MBS 8 Oxygen Transport

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  1. What two things do myoglobin and hemoglobin have in common?
    Both proteins have high alpha-helical content and contain a heme prosthetic group, which is the oxygen carrier
  2. myoglobin
    it delivers the oxygen in muscle; required for metabolism in actively exercising muscle (Myo --> Muscle)
  3. What does the heme group do?
    carries the oxygen in myoglobin and hemoglobin
  4. What is the difference between a prosthetic group (or coFACTOR) and a coenzyme?
    • • a prosthetic group is firmly attached to a protein and usually won't be removed during protein purification
    • • a coenzyme is an organic molecule that is less firmly attached and is removable during protein purification
  5. What is the oxidation number of the heme iron found in oxygenated and deoxygenated myoglobin?
    Iron is in its ferrous state (Fe2+) irrespective of oxygen binding in both myoglobin and hemoglobin
  6. metmyoglobin
    oxidized myoglobin, meaning its iron (Fe) group has a 3+ charge; in this state the heme cannot transport oxygen
  7. Why is heme is located in a central, nonpolar region of myoglobin?
    When exposed to water, Fe is oxidized to the 3+ state where it can't hold oxygen; if sequestered in a nonpolar region of the protein, heme can maintain its oxygen-carrying Fe2+ state
    • oxygenation: Hb Fe2+ and O2 (oxymyoglobin)
    • oxidation: Hb: Fe3+ (metmyoglobin)
  9. What role do histidines in the heme pocket play?
    the amino acid histidine (F8) binds iron; movement of this residue helps the protein sense whether or not O2 is bound to the heme group
  10. If CO (carbon monoxide) binds to isolated heme 25000x more tightly than O2, how can O2 be carried by heme at all?
    • • in isolated heme, CO binds to Fe at a 180 and O2 binds at 120 (bent)
    • • however in myoglobin histidine E7 forces a substrate to bind at 120 degrees, therefore optimal CO binding is prevented, but O2 binding is ideal
  11. What triggers myoglobin to undergo a conformational change when it binds oxygen?
    When it binds to oxygen, the oxygenated ferrous ion moves into the plane of the porphyrin ring, pulling along some of the protein with it (mediated by histidine F8)
  12. *hemoglobin gives up its oxygen in:
    capillaries where there is a LOW partial pressure (content) of oxygen
  13. partial pressure of O2
    represents the level of dissolved oxygen in plasma, or whatever surroundings/environment being discussed (outside the globin)
  14. Describe the shape of the myoglobin oxygen dissociation curve. What does it suggest with regards to the protein's kinetics?
    hyperbolic: suggests that simple equilibrium processes are involved in binding and release.
  15. Describe the shape of the hemoglobin oxygen dissociation curve. What does it suggest with regards to the protein's kinetics?
    Sigmoidal (sort of looks like an S): indicates cooperativity among multiple binding sites
  16. hemoglobin
    It transports oxygen between the lungs and tissues; the protein is made up of four myoglobin-like subunits, two alpha type and two beta
  17. Hill coefficient
    • describes the effect ligands bound to a macromolecule have on binding a second or additional ligand to that same macromolecule
    • • n>1 = positive cooperatively: binding of one ligand promotes binding of another
    • • n=1 --> no cooperativity
    • • n<1 negative cooperatively: binding one ligand inhibits binding of a second
  18. What is the relationship between the alpha and beta subunits of hemoglobin?
    each alpha subunit is in close contact with both beta subunits; in contrast, there are FEW interactions between like subunits
  19. Which is an allosteric protein, myoglobin or hemoglobin?
    Hemoglobin is an allosteric protein. Myoglobin, which binds only a single molecule of O2, is not.
  20. How many oxygen molecules do myoglobin and hemoglobin bind to?
    • • myoglobin binds to ONE oxygen molecule
    • • hemoglobin binds up to FOUR oxygen molecules
  21. What is meant by the statement 'the binding of oxygen to hemoglobin is cooperative'?
    It means that binding of oxygen to one site influences the oxygen affinity of the remaining sites on Hb
  22. What is the Hill coefficient of myoglobin? Hemoglobin?
    • M = 1
    • Hb = 2.8
    I dunno some conserved question, morphology? Protein folding question? Just know they're nearly identical.
  24. How do heme groups communicate with each other?
    They are too far apart to interact directly, therefore they must communicate through conformational changes transmitted across the subunit interfaces. The cooperativity of oxygen in hemoglobin (Hill coefficient) is what indicates said communication.
  25. _____hemoglobin contains more hydrogen bonds between the subunits than _____hemoglobin
    DEoxyhemoglobin contains more hydrogen bonds between the subunits than OXYhemoglobin because once oxygen is bound the subunits rotate
  26. Oxyhemoglobin is said to be in which conformational state?
    The relaxed state (It has oxygen so it is relaxed)
  27. Deoxyhemoglobin is said to be in which conformational state?
    the taut state
  28. Which hemoglobin conformational state has the greatest affinity for oxygen?
    The relaxed state
  29. cooperativity is mediated by changes in the:
    quaternary structure - structure formed by the interaction of separate polypeptides, eg. alpha and beta subunits
  30. How do high CO2 and rising H+ levels (low pH) affect hemoglobins' affinity for oxygen? What is this effect called?
    Both CO2 and low pH promote the release of oxygen by lowering the oxygen affinity of hemoglobin. This is known as
