Metabolism

1. Metabolism • Definition: Sum of all chemical reactions in the body • Anabolic versus Catabolic Reactions • Anabolic Rxns = use chemical energy to synthesize products • Catabolic Rxns = break down substances to generate chemical energy

2. Chemical Energy Production Energy (sunlight) Photosynthesis (plants) CO2 + H2O Carbohydrates + O2 Respiration (animals and plants) Carbohydrates + O2 CO2 + H20 + ATP

3. Food Consumption Food ingested is digested to elementary units by catabolic reactions that convert: a. Lipids to glycerol and fatty acids b. Proteins to amino acids c. Complex carbohydrates to simple sugars

4. Food Utilization Elementary units (glycerol, f.a., a.a., simple sugars) produced by digestion and ab- sorption are: • used for energy production • stored • converted to other cellular products • used for production of other cell components

5. Carbohydrate Metabolism • Carbohydrates can be used to generate ATP • Can be stored as glycogen • mostly in liver and skeletal muscle tissue • Can be converted to fat and stored

6. Fat Metabolism • Triglycerides are used to generate energy (ATP) • F.A. generate acetyl Coenzyme A which enters Kreb’s cycle and generates ATP • At rest, @ half of energy used by muscle, liver and kidneys comes from f.a. catabolism • Glycerol can be converted to glucose • Anaerobic and/or aerobic metabolism of glucose can generate ATP • Glucose can be converted to fat and stored

7. Fat Metabolism (continued) • Can be stored as fat • Accounts for majority of energy stored in body • Most cells can store some fat • Adipocytes = specialized cells designed for storing fat • Body will preferentially convert reserves to fat for storage because gram per gram, fat generates more energy than does protein or carbohydrate

8. Protein Metabolism • Proteins broken down to amino acids • Amino acids can be used to generate ATP • the amino group cannot be used to generate ATP • the remainder of most amino acids can generate intermediates that can enter the glycolytic pathway or the Kreb’s cycle H O H - N - C - C - OH H R

9. Protein Anabolism • Nonessential amino acids are those that can be synthesized by the body • glucose and fats can be used to generate some amino acids • Essential amino acids (8) cannot be synthesized in body • must be obtained from dietary intake

10. Energy Considerations • Catabolic reactions release energy • Majority released as heat energy • Homeostasis strives to maintain constant internal environment, including constant internal temperature • Pathways combine multiple reactions, each of which generates small amounts of energy, to minimize heat generation

11. Metabolic Pathway • Definition: A sequence of enzyme-mediated reactions leading to the formation of a particular product • Mechanism for controlling thermal energy release associated with chemical reactions

12. Anaerobic Metabolism DOES NOT Require oxygen Occurs in cytoplasm Converts glucose to pyruvate by glycolysis Generates ATP Generates much lower levels of ATP than aerobic metabolism of glucose Aerobic Metabolism DOES require oxygen Occurs in mitochondria Converts pyruvate to Acetyl CoA Generates ATP via the Kreb’s cycle and electron transport chain Generates much more ATP than anaerobic metabolism Anaerobic versus Aerobic Energy Production

13. Chemical Oxidation & Reduction • GER = GAIN OF ELECTRONS • gain of an electron equivalent to gain of H atom • when a molecule gains electrons it becomes REDUCED • LEO = LOSS OF ELECTRONS • loss of electron equivalent to loss of H atom • when molecule loses electrons it becomes OXIDIZED

14. NAD and FAD • NAD = nicotinamide adenine dinucleotide • derived from vitamin B3 • FAD = flavin adenine dinucleotide • derived from vitamin B2 • Participate in oxidation/reduction reactions • NAD and FAD are coenzymes for several reactions in the Kreb’s cycle • Become ‘reduced’ when they accept Hatoms • Become ‘oxidized’ when they donate their H atoms • Shuttle hydrogen atoms between molecules by vacillating back and forth between oxidized and reduced forms

15. NAD and ATP Production • Oxidized form = NAD+ • Reduced form = NADH + H+ • Each molecule of reduced NAD (NADH + H+)formed produces 3 ATP by oxidative phosphorylation in the mitochondria

16. FAD and ATP Production • Oxidized form = FAD • Reduced form = FADH2 • Each reduced FAD (FADH2) formed produces 2 ATP by oxidative phosphorylation in the mitochondria • 2 FADH2 produced in Kreb’s cycle (one per molecule of pyruvate) • produces 4 molecules of ATP by oxidative phosphorylation

