Unformatted text preview: Bioc 385 – Spring 2016 Dr. Miesfeld Homework 6 1. It has been observed that there is a higher frequency of glucose-6P dehydrogenase (G6PD) deficiencies in human populations that live in areas of the world where malaria is prevalent (or has been prevalent), compared to areas of the world too far north or too far south for malarial mosquitoes to survive. Which ONE statement below BEST provides a biochemical explanation for this epidemiological data? People who are most likely to get malaria from infected mosquitoes, primarily live in tropical hot climates where Anopheles mosquitoes live. Therefore, G6PD defiiciencies are more prevalent in tropical hot climates than in areas farther north of south of the equator. The correlation between G6PD deficiencies and exposure to malaria is controversial because no one knows for sure why mosquitoes prefer to bite people with normal levels of G6PD. One explanation is that people living in Africa, South America, and Southease Asia do not move around much and the gene pool is limited. A mutation in the G6PD gene is beneficial because it changes the pheromones in your skin so that mosquitoes are not attracted to you. Therefore, G6PD deficiencies protect against mosquito bites. The G6PD enzyme is responsible for generating NADPH, which is required to maintain glutathione in the reduced form. Since reduced glutathione is toxic to the malarial parasite, this deficiency protects against malaria and the gene mutation is maintained in the population. G6PD is required for the Pentose Phosphate Pathway, and glutathione is required for detoxification of reactive oxygen species. Therefore, it is beneficial to have a G6PD deficiency because it provides protection against favism. NADPH maintains glutathione in the reduced form as a result of the glutathione reductase reaction. Since glutathione is required in the glutathione peroxidase reaction to reduce hydrogen peroxide, it makes sense that G6PD deficiencies would occur at a higher frequency in areas where malaria is prevalent. G6PD deficiencies result in elevated reactive oxygen species in human red blood cells, which is a hostile environment for the malarial parasite. Therefore, it is beneficial to carry the G6PD deficiency in the population because it protects against death due to malaria. People who live in areas of the world where malaria is, or has been, prevalent, tend to eat a lot of fava beans. Therefore, the positive correlation between malaria and G6PD deficiencies is actually related to a diet rich in fava beans and malaria. 2. Select the statement(s) below that accurately describe the difference between the oxidative phase and nonoxidative phase of the Pentose Phosphate Pathway. The oxidative phase occurs in the mitochondria where oxygen is available and the nonoxidative phase occurs in the muscle, which uses anaerobic metabolism and generates lactic acid. The oxidative phase is responsible for regenerating glucose-6P, whereas the nonoxidative phase is responsible for generating NADPH. The oxidative phase generates 2 NADPH for each glucose-6P that is converted to ribulose-5P, whereas the nonoxidative phase generates 5 glucose-6P for every 6 ribulose-5P that are metabolized in the oxidative phase. The nonoxidative phase is dependent on glutathione reductase, however the oxidative phase is dependent on glucose-6P dehydrogenase. The nonoxidative phase is responsible for regenerating ribulose-5P, whereas the oxidative phase is responsible for generating NADPH. The nonoxidative phase produces ribulose-5P for nucleotide synthesis and the oxidative phase generates NADPH for biosynthetic reactions in the cell. The oxidative phase requires the enzyme glucose-6P dehydrogenase and the nonoxidative phase requires the enzyme transketolase. The nonoxidative phase interconverts C3, C4, C5, C6, and C7 sugars with no change in total carbons, whereas in the oxidative phase the conversion of glucose-6P to ribulose-5P leads to a loss of a carbon as carbon dioxide. 1 Bioc 385 – Spring 2016 Dr. Miesfeld 3. Which statement(s) below BEST describe(s) differences between the glycolytic and gluconeogenic pathways. There are FOUR correct statements below. Citrate inhibits glycolysis but activates gluconeogenesis, whereas F-1,6-BP activates glycolysis and inhibits gluconeogenesis. Glycolytic enzymes are all found in the cytosol, whereas gluconeogenic enzymes are found in the cytosol and the mitochondrial matrix. Insulin inhibits flux through the gluconeogenic pathway, whereas glucagon inhibits flux through the glycolytic pathway. Gluconeogenesis is only found in liver and kidney cells, whereas glycolysis is only found in liver and pancreatic cells. Flux through glycolysis is activated by low energy charge in the cell, whereas flux through the gluconeogenic pathway is inhibited by high energy charge in the cell. Three of the enzymes in glycolysis are reciprocally regulated by allosteric