  31. The Bohr Effect
    the oxygen binding affinity of hemoglobin is reduced by increased CO2 and H+ concentration (low pH)
  32. Describe the physical movement that occurs between the subunits of hemoglobin when an oxygen molecule binds to a heme group:
    When oxygen binds to a ferrous iron, one pair of alpha-beta subunits rotates by 15 degrees relative to the other pair of alpha-beta subunits in the hemoglobin heterotetramer
  33. Where on hemoglobin does carbon dioxide bind?
    • Carbon dioxide binds to the N-terminal amino groups of the alpha subunits
    • • this is DIFFERENT from carbon monoxide, which binds to the oxygen binding site
  34. How does the binding of carbon dioxide to hemoglobin reduces oxygen affinity?
    • • CO2 reacts with an N-terminal amino group of an alpha subunit & forms a carbamate
    • • carbamate groups ionically bond and stabilize the taut (deoxy) state of Hb --> lowering the oxygen affinity of hemoglobin
  35. What are the negative allosterics with respect to hemoglobin and why are they called that?
    H+ and CO2: they reduce the O2 affinity of hemoglobin without binding directly to the oxygen binding site
  36. Which conformational state of hemoglobin has a greater affinity for protons?
    The taut (deoxy) state.
  37. BPG (2,3-bisphosphoglycerate)
    • another molecule that lowers hemoglobin's oxygen affinity by binding and stabilizing deoxyhemoglobin
    • • BPG is negatively charged & binds to hemoglobin through electrostatic interactions
  38. What is the role of 2,3-bisphosphoglycerate (BPG) with regards to hemoglobin affinity for oxygen? How does high altitude affect levels of 2,3-BPG?
    • • 2,3-BPG reduces the oxygen affinity of hemoglobin
    • • 2,3-BPG levels increase at high altitude where oxygen is scarce.
  39. How many 2,3-BPG binding sites are there in one molecule of hemoglobin and where are they found?
    One located in a central cavity between the beta subunits
  40. Describe the nature of the bond that forms between 2,3-BPG and hemoglobin. Which state does 2,3-BPG stabilize?
    2,3-BPG is negatively charged and binds to hemoglobin primarily through electrostatic interactions. 2,3-BPG reduces oxygen affinity and therefore stabilizes the taut (deoxy) form of hemoglobin.
  41. What are the subunits of fetal hemoglobin? What are the subunits of adult hemoglobin?
    • • Fetal hemoglobin (HbF) is composed of two alpha and two gamma subunits
    • • Adult hemoglobin (HbA) is composed of two alpha and two beta subunits.
  42. HbF binds oxygen with a ______ affinity than HbA
  43. Which has a higher higher oxygen affinity, fetal hemoglobin or adult hemoglobin?
    • • the gamma subunits in HbF have fewer positively charged amino acid residues in the BPG binding region than beta subunits in HbA, therefore FETAL HEMOGLOBIN binds oxygen with higher affinity because
    • • BPG binds less to fetal hemoglobin
  44. What is the molecular defect associated with sickle cell anemia?
    It is an amino acid substitution of a valine for a glutamate on the exterior of hemoglobin that results in an altered charge of the beta subunit
  45. What causes sick cell hemoglobin (HbS) to polymerize?
    The oxygenated form of HbS has normal solubility, but the deoxygenated form is relatively insoluble. In areas of low oxygen (such as high altitude), HbS polymerizes and distorts red cells, leading to clogging of capillaries and blood vessels.
  46. Why do sickle cell anemia symptoms not become apparent until 3 to 6 months after birth?
    It is not until then that the beta subunits of adult hemoglobin are produced. The symptoms associated with sickle cell anemia correlate with decreased synthesis of gamma subunits and increased synthesis of beta subunits.
  47. Treatment of Sickle Cell Anemia
    • • Antibiotic therapy: prevents secondary infections
    • • Hydroxyurea: stimulates the production of HbF
    • • Bone marrow transplantation: replaces HbS with HbA
    • • Gene therapy: works in mice, clinical trials in 2014?
  48. Name two drugs that are used to treat sickle cell anemia and explain how they work:
    Hydroxyurea (increases the production of gamma subunits of HbF) and erythropoetin (increases proliferation of red cells containing HbF)
  49. In Sickle Cell anemia what is the result of the substitution of valine for glutamate?
    • a hydroPHOBIC patch is created on the surface of the hemoglobin molecule

    • oxygenated HbS has normal solubility, but the DEoxyhemoglobin form of HbS is insoluble

    • in areas of low oxygen concentration, HbS polymerizes and distorts the red cell, clogging capillaries & blood vessels

    • this further reduces the local oxygen concentration and enhances HbS polymerization --> long term result = organ damage
  50. What is the oxidation number of the heme iron in methemoglobin?
    Fe3+ (ferric); this is an abnormal state that can't bind oxygen
  51. List two causes of methemoglobinemia:
    • 1) ingestion of large amounts of oxidizing agents such as nitrates
    • 2) mutations near the heme group
  52. How is methemoglobinemia treated?
    by administering reducing agents like vitamin C or methylene blue
  53. What is the defect in alpha-thalassemias and what does it cause?
    • alpha-thalassemias result from a defect in the synthesis of the alpha-subunits of hemoglobin --> leads to an imbalance in the amount of alpha-globin vs. beta-globin

    • treatment usually involves blood transfusion
  54. Myoglobin vs. hemoglobin: which one binds oxygen more tightly?
    Myoglobin binds oxygen more tightly than hemoglobin
Card Set:
MBS 8 Oxygen Transport
2016-08-28 21:07:32
MBS Biochem
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