17. Phosphorylation • Definition: Addition of phosphate group to an organic molecule • Two types of phosphorylation • Substrate level • The process of transferring a phosphate group between two organic molecules • i.e. make ATP by transferring a phosphate group from some organic molecule to ADP to form ATP • Oxidative • The process of adding an inorganic phosphate to an organic molecule • i.e. make ATP by adding a free phosphate group (unattached to any organic molecule) to ADP

18. Oxidative Phosphorylation • Formation of ATP by adding inorganic phosphate to ADP • Occurs in mitochondria • Energy used to drive the production of ATP comes from the production of water (H2O) by the combining of H atoms and oxygen • H + O2 H2O • ADP + Pi ATP • Reduced NAD and FAD provide the H atoms that combine with oxygen to form water

19. Glycolysis • Conversion of glucose pyruvate • one 6-carbon sugar two 3-carbon molecules • Occurs in the cytoplasm • USES 2 ATP molecules • transfers 2 phosphates from ATP to ‘trap’ glucose and later intermediates inside the cell • Gross ATP production = 10 ATP • Net ATP production = 6 ATP per molecule of glucose utilized (8 ATP in heart and liver)

20. Gross ATP Production by Glycolysis • 4 ATP by substrate-level phosphorylation (SLP) • 6 ATP by oxidative phosphorylation (OP) • 2 molecules of reduced NAD (NADH + H+) • 3 ATP per molecule of reduced NAD • Gross ATP = ATP by SLP + ATP by OP • Gross ATP = 4 + 6 = 10 ATP

21. Glycolysis and ATP Consumption • 2 ATP molecules used for each molecule of glucose converted to pyruvate • One to trap glucose inside cell • One to energize intermediate • 2 ATP molecules used to supply energy to transport reduced NAD to mitochondria • Exception: liver and heart, which move reduced NAD to mitochondria by non-ATP dependent process

22. Net ATP Production by Glycolysis • Net ATP = Gross ATP produced – ATP used • In Most Tissues = 10 – 4 = 6 ATP • In liver and heart = 10 – 2 = 8 ATP

23. Fate of Pyruvate Generated in Glycolysis • If oxygen is present pyruvate is converted to Acetyl CoA • 1 molecule glucose yields 2 molecules pyruvate in glycolysis and so can produce 2 molecules of Acetyl CoA • Acetyl CoA enters mitochondria and is shuttled into the Kreb’s cycle • If oxygen is absent pyruvate is converted to lactate and handled by Cori cycle

24. Kreb’s Cycle • Occurs in mitochondria • Acetyl CoA feeds into cycle that 1. Generates 3 reduced NAD and 1 reduced FAD per revolution -reduced NAD yields 9 ATP per revolution -reduced FAD yields 2 ATP per revolution 2. Generates one ATP by substrate-level phosphorylation per revolution • Two revolutions occur per molecule glucose metabolized

25. ATP Production via Kreb’s Cycle • Per revolution = 12 ATP • 11 ATP by oxidative phosphorylation • 1 ATP by substrate level phosphorylation • Two revolutions per glucose molecule yields 24 (I.e. 12 X 2 = 24) ATP total per molecule of glucose metabolized via Kreb’s cycle

26. By glycolysis 4 by SLP 6 by OP Gross = 10 ATP Net = 6 (or 8 in liver and heart) ATP 2 used to trap and energize 2 used to transport reduced NAD to mitochondria (except in liver and heart) 6 (8 in liver and heart) by glycolysis 6 by OP in conversion of pyruvates to Acetyl CoA 24 by Kreb’s cycle 22 by OP 2 by SLP ATP per glucose molecule Anaerobic Metabolism Anaerobic Metabolism

27. Cori Cycle • In the absence of oxygen, pyruvate is converted to lactate (lactic acid) • Cori cycle = cycle by which lactate is handled in the body

28. Cori Cycle • Lactate moves from muscle to blood; pyruvate cannot leave muscle • Lactate moves from blood to liver • in liver, lactate is converted back to pyruvate • pyruvate is converted back to glucose • glucose can enter bloodstream and return to muscle for energy production or be stored in liver as glycogen

29. Cori Cycle MUSCLE BLOOD LIVER Glycogen Glycogen Glucose Glucose Glucose Pyruvate Pyruvate Lactate Lactate Lactate

30. Metabolic States • Absorptive state • period when ingested nutrients are entering the bloodstream from the G.I. Tract • takes around 4 hours to completely absorb average meal • Post-absorptive state • period when G.I. tract is empty of nutrients and energy must be supplied by body’s stored reserves

