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BC 368 Biochemistry of the Cell II

BC 368 Biochemistry of the Cell II. Integration of Mammalian Metabolism May 7, 2015. Highlights of Metabolism. 1. ATP = universal energy currency. expended to ensure unidirectionality of each metabolic pathway and complete conversion to products.

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BC 368 Biochemistry of the Cell II

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  1. BC 368 Biochemistry of the Cell II Integration of Mammalian Metabolism May 7, 2015

  2. Highlights of Metabolism 1. ATP = universal energy currency • expended to ensure unidirectionality of each metabolic pathway and complete conversion to products coupling ATP hydrolysis to a reaction increases K by a factor of ~108.

  3. Highlights of Metabolism 1. ATP = universal energy currency • expended to ensure unidirectionality of each metabolic pathway and complete conversion to products • an important allosteric regulator • generated by the oxidation of fuel molecules: NADH and FADH2 shuttle electrons to the ETC where the bulk of ATP is formed via oxidative phosphorylation.

  4. 2. NADPH is the major electron donor in reductive biosynthesis • formed primarily via the pentose phosphate pathway 3. Central metabolic pathways have both anabolic and catabolic roles. • TCA is an excellent example of an amphibolic pathway.

  5. Carbs, Amino Acids Fats, Amino Acids Amino Acids • TCA is an excellent example of an amphibolic pathway.

  6. 4. Distinct pathways for biosynthesis and degradation • ensures favorable thermodynamics for both directions • separate, but interrelated, control mechanisms (often the 1st step) • compartmentalization (e.g., cytosol vs. mitochondrial matrix)

  7. 5. Many coenzymes coenzymerole example Niacin/B3 (NAD+) redoxmalate dehydrogenase Riboflavin/B2 (FAD) redoxsuccinate dehydrogenase Pantothenic acid/B5 (CoA) acyl transferpyruvate dehydrogenase Pyridoxal phosphate/B6 transamination-KG --> Glu Vitamin B12 rearrangementshomocysteine--> Met Thiamine/B1 (TPP) decarboxylationpyruvate dehydrogenase Biotin/B7 CO2 carrierpyruvate carboxylase Lipoic acid acyl carrierpyruvate dehydrogenase Folic Acid/B9 carbon carrieramino acid degradation

  8. Which of the following coenzymes often participates in carboxylation reactions? • Vitamin B12 • TPP • FAD • Coenzyme A • Biotin

  9. glycogen pyruvate ribose-5-P acetyl-CoA lactate alanine OA CO2 fatty acids ketone bodies 6. Several molecules act as metabolic junction points. glucose-6-phosphate pyruvate acetyl-CoA

  10. 7. A defect in a single enzyme of metabolism can be disastrous. • Lack of an essential metabolite? • Build-up of a toxic metabolite? Small Molecule Investigation

  11. 8. Tissues & organs are specialized.

  12. 7. Tissues & organs are specialized. • Maintainers supply fuel for the consumers. • Maintainers: liver and adipose tissue • Consumers: skeletal muscles, heart, brain Brain Fuel

  13. Interactions between tissues and organs are mediated by hormone signals carried via bloodstream.

  14. Specialized Metabolism Which of the following is false about the metabolism of the liver? • It processes most, but not all, dietary amino acids. • The presence of glucose-6-phosphatase makes the liver uniquely able to release glucose from glycogen into the bloodstream. • It synthesizes most of the urea produced in the body. • It normally fuels the body by releasing its fat stores during fasting. • One of its major jobs is to provide fuels for the brain.

  15. Metabolic Interrelationships

  16. Liver- #1 metabolic player • Responds quickly to dietary conditions because of rapid turnover of its enzymes • Processes most incoming nutrients • Maintains constant concentrations of nutrients in blood (e.g., via gluconeogenesis), smoothing out fluctuations due to the Starve-Feed Cycle • Processes toxins and wastes (e.g., through urea cycle) • Synthesizes and secretes plasma proteins

  17. Liver- #1 metabolic player • Primarily depends on b-oxidation of fatty acids for its own energy needs.

  18. Liver • Amino acids go directly to the liver through the portal vein after absorption. • Uses them to make proteins, for gluconeogenesis, for biosynthesis of nitrogen-containing molecules, or for fuel.

  19. triglycerides fatty acids + glycerol transport in blood Albumin muscle heart liver Adipose Tissue- maintainer #2 • Stores triglycerides and releases FA’s and glycerol as signaled by glucagon/ epinephrine • Turnover is 50-60 g/day. cAMP-activated lipases

  20. Two distinct types: white adipose tissue and brown adipose tissue. • Brown fat has high levels of thermogenin, which are metabolically activated by cold exposure. Huffington Post

  21. Skeletal Muscle (big consumer)

  22. Case Study: Paul J. cramps up Less than two weeks after finishing the 2010 Boston Marathon in 4:10, disaster struck for Paul J. in the Pittsburgh Marathon. He ran the first half in 2:04 and the second half in 2:40. Severe leg cramps set in at around mile 20, and he ended up on the ground screaming in pain. The day was cool, and he took in lots of electrolytes.

  23. Case Study: Paul J. cramps up What probably went wrong for Paul? a) Lactic acid! b) His fat stores ran out. c) His blood sugar dropped. d) Carnitine deficiency! e) Hyponatremia! Less than two weeks after finishing the 2010 Boston Marathon in 4:10, disaster struck for Paul J. in the Pittsburgh Marathon. He ran the first half in 2:04 and the second half in 2:40. Severe leg cramps set in at around mile 20, and he ended up on the ground screaming in pain. The day was cool, and he took in lots of electrolytes.

