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BIOMOLECULES AND METABOLISM 3. Metabolism and Its Control

BCH 1002 Biochemical Aspects of Health and Disease. BIOMOLECULES AND METABOLISM 3. Metabolism and Its Control. Prof. K. M. Chan Dept. of Biochemistry Chinese University Rm 513B, Basic Medical Sciences Building Tel: 3163-4420; Email: kingchan@cuhk.edu.hk. Contents.

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BIOMOLECULES AND METABOLISM 3. Metabolism and Its Control

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  1. BCH 1002 Biochemical Aspects of Health and Disease BIOMOLECULES AND METABOLISM3. Metabolism and Its Control Prof. K. M. Chan Dept. of Biochemistry Chinese University Rm 513B, Basic Medical Sciences Building Tel: 3163-4420; Email: kingchan@cuhk.edu.hk

  2. Contents • Anabolism, catabolism, reducing power and energy production • Enzyme actions • Glycolysis & Krebs cycle • B oxidation and fat metabolism • Regulation of metabolism by hormones

  3. 3.1 Aabolism, catabolism, reducing power and energy (ATP) production • Living processes are complex of anabolic (biosynthesis) and catabolic (disintegration) reaction pathways that use carbohydrates, lipids, and proteins as energy sources and biosynthetic precursors. The processes are precisely regulated by the following ways. • Compartmentation: different organs have different functions, and different pathways take place in various organelles in the cells. • Each step in the pathways requires specific enzyme, co-factors and optimal pH (buffered) amd is tightly controlled by various factors.

  4. 3.1.1 Catabolism has three stages • Nutrient molecules (proteins, polysaccharides and fats from food) are hydrolyzed to their building block units by digestions. • Building block units are converted to easily oxidized forms (primarily acetyl CoA). • Acetyl CoA is completely oxidized to form CO2 and H2O. Energy is captured when ATP synthesis is linked to the electron transport pathway using ATP synthase.

  5. Catabolism processes FOOD Proteins Carbohydrates Fats Glucose Fatty acids and glycerol Amino acids ATP Glycolysis Pyruvate ATP Acetyl CoA Oxidative phosphorylation Krebs (Citric acid) cycle

  6. 3.1.2 Anabolism • Large complex molecules are synthesized from smaller precursors. • Building block molecules (amino acids, sugars and fatty acids) are produced or acquired from the diet. • Because anabolic processes include the synthesis of polysaccharides and proteins from sugars and amino acids, the biosynthetic pathways increase order and complexity, they require inputs of free energy (ATP and NADPH). http://www.accessexcellence.org/RC/VL/GG/ecb/ATP_ADP.html

  7. ATP plays an extraordinary role within cells: currency or input of energy. Hydrolysis of ATP provides an immediate and direct input of free energy to drive a variety of endergonic (energy requiring) biochemical reactions. Chemical coupling allows the cell to get the energy produced by catabolism. Thioester is also important in energy harvesting pathways for breakdown of molecules. Acetyl CoA carries one acetyl group for further catabolism of carbohydrates. 3.1.3. ATP energy and Acetyl Coenzyme A (acetyl CoA) CH3 Coenzyme A – S – C = O

  8. 3.1.4 Reducing power • Both energy capturing and releasing processes consist largely of redox reactions. • Electron donor (reducing agent) • Electron acceptor (oxidizing agent) ½ O2 2 e- NAD+ + H+ + 2 e- NADH ATP FADH2 FAD + 2H+ + 2 e- Cu+ + Fe3+ Cu2+ + Fe2+

  9. http://en.wikipedia.org/wiki/Image:NADplus.png NAD: Nicotinamide Adenine Dinucleotide http://www.estrellamountain.edu/faculty/farabee/biobk/BioBookEnzym.html

  10. 3.1.5 Division of labor in our body • Liver for metabolism; stomach and duodenum for digestion. • Intestine for absorption. • Circulation for transport (water distribution between plasma and interstitial fluid compartments). • Renal system for excretion (control of body fluid and electrolyte balance) • Muscle plays an important part to burn the energy from food when fed or from fat when starved. • Importance of nutrients, exercise and sport (control of body composition and energy expenditure). • The best way to keep your body in good shape is to do exercise.

