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Flashcards

Hb and Mb Protein Structure and Function

Kelly Scott Biochemistry English 44 cards

Cards in this deck (44)

  1. 1Types of 3D complex structuresGlobular or fibrous
    Structure depends on sequence and interactions
  2. 2Aerobic metabolism in large organismsCan't rely on diffusion as O2 solubility too low for large organisms.
    O2 is stored in globular proteins in muscle (myoglobin) and transported in the blood (haemoglobin)
    O2 is used by the mitochondria for respiration. Haemoglobin also removes CO2
  3. 3MyoglobinMonomeric heme protein that binds and releases O2 in tissue that is delivered to mitochondria
  4. 4HaemaglobinTetrameric heme protein that transports O2 from lungs or gills to peripheral tissues and returns CO2 to gills or lungs for exhalation
  5. 5ErythrocytesHb is transferred in the vasculature in Erythrocytes. These contain 3x10^6 Hb molecules, allowing for 100x greater O2 delivery than if it were dissolved in plasma
  6. 6Myoglobin functionShort range O2 transport in tissues and storage for muscle activity which requires more O2 than can be delivered via Haemoglobin. Responsible for the red colour of skeletal muscle
    Monomeric protein (single polypeptide chain) with 153 AA, not a quaternary structure
  7. 7Deep diving aquatic mammals10-30 x more Mb than land mammals to support lifestyle
  8. 8Structure of myoglobinTertiary globular structure
    Heme is space filling, inserting into pocket between helices
  9. 9Prosthetic groupAccessory molecule
    Gives the myoglobin additional properties that it can't get from the amino acids
    Heme reversibly binds oxygen
  10. 10Haemaglobin structureTetramer with a quaternary structure of 4 polypeptide subunits (2 a and 2 b) that each resemble Mb. Each one contains a heme molecule and each heme can bind one O2 molecule
  11. 11Chemical properties of heme for binding oxygenMetal ions, Fe2+ is best.
    O2 can oxidise Fe2+ to Fe3+. This is toxic to animals, Fe2+ alone is not suitable for reversible binding. Fe2+ must be contained within heme molecule.
  12. 12Heme structure and functionHeme is a prosthetic (non AA) molecule that binds to Mb and Hb that contains Fe2+ enabling the reversible binding of oxygen
    Fe2+ forms 4 bonds (with nitrogen) in the planar heterocyclic tetrapyrrole porphyrin. Can accept 2 other bonds! One to protein and one for oxygen
  13. 13Binding of O2One bond is in the proximal histidine of the side chain. Oxygen occupies the 6th position opposite to this.
    The distal histidine stabilises the O2 via H-bonding
  14. 14Prevention of oxidationHeme is enclosed in a hydrophobic pocket of the Hb or Mb to prevent free Fe2+ and oxidation
    Can bind oxygen without becoming oxidised
  15. 15KdDissociation constant
    [Mb][O2]/[MbO2]
  16. 1650% saturation point for MbIndicates partial pressure of oxygen required for half saturation P50
    -high affinity
    This means that Mb can bind O2 from Hb in blood and release it to the mitochondria. Has a single heme and a hyperbolic O2 binding curve. Only released when PPO2 is lowered in muscle during exercise
  17. 17Hb binding curveSigmoidal curve
    Hb O2 binding is allosteric with cooperative binding: binding at one site changes the affinity at other sites
    This results in efficient binding at the lungs and release in tissues
  18. 18Hb vs Mb ssaturationNearly saturated in the lungs and releases 40% of oxygen in respiring tissues
    High values of oxygen are required to saturate Hb. P50 is high, Hb has a lower oxygen affinity than Mb
  19. 19Why does Hb have a sigmoidal binding curve?Hb has two states:
    High O2 affinity in the lungs
    Low O2 affinity in respiring tissues
    *Cooperative binding: O2 affinity increases as more sites are occupied by O2. Also cooperative release.
  20. 20Cooperative Hb O2 bindingPositive homotrophic cooperativity (O2 binding at one heme subunit facilitates binding at other 3 subunits of the tetramer - bind O2 more easily) explained by symmetry model for Hb - Hb exists in an equilibrium of T and R state
  21. 21Two forms of Hb tetramer quaternary structures at equilibriumHb R state - high oxygen affinity
    Hb T state - low oxygen affinity
    Balance depends on partial pressure of oxygen and location of Hb in circulatory system
  22. 22Symmetry model of cooperative O2 binding in HbIncreasing PPO2 shifts Hb from T to R state
    Cooperativity not possible for a single subunit protein Mb
  23. 23Structural change in Hb when changing from T to RInitiated by O2 binding heme Fe2+
    Results in a rotation of the alpha1beta1 dimer relative to the alpha2beta2 dimer
    Central cavity much larger in T state
  24. 24Transition from T to RRequires disruption of non covalent interaction (salt bridges) between the subunits of the tetramer and a 2,3-BPG that stabilises the T state resulting in a small R state cavity that can't bind 2,3-BPG
