucose 6-phosphatase Activated by High glucose levels, Insulin, Adrenalin Low glucose, Glucose 6-phosphate Inhibited by Glucose 6-phosphate Enzyme Phosphofructokinase Fructose 1,6-bisphosphatase Activated by ADP, AMP Low glucose levels, Glucagon Inhibited by ATP ADP, AMP, Insulin Enzyme Pyruvate kinase Pyruvate carboxylase Activated by Fructose 1,6-bisphosphate Low glucose levels, Glucagon Inhibited by ATP, Acetyl CoA Insulin

11 The Cori Cycle Gluconeogenesis using Lactate as a source is particularly important because of Lactate formation during strenuous exercise. Lactate produced diffuses from muscle cells into the bloodstream & is transported to liver. Enzyme Lactate dehydrogenase converts Lactate to Pyruvate in liver. Pyruvate is then via Gluconeogenesis converted to Glucose enters the bloodstream & transported back to the muscles.

12 The Cori Cycle Stoker 2014, Figure p909

13 The relationships among 4 metabolic pathways that involve glucose Stoker 2014, Figure p910

14 Glucose Metabolism Stoker 2014, p912

15 The Citric Acid Cycle (CAC) Krebs Cycle (Hans Adolf Krebs) Tricarboxylic Acid Cycle Is a series of biochemical reactions, in which the Acetyl portion of Acetyl CoA is oxidized to CO 2 & reduced forms of coenzymes NADH & FADH 2 are produced (they carry electrons into the ETC). Takes place in the mitochondrial matrix (here the enzymes of the CAC are located) in the presence of oxygen. Consists of 8 steps 4 of these steps involve redox reactions.

16 Stoker 2014, Figure p861

17 1. Formation of Citrate Acetyl CoA (the C 2 fragment from degradation of carbohydrates, fats & proteins) combines with Oxaloacetate (the C 4 fragment ) producing Citrate (the C 6 fragment ). Catalyzed by the enzyme Citrate synthase.

18 2. Formation of Isocitrate Isomerisation reaction catalyzed by the enzyme Aconitase. Forming Isocitrate (2 0 alcohol) a less symmetrical isomer of Citrate (3 0 alcohol).

19 3. Oxidative Decarboxylation of Isocitrate 1 st redox reaction (NAD) The C-chain is shortened by the removal of COOH group as CO 2. Catalyzed by the enzyme Isocitrate dehydrogenase.

20 4. Oxidative Decarboxylation of α-ketoglutarate 2 nd redox reaction (NAD) Catalyzed by a 3-enzyme system α-ketoglutarate dehydrogenase complex TPP (Thiamin) & Mg 2+ are involved.

21 5. Formation of Succinate & GTP Formation of GTP a high-energy triphosphate molecule direct substrate level phosphorylation. Catalyzed by the enzyme Succinyl-CoA synthetase.

22 Steps 6 8 of the CAC Involve a sequence of functional group changes that can be summarized in the following:

23 6. Oxidation of Succinate 3 rd redox reaction (FAD) Catalyzed by the enzyme Succinate dehydrogenase.

24 7. Hydration of Fumarate H 2 O is added to Fumarate to produce L-Malate. Catalyzed by the enzyme Fumarase.

25 8. Oxidation of L-Malate 4 th redox reaction (NAD) Oxaloacetate is produced, which enters the 1 st step again to combine with another Acetyl CoA & form Citrate. Catalyzed by the enzyme Malate dehydrogenase.

26 Stoker 2014, p865

27 Summary of the CAC One complete cycle produces 2CO 2, 1GTP, 3 NADH & 1 FADH 2, which carry e - & H + into the ETC where ATP is formed. 4 B vitamins are required for the correct function of the CAC Thiamin, Riboflavin, Niacin & Pantothenic acid.

28 Regulation of the CAC The rate at which the CAC operates is controlled by the body s needs for energy (ATP) & NADH levels. When ATP supply is high ATP inhibits Citrate synthase (Step 1 of CAC). When ATP levels are low & ADP levels are high ADP activates Citrate synthase & the CAC speeds up. A similar control mechanism exists at Step 3 Isocitrate dehydrogenase ADP acts as an activator & NADH acts as an inhibitor.

29 Readings & Resources Stoker, HS 2014, General, Organic and Biological Chemistry, 7 th edn, Brooks/Cole, Cengage Learning, Belmont, CA. Stoker, HS 2004, General, Organic and Biological Chemistry, 3 rd edn, Houghton Mifflin, Boston, MA. Timberlake, KC 2014, General, organic, and biological chemistry: structures of life, 4 th edn, Pearson, Boston, MA. Alberts, B, Johnson, A, Lewis, J, Raff, M, Roberts, K & Walter P 2008, Molecular biology of the cell, 5 th edn, Garland Science, New York. Berg, JM, Tymoczko, JL & Stryer, L 2012, Biochemistry, 7 th edn, W.H. Freeman, New York. Dominiczak, MH 2007, Flesh and bones of metabolism, Elsevier Mosby, Edinburgh. Tortora, GJ & Derrickson, B 2014, Principles of Anatomy and Physiology, 14 th edn, John Wiley & Sons, Hoboken, NJ. Tortora, GJ & Grabowski, SR 2003, Principles of Anatomy and Physiology, 10 th edn, John Wiley & Sons, New York, NY.

Bioenergetics and metabolic pathways

Bioenergetics and metabolic pathways BIOB111 CHEMISTRY & BIOCHEMISTRY Session 17 Session Plan Introduction to Bioenergetics Metabolism Metabolic Pathways Metabolism & Cell Structure Mitochondria Compounds