  11. 3.2 Enzymatic Control of Metabolism http://www.estrellamountain.edu/faculty/farabee/biobk/BioBookEnzym.html

  12. Interconversion of the macronutrients • Protein, carbohydrate and fat are energy producing macronutrients • Pathways are regulated at the following levels: • certain regulatory enzymes by substrate availability, • allosteric mechanisms, and • covalent modification such as phosphorylation.

  13. 3.3 Carbohydrate metabolism and energy production • Glycolysis (in cytoplasm) • Krebs cycle (in matrix inside mitochondria) • Aerobic and anaerobic metabolism • Gluconeogenesis

  14. 3.3.1 GLYCOLYSIS • Glucose can also be available from food intake. • Glucose is also stored as glycogen (glycogenesis). • After gluconeogenesis, glucose is converted from glycogen in liver or muscle for glycolysis. • Glycolysis is the break down of a 6 C glucose sugar to two 3C pyruvate.

  15. Central role of liver in metabolism • Glucose entering the hepatocyte is phosphorylated by glucokinase to glucose-6-phosphate (G-6-P). • Other monosaccharides are also made to G-6-P via gluconeogenesis, then glucose can be stored as glycogen. • When we need energy, glycolysis converts G-6-P to pyruvate and acetyl coA to enter Citric acid cycle to produce ATP energy via oxidative phosporylation (aerobic metabolism).

  16. Glycolysis: break down of glucose in cytoplasm UDP-glucose Glucose-1-phosphate Glycogen Lactate Lactate Dehydrogenase Glucose-6-phosphate Hexokinase Glucose ADP ATP Fructose-6-phosphate 6 C ADP Pyruvate ATP Fructose-1, 6-biphosphate Glycerol Dihydroxyacetone phosphate (DHAP) ATP Glyceraldehyde-3-phosphate ADP 3 C NAD + Pi H2O ATP ADP Phospho-enol-pyruvate NADH + H+ Glycerate-3-phosphate Glycerate-2-phosphate Glyceraldehyde-1, 3-bisphosphate ATP ADP H2O

  17. http://www.accessexcellence.org/RC/VL/GG/ecb/outline_glycolysis.htmlhttp://www.accessexcellence.org/RC/VL/GG/ecb/outline_glycolysis.html

  18. Pyruvate is transported across the inner mitochondrial membrane and oxidized within the matrix to acetyl CoA via TCA (Krebs) cycle. • Acetyl Co A can also be produced fromβoxidation of fatty acids in the mitochondria. • From which the NADH produced in the mitochondria is used for oxidative phosphorylation in the inner membrane of mitochondria to make ATP energy using water and oxygen.

  19. Glycolysis Fat,triacylglycerol Carbohydrate, Glycogen and glucose (6C) Protein Fructose Amino acids Triose P (3C) Glycerol 3-P Fatty Acids Cholesterol Phosphoenolpyruvate(PEP) Cysteine Alanine Pyruvate (3C) PhenylalanineTyrosine Leucine Acetoacetate Serine Histidine Acetyl CoA (2C) Oxaloacetate (4C) Citrate (6C) Glutamate Krebs Cycle(Citric acid cycle) Fumarate (4C) Proline Ketoglutarate (5C) Succinyl CoA (4C) Valine Hydroxylproline

  20. 3.3.2 Importance of Krebs Cycle • Kreb cycle (Citric acid cycle or TCA cycle) is a amphibolic pathway: oxidative catabolism and provide precursor molecules for anabolism, particularly gluconeogenesis. • Energy (2 ATPs per cycle) will be produced from succinyl Co A. Other compounds produce NADH and FADH2 for oxidative phosphorylation in the mitochondria to make 26 more ATP.

