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12.4 - ATP Synthase

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  1. Front
    ATP synthase
    Back
    Mitochondrial enzyme complex that uses the proton gradient to synthesize ATP from ADP and Pi
  2. Front
    Major parts of ATP synthase
    Back
    F₁ and F₀
  3. Front
    F₁ of ATP synthase
    Back
    Matrix-side catalytic head that contains the catalytic site for ATP synthesis
  4. Front
    F₀ of ATP synthase
    Back
    Membrane-embedded proton channel that rotates as protons pass toward the matrix
  5. Front
    F₁ subunit composition
    Back
    3α, 3β, γ, δ, ε
  6. Front
    Number of subunits in F₁
    Back
    Nine subunits
  7. Front
    F₀ c subunits
    Back
    Twelve c subunits
  8. Front
    Function of F₀
    Back
    Allows H⁺ to move through the inner mitochondrial membrane and converts proton flow into rotation
  9. Front
    Function of F₁
    Back
    Uses mechanical rotational energy to synthesize ATP from ADP and Pi
  10. Front
    ATP synthase as a machine
    Back
    A rotary molecular machine that couples proton flow to ATP synthesis
  11. Front
    Mechanism of ATP synthase
    Back
    Proton flow through F₀ rotates the rotor, changing F₁ conformation and producing ATP
  12. Front
    Oligomycin
    Back
    Inhibitor of oxidative phosphorylation that blocks F₀
  13. Front
    Effect of oligomycin
    Back
    Blocks proton flow back into the matrix, stops ATP synthase, and stops oxidative phosphorylation
  14. Front
    Importance of oligomycin
    Back
    Demonstrates that proton flow through ATP synthase is required for ATP formation
  15. Front
    Driving force for ATP synthase rotation
    Back
    Return flow of H⁺ into the matrix
  16. Front
    Reason proton return can drive ATP synthesis
    Back
    Protons were pumped out of the matrix by the respiratory chain and their return is energetically favorable
  17. Front
    Subunit whose rotation is emphasized
    Back
    The γ subunit
  18. Front
    Rotation sequence in ATP synthase
    Back
    Proton flow rotates the c-ring, which turns the γ shaft inside the α₃β₃ head
  19. Front
    Proton requirement for ATP synthase
    Back
    About 3 H⁺ passing through F₀ are required to synthesize 1 ATP
  20. Front
    Binding-change mechanism
    Back
    Model in which catalytic sites of ATP synthase cycle through different conformations to bind substrates, make ATP, and release ATP
  21. Front
    Catalytic subunits of F₁
    Back
    Three chemically identical but conformationally distinct α/β subunits
  22. Front
    O state
    Back
    Open, inactive, low affinity for ligands
  23. Front
    L state
    Back
    Loose, inactive, loosely binds ligands
  24. Front
    T state
    Back
    Tight, active, tightly binds ligands
  25. Front
    Function of O state
    Back
    Releases ATP and can accept ADP and Pi
  26. Front
    Function of L state
    Back
    Binds ADP and Pi and holds them in place
  27. Front
    Function of T state
    Back
    Catalytically active state where ATP is formed
  28. Front
    Conformational cycle of ATP synthase
    Back
    O → L → T → O
  29. Front
    Meaning of rotational catalysis
    Back
    Rotation of γ forces each catalytic site to change conformation in sequence
  30. Front
    Three simultaneous jobs of catalytic sites
    Back
    One site loads substrates, one site forms ATP, and one site releases ATP
  31. Front
    Rate-limiting step of ATP synthase
    Back
    Release of newly made ATP
  32. Front
    Important subtlety of ATP synthase
    Back
    The critical conformational energy is needed for ATP release rather than ATP bond formation
  33. Front
    Requirement for oxidative phosphorylation
    Back
    Mitochondrial membrane transporters are required in addition to ATP synthase
  34. Front
    Reason transporters are required
    Back
    The inner mitochondrial membrane is impermeable and key metabolites must be moved across it
  35. Front
    Main molecules that must be transported
    Back
    ADP into the matrix, ATP out of the matrix, and Pi into the matrix
  36. Front
