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    TCA Cycle, ETC, and Oxidative Phosphorylation

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    Santino Majok
    The document provides an overview of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation. It discusses the purpose and steps of the TCA cycle and ETC, how they are regulated, and how oxidative phosphorylation uses the proton gradient created by the ETC to synthesize ATP. Key points covered include the net ATP production from aerobic glycolysis being 32 molecules of ATP.

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    TCA Cycle, ETC, and Oxidative Phosphorylation

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    Santino Majok
    19 views56 pages
    The document provides an overview of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation. It discusses the purpose and steps of the TCA cycle and ETC, how they are regulated, and how oxidative phosphorylation uses the proton gradient created by the ETC to synthesize ATP. Key points covered include the net ATP production from aerobic glycolysis being 32 molecules of ATP.

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    The document provides an overview of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation. It discusses the purpose and steps of the TCA cycle and ETC, how they are regulated, and how oxidative phosphorylation uses the proton gradient created by the ETC to synthesize ATP. Key points covered include the net ATP production from aerobic glycolysis being 32 molecules of ATP.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    19 views56 pages

    TCA Cycle, ETC, and Oxidative Phosphorylation

    Uploaded by

    Santino Majok
    The document provides an overview of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation. It discusses the purpose and steps of the TCA cycle and ETC, how they are regulated, and how oxidative phosphorylation uses the proton gradient created by the ETC to synthesize ATP. Key points covered include the net ATP production from aerobic glycolysis being 32 molecules of ATP.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
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    of 56

    TCA Cycle, Electron Transport Chain,

    and Oxidative Phosphorylation

    September 23, 2010


    Juba University College of Medicine

    Lecturer: Chitra Akileswaran


    Announcements

    • Biochemistry lectures
    – Today: Citric acid cycle, electron transport chain,
    and oxidative phosphorylation
    – Next Wednesday at 2:00pm: HMP shunt and
    glycogen metabolism
    – Quiz next Friday covering carbohydrate metabolism
    • I expect you to be on time with cell phones
    off
    • Grand Rounds this Saturday!
    Grand Rounds
    this Saturday, 25/9 at 9:00am
    “Postpartum Hemorrhage and Maternal Mortality in
    Southern Sudan”
    ‐featuring‐
    Deng Simon Garang and Alyaa Helal,
    3rd year students

    Learn about physiology of hemorrhage, the physiology of pregnancy, and


    physical findings related to cardiovascular instability
    Review Questions

    • What are the major energy carriers for


    metabolism?
    • What is the rate-limiting step of glycolysis?
    • What is the net ATP production from
    glycolysis?
    • What is the end product for anaerobic
    glycolysis?
    Review Questions--Answers

    • NADH, FADH2, ATP


    • Step 3: phosphorylation of F6P using
    PFK-1
    • Net ATP production: 2
    • Lactate
    Lecture objectives (1 of 2)

    • What is the purpose of the TCA cycle?


    Where does it occur?
    • Name the steps of the TCA cycle (hint:
    CIOOPOHO).
    • What are the regulated steps? What
    enzymes are used? What activates and
    inhibits these enyzmes?
    Lecture objectives (2 of 2)

    • What is the purpose of the Electron Transport


    Chain? Where does it occur?
    • Name the 5 Complexes. What is the pathway
    of electron flow?
    • What is oxidative phosphorylation? How
    does it result in ATP?
    • What is the net ATP production of aerobic
    glycolysis?
    • Name the inhibitors of the ETC. How does
    uncoupling work?
    Central Equation of Glycolysis

    Glucose has 3 choices:


    1) Glycolysis to pyruvate
    2) Storage as glycogen
    3) Oxidation via Pentose
    Phosphate Pathway

    Glucose + 2Pi + 2ADP + 2NAD+ --> 2Pyruvate + 2ATP + 2NADH + 2H+ + 2H2O
    Alternative Fates of Pyruvate

    1) Oxidative decarboxylation
    to acetyl coA (next step of
    aerobic glycolysis)

    2) Carboxylation of pyruvate to
    oxaloacetate (first step of
    gluconeogenesis)

    3) NOT SHOWN: Reduction of


    pyruvate to ethanol (in
    yeast and microorganisms,
    not humans)
    From Glycolysis to TCA Cycle

    • Pyruvate is converted to
    Acetyl CoA
    • Acetyl CoA can enter the
    TCA cycle
    • For each pyruvate, TCA
    cycle produces 2CO2, 8
    electrons (accepted by
    energy carriers), 1 ATP
    Tricarboxylic Acid Cycle
    • Tricarboxylic acid cycle aka Krebs cycle aka
    Citric Acid Cycle
    • Breaks down remainder of carbon skeleton,
    leaving only reducing equivalents
    • Final common pathway for the aerobic
    metabolism of carbohydrates, amino acids,
    fatty acids--produces most ATP for animals
    • Takes place in the mitochondrial matrix: it is
    tied to oxidative phosphorylation (the process
    by which NAD+ and FADH+ are regenerated
    and ATP is produced)
    Tricarboxylic Acid Cycle
    Step 1: Oxidative decarboxylation of pyruvate