  24. Energy Systems of Skeletal Muscle (Phosphagen system)

  25. Match the photo to the energy system! a) 1= lactate; 2= phosphagen; 3= aerobic b) 1= phosphagen; 2= aerobic; 3= lactate c) 1= aerobic; 2= lactate; 3= phosphagen d) 1= aerobic; 2= phosphagen; 3= lactate 1. 2. 3.

  26. Anaerobic Conditions- bursts of heavy activity • ATP exhausted rapidly (1 or 2 sec); replenished by: Phosphagen System

  27. Anaerobic Conditions- bursts of heavy activity • phosphocreatine lasts ~10 seconds • next 1 to 2 minutes • glycogen -> G-6P -> pyruvate -> lactate

  28. Fate of Lactate • Cooperation between muscle and liver (Cori cycle) to regenerate glucose from lactate. • Heart also burns lactate.

  29. Lactate Threshold • With low intensity work, lactate is cleared from the bloodstream as fast as it is made. • As work increases, there is a point when lactate is produced too fast for the body to clear it. Exercise cannot be sustained for more than a minute or two after lactate threshold because of PFK-1 inhibition work

  30. Aerobic Conditions- rest, slow runs,light activity 1. glycogen -> G-6P -> pyruvate -> CO2 + H2O • 1- 2 hour supply, moderately fast • Limited by entry of pyruvate into mitochondria and/or O2 supply 2. fatty acids -> acetyl-CoA -> CO2 + H2O • Many hours supply, slow • Limited by diffusion of FA’s from blood, carnitine

  31. Cross Country Collapse Emily, the #2 ranked female high school cross country runner in the state, is competing in the Western Maine championship. She goes into the woods just before the mile mark but doesn’t come out. She had been struggling the entire season, feeling weak and tired, and had dropped out of three races prior to this meet. What type of testing would you do on Emily?

  32. Cross Country Collapse Emily, the #2 ranked female high school cross country runner in the state, is competing in the Western Maine championship. She goes into the woods just before the mile mark but doesn’t come out. She had been struggling the entire season, feeling weak and tired, and had dropped out of three races prior to this meet. What type of tests would you do on Emily? • Test for a glycogen storage disease • Test for cardiomyopathy • Test for diabetes • Test for anemia • Test for pregnancy

  33. Aerobic training effects • Increased number of mitochondria • Increased hemoglobin and hematocrit (percentage of red cells in blood; normally 36-49%) • Increased heart efficiency • Result is increased O2 uptake and use by tissues: VO2 max: normally ~35 mL O2/kg/ min

  34. VO2 max of Elite Aerobic Athletes Joan Benoit Bjorn Daehlie Lance Armstrong 79 mL/kg/min 90 mL/kg/min 84 mL/kg/min

  35. VO2 max of Elite Animal Athletes Pronghorn Antelope 300 mL/kg/min 10K- under 10 minutes!

  36. Changes in metabolism over time • During endurance exercise, the respiratory quotient (CO2 exhaled/O2 consumed) falls, indicating increased use of fatty acids. • RQ =1.0 for carbohydrates • RQ= 0.70 for fats (more highly reduced)

  37. Changes in metabolism over time • During endurance exercise, the respiratory quotient (CO2 exhaled/O2 consumed) falls, indicating increased use of fatty acids. • Increased [acetyl CoA] from  oxidation slows bridging reaction • Effect is decreased funneling of sugar into TCA.

  38. Changes in metabolism over time • During endurance exercise, the respiratory quotient (CO2 exhaled/O2 consumed) falls, indicating increased use of fatty acids.

  39. Case Study: Paul W. is confused Paul W. turned the corner for the last 200 yards of the 1990 Boston Marathon. He was well ahead of me, having passed me in Wellesley. In the last few minutes of the race, however, he became confused. As he passed by “The Pru,” he started walking in circles. He ended up finishing 15 minutes behind me. What went wrong for Paul W.?

  40. Case Study: Paul W. is confused What probably went wrong for Paul? a) Lactic acid! b) His fat stores ran out. c) His blood sugar dropped. d) Carnitine deficiency! e) Hyponatremia! Paul W. turned the corner for the last 200 yards of the 1990 Boston Marathon. He was well ahead of me, having passed me in Wellesley. In the last few minutes of the race, however, he became confused. As he passed by “The Pru,” he started walking in circles. He ended up finishing 15 minutes behind me. What went wrong for Paul W.?

  41. Brain • No significant energy reserves. • Dependent on blood glucose at ~4.5 mM to maintain ion gradients. • Uses 20% of the total O2 consumed by a resting human (only 2% of the body mass) • After several days of low glucose, switches to use of ketone bodies, which are degraded via TCA. Conserves body’s proteins.

  42. Heart • Cardiac muscle is aerobic only with circulating fats the preferred fuel. • Lack of O2 leads to tissue death (myocardial infarction).

  43. Hormones Which of the following pathways is inhibited by the action of insulin? • Glycolysis • Kreb’s cycle • Gluconeogenesis • Glycogen synthesis • Fatty acid synthesis

  44. 1. Insulin (high blood sugar) • Insulin deficiency or resistance can lead to hyperglycemia, metabolic syndrome, and diabetes.

  45. The insulin receptor is a receptor tyrosine kinase (RTK). • Insulin binding triggers auto- phosphorylation at Tyr.

  46. 2. Epinephrine (fight or flight)

  47. Epinephrine receptors act through G proteins.

  48. 3. Glucagon (low blood sugar)

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