  25. 25In the absence of oxygenT state is favoured due to non covalent interactions / salt bridges
  26. 26How does oxygen binding promote change from T to R state?In T state, Heme Fe2+ sits out of the heme plane in a tense domed heme structure as there is no O2 in the 6th position
    When O2 binds, it pulls the Fe2+ into the plane of the heme causing steric strain between the Flattened heme and the proximal His and Val which then move
  27. 27Change to Fe2+ when O2 bindsIonic radius becomes smaller when it is binding 6 things, allows it to fit inside the heme. Fe2+ remains attached to the histidine, pulling on it's helix and moves the FG corner that contacts another subunit resulting in the breaking of the non covalent interactions in that subunit changing affinity
  28. 28Structural change to HbO2 binding mechanisms changes the quaternary structure of the tetramer
  29. 29Allosteric effectors of hemoglobinEffective Oxygen and CO2 transport requires other molecules (heterotrophic effectors)
    Negative hetertrophic effectors: reduce oxygen affinity of heme, favour the T state
  30. 30Negative heterotrophic effectorsH+, CO2, 2,3-PBG
    NOT CO, CO is a competitive ligand to Oxygen as it has a higher affinity to Hb Fe2+ than Oxygen
  31. 31Hb pH responseThe Bohr effect
    Hb has a pH dependent affinity to O2 - decreases affinity with decreasing pH.
    T state is a stronger base than the R state, so increased [H+] (lower pH) favours T state and has an increased P50. A higher concentration of oxygen is required to half saturate the Hb. If more oxygen is required, it means the Hb has a lower affinity. Helps offload oxygen in the tissue
  32. 32Molecular basis of Bohr effectProtons favour T state as it is a stronger base than R. Can accept protons and they stabilise the T state. H+ protonate Hb histidine side chains. H+ binding promotes O2 release. Protons are often present in respiring tissues. CO2 also a source of H+
    Lowering the [H+] increasing the pH drives the equilibrium towards R state
  33. 33Protonation of T stateProtonation of Histidine N terminus forms the T state salt bridges that stabilise the T state and decrease the affinity for O2
  34. 34Physiological consequences of Bohr effectGreater offloading of oxygen in tissues with more protons
  35. 35CO2Waste product of aerobic respiration
    Must be removed from respiring tissues
    Carbonic anhydrase: forms H2CO3 from CO2 and H20. This forms H+ and HCO3-
    More CO2, More T state and more O2 offloading
  36. 36Lungs and H+High pO2 in lungs oxygenates Hb by stabilising Hb causing H+release promoting reverse reaction to release CO2. Hb can then transport O2 fro lungs to tissues and CO2 as dissolved HCO3- to lungs for gas exchange
  37. 372,3-BPGNegative allosteric effector
    Decreases O2 affinity
    Stabilises the Hb T state and shifts O2 binding curve to the right so it has a higher P50 (More O2 required to saturate 50% of HB)
    Favours release of oxygen from R state Hb to form T state Hb. R state is too small to bind 2,3-BPG
    [BPG]=[
  38. 38Physiological function of 2,3-BPGWithout BPG, Hb affinity would be too high and too little O2 would be released into tissue. Alteration of [BPG] is a regulatory mechanism eg. in high altitude or low O2 areas
    Decreased BPG affinity in fetal Hb results in a higher affinity to offload O2 from maternal Hb
  39. 39Control of Hb O2 affinity summaryHomotrophic cooperative O2 binding
    Negative allosteric effectors stabilise the T state and help release oxygen into tissue by lowering oxygen affinity
  40. 40FishBuoyancy and water pressure. Use Bohr effect to regulate buoyance in swim bladder in eyes by using ATP and lactate instead of 2,3-BPG
  41. 41Hb structure and function and genetic diseaseMutation in heme pocket or a1-b2 Hb tetramer contact region
    These interfere with the allosteric T to R mechanism via change in erythrocyte shape or a change in O2 affinity
  42. 42Arginine to histidine mutationT state is less stable, impaired O2 release and diminished Bohr effect, increased O2 affinity
  43. 43Mutations that impair BPG bindingResults in an increase of Hb O2 affinity
  44. 44Sickle cell anaemiaSingle AA change due to mutation. Change from Glu to Val resulting in a change in chemical properties resulting in a change in the shape of the erythrocyte from a biconcave shape to a sickle shape that are fragile. Results in anaemia as they are prone to rupture and lysis

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Biochemistry Flashcards on Hb and Mb Protein Structure and Function, created by Kelly Scott on 27/07/2020.
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Kelly Scott
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