    Consequence of absent transporters
    Back
    ATP synthase runs out of ADP or Pi, ATP accumulates inside, and oxidative phosphorylation slows or stops
  37. Front
    Three linked systems of oxidative phosphorylation
    Back
    Respiratory chain proton pumping, ATP synthase proton return and ATP production, and membrane transport of ATP, ADP, and phosphate
  38. Front
    ATP production system in mitochondria
    Back
    ETC plus ATP synthase plus metabolite transport
  39. Front
    ATP yield from NADH oxidation
    Back
    Approximately 2.5 ATP
  40. Front
    ATP yield from FADH₂ oxidation
    Back
    Approximately 1.5 ATP
  41. Front
    Protons pumped per NADH oxidation
    Back
    About 10 H⁺ per 2 electrons transferred from NADH to O₂
  42. Front
    Protons pumped per FADH₂ oxidation
    Back
    About 6 H⁺ per 2 electrons transferred from FADH₂ to O₂
  43. Front
    Total proton cost per ATP synthesis
    Back
    About 4 H⁺ total
  44. Front
    Breakdown of proton cost per ATP
    Back
    3 H⁺ through F₀/F₁ plus 1 H⁺ with phosphate symport
  45. Front
    Reason NADH yields 2.5 ATP
    Back
    Electrons enter at Complex I and proton pumping occurs at Complexes I, III, and IV for a total of about 10 H⁺
  46. Front
    Reason FADH₂ yields 1.5 ATP
    Back
    Electrons enter at Complex II, bypass Complex I, and only Complexes III and IV pump protons for a total of about 6 H⁺
  47. Front
    P/O ratio
    Back
    Number of ATP-forming phosphates incorporated per atom of oxygen reduced
  48. Front
    P/O ratio for NADH to O₂
    Back
    2.5
  49. Front
    P/O ratio for FADH₂ to O₂
    Back
    1.5
  50. Front
    P/O ratio for cytochrome c to O₂
    Back
    0.5
  51. Front
    Electron transfer chain inhibitors
    Back
    Molecules that block electron flow at specific points in the respiratory chain
  52. Front
    Use of inhibitors in ETC research
    Back
    Helped reveal the mechanism and order of the respiratory chain
  53. Front
    Logic of inhibitor mapping
    Back
    Carriers before the block become reduced and carriers after the block remain oxidized
  54. Front
    Consequence of ETC inhibition
    Back
    Proton pumping stops, ATP synthesis stops, and oxygen cannot be used properly for oxidative phosphorylation
  55. Front
    Why ETC inhibitors are dangerous
    Back
    Tissues with high ATP demand are especially vulnerable
  56. Front
    Complex I inhibitors
    Back
    Rotenone and amobarbital (amytal)
  57. Front
    Complex III inhibitor
    Back
    Antimycin A
  58. Front
    Complex IV inhibitors
    Back
    Carbon monoxide, cyanide, azide, and hydrogen sulfide
  59. Front
    Most lethal ETC inhibitor group
    Back
    Complex IV inhibitors because they block the final reduction of oxygen
  60. Front
    Cyanide primary biochemical target
    Back
    Complex IV
  61. Front
    Effect of cyanide on respiration
    Back
    Oxygen may be present but cells cannot use it for oxidative phosphorylation
  62. Front
    Concept underlying cyanide poisoning
    Back
    Histotoxic hypoxia, where oxygen is available but unusable by cells
  63. Front
    Primary organ system target of cyanide
    Back
    The central nervous system
  64. Front
    Reason CNS is vulnerable to cyanide
    Back
    The CNS depends heavily on aerobic ATP production
  65. Front
    Rhodanese
    Back
    Enzyme involved in detoxification of cyanide-related species
  66. Front
    Rhodanese reaction mentioned in lecture
    Back
    Converts cyanate to thiocyanate (SCN⁻)
  67. Front
    Thiocyanate (SCN⁻)
    Back
    Less toxic detoxification product of cyanide-related species
  68. Front
    Food sources of cyanide-related compounds
    Back
    Almonds, pits from stone fruits, sorghum, and cassava
  69. Front
    Environmental sources of HCN
    Back
    Automobile exhaust, cigarette smoke, and fire smoke
  70. Front
    Most important fact about cyanide
    Back
    Cyanide blocks Complex IV
  71. Front
    Uncouplers
    Back
    Ionophores that carry H⁺ back to the matrix and dissipate the proton gradient
  72. Front
    Effect of uncouplers on gradient
    Back