effectors that convert them into gluconeogenic enzymes, i.e., PFK-1 becomes PFK-2 and FBPase-1 becomes FBPase-2. This is not true of any enzymes in the gluconeogenic pathway. Insulin stimulates flux through the glycolytic pathway, whereas glucagon stimulates flux through the gluconeogenic pathway. Gluconeogenesis generates glucose from non-carbohydrate sources, whereas glycolysis generates pyruvate from glucose. _________________________________________________________________________________ 4. Using the diagram provided in this question, choose the BEST statement(s) below that accurately describe(s) relative metabolic flux and F-2,6-BP concentrations in the cell under condition "A" and condition "B." There are TWO correct statements. A) F-2,6-BP levels are high A) F-2,6-BP levels are low B) F-2,6-BP levels are low B) F-2,6-BP levels are high A) F-2,6-BP levels are low A) Gluconeogenic flux is high B) Glycolytic flux is high B) F-2,6-BP levels are low A) F-2,6-BP levels are high A) F-2,6-BP levels are high B) Gluconeogenic flux is low B) Gluconeogenic flux is high A) Gluconeogenic flux is low A) Gluconeogenic flux is low B) Glycolytic flux is high B) Glycolytic flux is low 2 Bioc 385 – Spring 2016 Dr. Miesfeld 5. Order the following steps in glycogen particle synthesis. __5__ Glycogen synthase uses UDP-glucose to form α-1,4 glycosidic bonds that add to the glycogenin primer __2__ The glycogen synthase activity of glycogenin forms an α-1,4 glycosidic bonds that adds UDP-glucose to an O-linked glucose residue. __3__ The glycogen synthase activity of glycogenin forms an α-1,4 glycosidic bond that adds UDP-glucose to an O-linked glucose disaccharide. __4__ The glycogen synthase activity of glycogenin uses UDP-glucose to extend the chain up to 7 residues. __1__ The glycosyltransferase activity of glycogenin adds UDP-glucose to a tyrosine residue in glycogenin. __6__ A branching enzyme adds α-1,6 linkages 6. Choose the ONE BEST answer describing the functional role of glycogen in liver and muscle cells. Muscle glycogen is the largest depot of stored glucose in the body and it is the primary source of serum glucose in between meals, whereas liver glycogen provides energy for liver cells to synthesize lipids. Liver glycogen provides a mechanism to keep you alive at night when you sleep, whereas muscle glycogen keeps you alive during the day when you study. Liver glycogen provides stored glucose for release into the blood, whereas muscle glycogen provides stored glucose to generate ATP for muscle contraction. Glycogen degradation in liver cells generates glucose-1P, whereas glycogen degradation in muscle cells generates glucose-6P. None of these statements are correct. Muscle cells are important in the Cori Cycle, whereas liver cells are important in the Citrate Cycle. Muscle glycogen provides more energy to the brain than liver glycogen provides energy to muscle cells because muscle cells have the enzyme glucose-6-phosphatase. All of these statements are correct. 3 Bioc 385 – Spring 2016 Dr. Miesfeld 7. Muscle glycogen phosphorylase is regulated by both allosteric effectors, such as AMP and ATP, and by hormonal signaling. Allosteric effectors bind to the phosphorylated and unphosphorylated forms of the enzyme and shift the equilibrium between the inactive T conformation and the active R conformation. In contrast, hormonal regulation involves activation of kinase and phosphatase enzymes, which modulate the phosphorylation status of glycogen phosphorylase. Which TWO statement(s) below best explain the metabolic logic of this dual regulatory mechanism? Metabolic logic refers to the circuitry of hormone regulation much like a microprocessor controls the rate of voltage gradients. It is logical for ATP to inhibit glycogen phosphorylase activity in muscle cells and for insulin to stimulate gluconeogenesis because muscle cells store glycogen for use in energy conversion reactions. Both forms of control are important because they work together to ensure maximum interconversion of glucose and glycogen so that liver cells can maintain safe blood glucose levels at all times. Allosteric regulation by AMP and ATP provides a way to quickly shift the activity of muscle glycogen phosphorylase between the active and inactive states before hormonal signaling is fully stimulated. Glucagon and insulin control glucose metabolism using recipricol regulation such that decreased phosphorylase activity leads to increased glucose efflux from liver cells. Allosteric control is more precise than hormonal control so it makes sense to have both a fine tuning mechanism and a relative mechanism so that AMP binding to the phosphorylated R state conformation inhibits activity even further. This dual mechanism ensures that both energy charge and hormonal signaling are synchronized so that glucagon rapidly stimulates muscle glycogen phosphorylase to increase glucose levels in the blood when you are sleeping or hungry. Hormonal control provides a mechanism for the pancreas to use glucokinase as a glucose sensor and export glucose to the muscle cells during contraction. However, since AMP and ATP are only made in liver cells, you need both forms of regulation. 