  21. 3.3.3 Aerobic and anerobic metabolism • Glucose + 6 O2 → 6 CO2 + 6 H2O • Glucose + 2ADP + 2 Pi → 2 Lactate + 2ATP • Glucose + 6 O2 + 30 ADP + 32 Pi→ 6 CO2 + 6 H2O + 30 ATP • In glycolysis, initially 2 ATPs are used; one for hexokinase to phosphrylate glucose to G-6-P, another to make Fructose 6 Phosphate to Fructose 1,6, biphosphate. • This 6 C sugar is further divided into 2 3C sugars each producing 2 ATP to make a total of 4 ATP. • Net ATP production is 2 ATP from making glucose to pyruvate without using oxygen (anerobic).

  22. Acetyl CoA (2C from pyruvate, 3C) reacts with oxaloacetate (4C), citrate (6C) is formed to produce 3 NADH and FADH2. • The cycle goes on from citrate to isocitrate (6C), then forming ketoglutarate (5C), succinyl-CoA (4C), succinate (4C) , fumarate and Malate to Oxaloacetate (4C) again. • The 10 NADH and 2 FADH2 made from Kreb cycle are used for electron transport to generate proton gradient across inner membrane for ATP synthase to produce 26 ATP with oxidative phosphorylation. 2 ATP are made from TCA cycle and 2 ATP from glycolysis, 26 ATP are from oxidative phosphorylation to make a total of 30 ATP from one glucose.

  23. 3.3.4 Oxidative Phosphorylation takes place in mitochondria for more ATP production • Glycolysis takes place in the cytoplasm; after glycolysis, pyruvate is added with CoA using NAD+ to become Acetyl CoA, CO2 and NADH. • Acetyl CoA is the fuel for Krebs Cycle to take place in the matrix. • Oxidative phosphorylation depends on electron transfer and the respiratory chain linking to TCA cycle create proton gradient across the inner membrane of mitochondria. • The proton gradient powers the synthesis of ATP using ATP Synthase • When these steps are blocked or uncoupled by uncoupling proteins, no ATP made but only heat energy produced.

  24. Krebs Cycle in matrix Glycolysis in cytoplasm Matrix Inner mitochondria membrane Electron transport chain and oxidative phosphorylation H+ H+ H+ H+ H+ H+ Oxidative phosphorylation H+ Cytochrome B, Cytochrome C, Fe-S proteins, etc. ATP Synthase e- Electron Transport Chain H+ H+ H+ + 2 H+ + ½ O2 → H2O NADH H+ Uncoupling Proteins ATP production NAD H+ e.g. in brown fats for heat generation in small mammals. Matrix

  25. Overview of oxidative phosphorylation

  26. 3.3.5 Gluconeogenesis • Occurs within mitochondria • Lactate is made to pyruvate, but this is not the reverse of glycolysis • Pyruvate carboxylase converts pyruvate to Oxaloacetate with CO2 • PEPCK (PEP carboxykinase) converts oxaloacetate to PEP (Phosphoenol pyruvate to G-3-P, F-6-P to G-6-P. • Glucose-6-phosphatase converts G-6-P to glucose in endoplasmic reticulum

  27. Skeletal Muscle Liver The Cori Cycle Lactate Lactate blood LDH, Lactate Dehydrogenase LDH, Lactate Dehydrogenase Pyruvate Pyruvate Glycolysis Gluconeogenesis Glucose 6-phosphate Glucose 6-phosphate Glucose 6-phosphatase blood Hexokinase Glucose Glucose

  28. Metabolism in liver (amino acid for gluconeogenesis) • Amino acids in the liver can also be converted to pyruvate which is converted to glucose or acetyl coA. • Acetyl Co A can be made to fatty acid and triacylglycerols and stored as fat. • Fatty acids in the liver can be made to lipids for storage; or converted to acetyl CoA via βoxidation when needed.