    The pH gradient is dissipated
  73. Front
    Effect of uncouplers on ATP formation
    Back
    ATP synthesis is inhibited
  74. Front
    Effect of uncouplers on energy release
    Back
    Energy from electron flow is released as heat
  75. Front
    Meaning of uncoupling
    Back
    Breaks the link between electron transport and ATP synthesis
  76. Front
    Effect of uncouplers on ETC
    Back
    Electron transport can continue even though ATP synthesis falls
  77. Front
    Effect of uncouplers on oxygen consumption
    Back
    Oxygen consumption may continue or even increase
  78. Front
    Reason ATP falls with uncouplers
    Back
    Protons return without passing through ATP synthase
  79. Front
    Dissipation of proton gradient
    Back
    Collapses the driving force required by ATP synthase
  80. Front
    DNP
    Back
    2,4-dinitrophenol, a classic chemical uncoupler
  81. Front
    Nature of DNP
    Back
    A hydrophobic weak acid that shuttles protons across the inner mitochondrial membrane
  82. Front
    Danger of DNP
    Back
    Causes inefficient fuel oxidation, overheating, and ATP depletion
  83. Front
    Thermogenin
    Back
    A physiologically important uncoupler in brown adipose tissue
  84. Front
    Other name for thermogenin
    Back
    UCP or uncoupling protein
  85. Front
    Specific identity of thermogenin
    Back
    UCP1
  86. Front
    Location of thermogenin
    Back
    Brown adipose tissue
  87. Front
    Brown fat in newborns
    Back
    Found especially in the neck and upper back
  88. Front
    Reason brown fat appears brown
    Back
    It contains many mitochondria
  89. Front
    Mechanism of thermogenin
    Back
    Allows protons to return to the matrix without ATP synthase
  90. Front
    Purpose of thermogenin
    Back
    Heat production rather than ATP conservation
  91. Front
    Nonshivering thermogenesis
    Back
    Heat generation by uncoupled proton flow in brown fat
  92. Front
    Why newborns need brown fat
    Back
    Newborns have limited ability to generate heat by shivering
  93. Front
    Activation of thermogenin
    Back
    Fatty acids released from triglycerides in brown fat
  94. Front
    Hormonal regulation of thermogenin activity
    Back
    Hormone-induced fatty acid release activates thermogenin
  95. Front
    UCP2 and UCP3
    Back
    Uncoupling proteins whose expression is activated by thyroid hormones
  96. Front
    Effect of thyroid hormones on uncoupling
    Back
    Increases expression of UCP2 and UCP3
  97. Front
    Normal coupling in oxidative phosphorylation
    Back
    ETC pumps H⁺ out, H⁺ returns through ATP synthase, ATP synthase rotation makes ATP, and transporters move ADP, ATP, and Pi
  98. Front
    Effect of inhibitors on oxidative phosphorylation
    Back
    Block electron flow, stop proton pumping, and stop ATP synthesis
  99. Front
    Effect of uncouplers on oxidative phosphorylation
    Back
    Allow proton return without ATP synthase so ETC can continue, ATP falls, and heat rises
  100. Front
    F₀ in cheat sheet
    Back
    Membrane proton channel and rotor
  101. Front
    F₁ in cheat sheet
    Back
    Catalytic head in the matrix
  102. Front
    Catalytic activity in ATP synthase
    Back
    Associated conceptually with β subunits through O, L, and T states
  103. Front
    O state summary
    Back
    Open state that releases ATP and binds substrates
  104. Front
    L state summary
    Back
    Loose state that binds ADP and Pi
  105. Front
    T state summary
    Back
    Tight state that forms ATP
  106. Front
    Effective proton cost per ATP
    Back
    Approximately 4 H⁺ per ATP
  107. Front
    High-yield ATP yields
    Back
    NADH gives 2.5 ATP and FADH₂ gives 1.5 ATP
  108. Front
    High-yield inhibitor summary
    Back
    Complex I inhibitors are rotenone and amobarbital, Complex III inhibitor is antimycin A, and Complex IV inhibitors are cyanide, CO, azide, and H₂S
  109. Front
    High-yield uncoupler summary
    Back
    DNP is a chemical uncoupler and thermogenin/UCP1 is a physiologic uncoupler in brown fat

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