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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 coupling ATP hydrolysis to a reaction increases K by a factor of ~108. 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. 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. Carbs, Amino Acids Fats, Amino Acids Amino Acids •TCA is an excellent example of an amphibolic pathway. 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) 5. Many coenzymes coenzyme role Niacin/B3 (NAD+) redox Riboflavin/B2 (FAD) redox Pantothenic acid/B5 (CoA) acyl transfer Pyridoxal phosphate/B6 transamination Vitamin B12 rearrangements Thiamine/B1 (TPP) decarboxylation Biotin/B7 CO2 carrier Lipoic acid acyl carrier Folic Acid/B9 carbon carrier example malate dehydrogenase succinate dehydrogenase pyruvate dehydrogenase -KG --> Glu homocysteine--> Met pyruvate dehydrogenase pyruvate carboxylase pyruvate dehydrogenase amino acid degradation Which of the following coenzymes often participates in carboxylation reactions? A. Vitamin B12 B. TPP C. FAD D. Coenzyme A E. Biotin 6. Several molecules act as metabolic junction points. glucose-6-phosphate glycogen pyruvate ribose-5-P pyruvate acetyl-CoA lactate alanine OA acetyl-CoA CO2 fatty acids ketone bodies 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 8. Tissues & organs are specialized. 7. Tissues & organs are specialized. • Maintainers supply fuel for the consumers. Brain Maintainers: liver and adipose tissue Consumers: skeletal muscles, heart, brain Fuel •Interactions between tissues and organs are mediated by hormone signals carried via bloodstream. Specialized Metabolism Which of the following is false about the metabolism of the liver? A. It processes most, but not all, dietary amino acids. B. The presence of glucose-6-phosphatase makes the liver uniquely able to release glucose from glycogen into the bloodstream. C. It synthesizes most of the urea produced in the body. D. It normally fuels the body by releasing its fat stores during fasting. Metabolic Interrelationships 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 Liver- #1 metabolic player •Primarily depends on b-oxidation of fatty acids for its own energy needs. Liver •Amino acids go directly to the liver through the portal vein after absorption. •Uses them to make proteins, for gluconeogenesis, for biosynthesis of nitrogencontaining molecules, or for fuel. Adipose Tissue- maintainer #2 •Stores triglycerides and releases FA’s and glycerol as signaled by glucagon/ epinephrine •Turnover is 50-60 g/day. triglycerides cAMP-activated lipases fatty acids + glycerol transport in blood muscle heart Albumin liver •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 Skeletal Muscle (big consumer) 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. 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. 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! Energy Systems of Skeletal Muscle (Phosphagen system) 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. Anaerobic Conditions- bursts of heavy activity • ATP exhausted rapidly (1 or 2 sec); replenished by: Phosphagen System Anaerobic Conditions- bursts of heavy activity •phosphocreatine lasts ~10 seconds •next 1 to 2 minutes glycogen -> G-6P -> pyruvate -> lactate Fate of Lactate •Cooperation between muscle and liver (Cori cycle) to regenerate glucose from lactate. •Heart also burns lactate. 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 Aerobic Conditions- rest, runs, light activity slow 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 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? Cross Country Collapse Emily, the #2 ranked female high A. 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 B. doesn’t come out. She had been struggling the entire C. season, feeling weak and tired, and had dropped out of three races prior to D. this meet. What type of tests would you E. do on Emily? Test for a glycogen storage disease Test for cardiomyopathy Test for diabetes Test for anemia Test for pregnancy 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 VO2 max of Elite Aerobic Athletes Joan Benoit 79 mL/kg/min Bjorn Daehlie 90 mL/kg/min Lance Armstrong 84 mL/kg/min VO2 max of Elite Animal Athletes Pronghorn Antelope 300 mL/kg/min 10K- under 10 minutes! 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) 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 b oxidation slows bridging reaction Effect is decreased funneling of sugar into TCA. Changes in metabolism over time During endurance exercise, the respiratory quotient (CO2 exhaled/O2 consumed) falls, indicating increased use of fatty acids. 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.? 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.? 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! 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. Heart Cardiac muscle is aerobic only with circulating fats the preferred fuel. Lack of O2 leads to tissue death (myocardial infarction). Hormones Which of the following pathways is inhibited by the action of insulin? A. Glycolysis B. Kreb’s cycle C. Gluconeogenesis D. Glycogen synthesis E. Fatty acid synthesis 1. Insulin (high blood sugar) •Insulin deficiency or resistance can lead to hyperglycemia, metabolic syndrome, and diabetes. The insulin receptor is a receptor tyrosine kinase (RTK). Insulin binding triggers autophosphorylation at Tyr. 2. Epinephrine (fight or flight) Epinephrine receptors act through G proteins. 3. Glucagon (low blood sugar) Glucagon receptor also acts through G proteins.