  29. 3.4 REGULATION OF METABOLISM BY HORMONES • Feeding and Fasting • The Pancreatic Islet Hormones • Regulation of Fatty Acid Metabolism • Diabetes Mellitus

  30. 3.4.1 Feeding and Fasting • As glucose moves via the blood to the liver, insulin from the βcells in the pancreas is released to promote glucose uptake by muscle and adipose (for fat storage), and formation of glycogen in liver. Insulin also induce protein synthesis. • When the nutrient flow from intestine diminishes (fasting), blood glucose and insulin drop to normal and glucagon is released to prevent hypoglycemia by promoting glycogenolysis and gluconeogenesis in the liver. • Insulin can depress glycagon in αcells. They have opposing effects on blood glucose levels.

  31. FASTING Well-fed Glucose - INSULIN + Glucose + Glucagon - G-6-P G-6-P Fructose-6-P Fructose-6-P Fructose-1, 6- bis-P Fructose-1, 6- bis-P Cortisol - PEP (3C) PEP + + Oxaloacetate PEPCK - + Pyruvate Pyruvate

  32. 3.4.2 The Pancreatic Islet Hormones F cell secretes pancreatic polypeptides for digestion in duodenum Hyperglycemia (high blood glucose) stimulates Exocrine Acini Pancreas Beta cell secretes insulin Hepatic artery Spleen Abdominal aorta Alpha cell secretes glucagon Duodenum Delta cell secretes somatostatin (inhibits growth hormone) Hypoglycemia (low blood glucose) stimulates

  33. Feedback Regulation of the Secretion of Glucagon and Insulin

  34. Insulin • Increase glucose uptake in cells. • Convert glucose to glycogen (glycogenesis). • Increase amino acid uptake and protein synthesis. • Promote lipogenesis. • Slow down gluconeogenesis and glycogenolysis. • Blood glucose level drops • Hypoglycemia inhibits release of insulin.

  35. Glucagon • Acts on hepatocytes. • Converts glycogen to glucose (glycogenolysis). • Form glucose from lactic acid and amino acids (gluconeogenesis). • Glucose released from liver to make blood glucose increase to normal. • Hyperglycemia inhibits release of glucagon.

  36. http://www.medbio.info/Horn/Time%203-4/homeostasis_2.htm

  37. http://www.medbio.info/Horn/Time%203-4/homeostasis_2.htm

  38. http://www.medbio.info/Horn/Time%203-4/homeostasis_2.htm

  39. http://www.medbio.info/Horn/Time%203-4/homeostasis_2.htm

  40. 3.5.4 Diabetes Mellitus • Caused by deficiency of insulin secretion or actions • Type I diabetes (10%) is insulin-dependent (IDDM), starts early in life and could become very severe. Due to insufficient insulin secretion and thus injection of insulin is required to save the patients’ life. • Type II diabetes (90%) is non-insulin dependent, NIDDM, which is slow to develop with milder symptoms. Insulin is produced but the cells are not responding (insulin resistant), causing many complications including obesity.

  41. Biochemical complications of diabetes mellitus. • Both types of diabetes fail to uptake glucose, leading to hyperglycemia. Other symptoms of diabetes include thirst and frequent urination. • In IDDM, excessive glucagon level (due to lower insulin level) also reduces the level of F-2,6-BP in the liver, and inhibits glycolysis. • Gluconeogenesis and glycogen breakdown are also induced. • NIDDM produces excessive amount of glucose in blood leading to glucosuria. • Excessive glucose is thus produced into the blood leading to hyperglycemia (> 10 mM), even with glucose excreted in urine (hence named mellitus).

  42. Tutorial Questions: • Compare gluconeogenesis and glycogenolysis, and explain how insulin affects these processes. • Explain the consequences of using low carbohydrate and high protein diet for weigh loss plan. • What is the role of leptine on dieting? • Why untreated diabetes may die?

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