8. Glycogen phosphorylase catalyzes the removal of glucose from glycogen. The ΔGo’ for this reaction is 3.1 kJ/mol. a) Calculate the ratio of [Pi] to [glucose 1-phosphate] when the reaction is at equilibrium at 298K. (Hint: the removal of glucose units from glycogen does not change the glycogen concentration.) b) In muscle cells under physiological conditions, the measured ratio of [Pi]/[glucose 1-phosphate] is more than 100:1. What does this indicate about the direction of metabolite flow through the glycogen phosphorylase reaction in muscle? Choose one answer for part a and one answer for part b. a) [Pi]/[glucose 1-phosphate] = 0.28/1 a) [Pi]/[glucose 1-phosphate] = 0.99/1 a) [Pi]/[glucose 1-phosphate] = 1/1 a) [Pi]/[glucose 1-phosphate] = 3.5/1 4 Bioc 385 – Spring 2016 Dr. Miesfeld b) The concentration of glucose 1-phosphate is below the equilibrium value. Therefore, the rate of glucose 1- phosphate removal (through entry into glycolysis) is greater than the rate at which glucose 1-phosphate is produced by glycogen phosphorylase, so metabolite flow is from glycogen to glucose 1-phosphate. b) The concentration of glucose 1-phosphate is above the equilibrium value. Therefore, the rate at which glucose 1-
phosphate is produced by glycogen phosphorylase is greater than the rate of glucose 1-phosphate removal (through entry into glycolysis), so metabolite flow is from glucose 1-phosphate to glycogen. b) The concentration of glucose 1-phosphate is below the equilibrium value. Therefore, the rate of glucose 1-
phosphate removal (through entry into glycolysis) is greater than the rate at which glucose 1-phosphate is produced by glycogen phosphorylase, so metabolite flow is from glucose 1-phosphate to glycogen. b) The concentration of glucose 1-phosphate is above the equilibrium value. Therefore, the rate at which glucose 1-
phosphate is produced by glycogen phosphorylase is greater than the rate of glucose 1-phosphate removal (through entry into glycolysis), so metabolite flow is from glycogen to glucose 1-phosphate. 9. Individuals with McArdle's disease has defects in muscle glycogen phosphorylase. As a result, individuals with McArdle's disease have an exercise intolerance with fatigue and cramps, however, after a period of exercise they experience a "second wind" of energy. The second wind results from cardiovascular adjustments that allow glucose to be mobilized from liver glycogen to fuel muscle contraction, though this is less efficient. Choose the ONE best answer below that explains why the amount of ATP derived in the muscle from circulating glucose is less than the amount of ATP that would be obtained by mobilizing the same amount of glucose from muscle glycogen. Circulating glucose used in muscle cells to generate ATP is less efficient because the Pi group must be imported into the mitochondria, which has a cost of 1 H+/Pi. This means that the total yield is one fewer ATP, since it takes 3 H+ to make one ATP. The conversion of glucose to lactate in muscle generates 2 ATP. If muscle glycogen could be mobilized, the energy yield would be 3 ATP, since phosphorolysis of glycogen bypasses the hexokinase-catalyzed step of glycolysis that consumes ATP. It costs 1 ATP to import glucose into the muscle cell, so the total energy yield is less from circulating glucose than from mobilization of glucose from glycogen. The production of glucose 6-phosphate from glycogen via the enzyme phosphoglucomutase is coupled to the formation of ATP. Therefore mobilizing glucose from glycogen results in one more net ATP made than in the conversion of glucose to lactate via glycolysis. 10. Match the description on the left of specific steroid properties, which could include information about steroid synthesis, physiological function, pharmacological application, etc., with the one BEST steroid name on the right. You may need to use online searches to find the information you need if the class materials you have available are insufficient. __1__ Is synthesized in the ovaries, adrenal glands, and placenta. Functions primarily in the kidney to control Na+ and K+ __5__ concentrations;; antagonists of this steroid are used to treat hypertension. __4__ 2. Dihydrotestosterone RLM cloned the gene encoding the receptor for this steroid in 1984, which was the first ever steroid receptor gene isolated ;;-) Is derived from testosterone;; is produced in large amounts in __3__ ovarian follicular cells and produced in small amounts in the testes. __2__ 1. Progesterone 3. Estradiol 4. Cortisol 5. Aldosterone Is three times more potent than its steroid precursor;; high levels are associated with male alopecia. 5 ...
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