31. Absorptive State • Glucose = major energy source • Blood glucose levels high • Insulin secreted from beta cells of pancreas • insulin = protein hormone • stimulates transport of glucose from bloodstream into cells • all cells except brain and liver require insulin action to move glucose into cells • Net synthesis of glycogen, fat, and protein occurs

32. Insulin Actions in Liver • Glucose can enter liver cells without insulin • Promotes conversion of glucose to glycogen (storage form of carbohydrates) • Promotes conversion of fatty acids and amino acids to fat

33. Insulin Action in Muscle • Essential for transport of glucose into cells • skeletal muscle = majority of body mass and major consumer of metabolic fuel, even at rest • Promotes conversion of glucose to glycogen

34. Insulin Action in Fat • Promotes uptake of glucose from bloodstream • Promotes conversion of glucose and fatty acids to fat (triacylglycerols)

35. Insulin Action in Most Cells • Promotes uptake of glucose from bloodstream and use for energy (ATP) production • Promotes uptake of fatty acids and their use for energy (ATP) production • Promotes uptake of amino acids and their conversion to protein

36. Glucose and the Brain • Glucose can enter brain without insulin action • Brain cannot synthesize or store enough glucose to provide energy from ATP for more than a few minutes • Body strictly regulates blood glucose to meet brain’s needs

37. Post-absorptive State • Several hours after a meal • Blood glucose levels are low • Body must obtain glucose from reserves • Glucagon = main hormone in circulation, produced by alpha cells of pancreas

38. Post-absorptive State (continued) Catabolic reactions occur to: 1. Provide blood glucose a. Glycogen converted to glucose b. Gluconeogenesis = production of glucose from non-carbohydrate sources (i.e. Cori cycle lactate to glucose) 2. Promote glucose sparing (preferential use of fat over glucose in most tissues)

39. Actions of Glucagon in Liver • Stimulates glycogenolysis (glycogen to glucose) • Stimulates fats to fatty acids • Stimulates proteins to amino acids

40. Glucagon Action in Fat Stimulates fat conversion to fatty acids

41. Glucagon Action in Most Cells Stimulates protein conversion to amino acids

42. Sources of Glucose • Intestinal absorption • Glycogen breakdown (glycogenolysis) • Biosynthesis from non-carbohydrate sources (gluconeogenesis) • Most cells can synthesize glycogen from and hydrolyze glycogen to glucose • Only LIVER and KIDNEY can release glucose into bloodstream

43. Enzymes and Glucose Metabolism • Insulin and Glucagon • Glycogen Synthetase • needed to synthesize glycogen from glucose • found in most cells • Phosphorylase • needed to hydrolyze glycogen to glucose • found in most cells

44. Enzymes and Glucose Metabolism • Pyruvate carboxylase, phosphoenolpyruvate, and fructose 1,6 diphosphatase • enzymes needed for gluconeogenesis • found only in liver and kidney • Glucose-6-phosphatase • needed to release glucose into circulation • found only in liver and kidney

45. Liver and Glucose Production • Liver can produce glucose by gluconeogenesis • Liver can release synthesized glucose for use by other cells • When liver is producing and releasing glucose for use by other tissues it uses ketone bodies as source of energy • metabolic products produced by acetyl CoA • acetoacetate, b-hydroxybutyrate, and acetone

46. Caloric Content of Major Food Groups and Ethanol Groupcal/gm carbohydrate 4 protein 4 fat 9* ethanol 7 *fat provides most energy per unit weight of all foods; is best storage form of food

47. Exercise and Metabolism • At rest • skeletal muscle uses fatty acid metabolism to provide energy • blood glucose is reserved primarily for brain • Exercise increases glucose utilization by muscle

48. Exercise and Metabolism(continued) • Endogenous glucose production increased to meet demands of low intensity exercise • Exhaustive high demand exercise • first depletes glycogen stores • then depletes liver-derived glucose • eventually results in utilization of fatty acids

49. Regulation of Food Intake • Hypothalamus • site of feeding center (on switch for food intake) • site of satiety center (off switch for food intake) • Leptin • protein hormone produced by fat cells • acts at level of hypothalamus to decrease food intake • may be part of negative feedback loop that monitors body fat levels (lipostat)

50. Set-Point Theory • ‘Predetermined’ weight optimum • body strives to maintain setpoint and will defend attempts to alter it (i.e. diets) • Rhythm method of ‘girth’ control • repeated cycles of alternating weight gain followed by weight loss • when body has reason to anticipate episodes of starvation it adjusts metabolic processes to more efficiently absorb and store food when it is available