    • Pyruvate is shuttled to mitochondrial matrix (crosses


    inner mitochondrial membrane)
    • Regulated and irreversible
    • Catalyzed by pyruvate dehydrogenase
    Pyruvate Dehydrogenase

    • Complex of three enzymes


    • Requires coenzymes such as thiamine
    pyrophosphate (vitamin B1), Coenzyme A (CoA),
    lipoic acid
    Regulation of Pyruvate Dehydrogenase

    • Acetyl CoA
    directly
    inhibits
    • Kinase
    inactivates
    • Phosphatase
    activates
    Acetyl CoA

    Now we have acetyl CoA, a 2 carbon


    molecule ready for the TCA cycle
    Quiz Yourself

    • Where must pyruvate move to begin the TCA


    cycle?

    • What is the enzyme that catalyzes the first


    step of the TCA cycle?
    Overview of TCA Cycle
    How to remember TCA Cycle

    CIOOPOHO
    Entry point:
    Acetyl CoA+OAA
    2C+4C = 6C
    Products of TCA Cycle

    Released from cycle


    2 CO2
    1 GTP (like ATP)
    3 NADH
    1 FADH2
    For every molecule of glucose, how many of
    these will we get?
    Step 2: Condensation (synthesis of Citrate)

    • Catalyzed by citrate synthase


    • Citrate inactivates PFK-1
    Step 3: Isomerization of Citrate

    • Catalyzed by aconitase
    Step 4: Oxidative Decarboxylation of Isocitrate

    • 6 carbons becomes 5 carbons


    • Regulated (one of the rate-limiting steps)
    • Catalyzed by isocitrate dehydrogenase: activated by
    ADP, Ca2+, inhibited by ATP, NADH
    • Makes 1st molecule of NADH
    Step 5: Oxidative Decarboxylation of
    alpha-ketoglutarate

    • Regulated (one of the rate-limiting steps)


    • Catalyzed by alpha-ketoglutarate dehydrogenase:
    activated by ADP, inhibited by ATP, NADH
    • Similar to PDH: requires CoA, TPP, lipoic acid
    • Makes 2nd molecule of NADH
    Step 6: Phosphorylation of Succinyl CoA

    • Catalyzed by succinate CoA synthetase


    • Makes 1 molecule of GTP (interchangeable
    with ATP)
    Step 7: Oxidation of Succinate

    • Catalyzed by succinate dehydrogenase


    • Makes 1 molecule of FADH2
    Step 8: Hydration of Fumarate

    • Catalyzed by fumarase
    Step 9: Oxidation of Malate

    • Catalyzed by malate dehydrogenase


    • Makes 3rd molecule of NADH
    Quiz Yourself

    • How much NADH is produced by the TCA


    cycle? How much FADH2? How much ATP?

    • What happens during the condensation step


    of the TCA cycle?
    Regulation of TCA Cycle

    • Step 1: pyruvate to acetyl CoA (pyruvate


    dehydrogenase)

    • Step 4: oxidative decarboxylation of


    isocitrate (isocitrate dehydrogenase)

    • Step 5: oxidative decarboxylation of alpha-


    ketoglutarate (alpha-ketoglutarate
    dehydrogenase)
    Regulation of TCA Cycle
    Intro to Electron Transport Chain

    We now have:
    • Glycolysis: 2 ATP and 2 NADH
    • TCA cycle: 2 GTP (ATP), 6 NADH, 2 FADH2
    • What do we do with NADH and FADH2?

    We must have a way to regenerate NAD+ and


    FAD+…these are necessary for cells!
    Electron Transport Chain

    • ETC receives electrons from NADH and


    FADH2 (H-) and donates them to O2 to make
    H2O
    • Occurs in inner mitochondrial membrane
    – TCA cycle was in the matrix
    • The energy generated by the oxidation-
    reduction reactions (removing electrons from
    NADH and FADH2, donating electrons to O2)
    allows oxidative phosphorylation, which
    generates a lot of ATP
    Inner Mitochondrial Membrane
    Composition of ETC

    • Made up of 5 complexes
    • Each complex accepts electrons from the complex
    preceding it and donates it to the complex following it
    Pathway of electrons
    • NADHComplex I (NADH dehydrogenase) 
    Coenzyme Q aka ubiquinone  Complex III (cytochromes
    b+c1)  cytochrome c  Complex IV (cytochrome a+a3)
    O2
    – NADH becomes NAD+
    • FADH2Complex II (FADH2 dehydrogenase)
    Coenzyme Q aka ubiquinone…O2
    – FADH2 becomes FAD+
    • Coenzyme Q and cytochrome c are mobile electron
    carriers not part of the complexes
    • Cytochrome contain heme groups (iron-sulfur ring) and
    can help accept and donate electrons
    Composition of ETC
    Free Energy in ETC

    • As electrons are transported along the chain, free


    energy is released
    • The amount of free energy released determines
    how many ATP can be made (from ADP)
    – Phosphorylation of ADP requires 7300 cal/mol
    – Transport of electrons from NADH to O2 releases
    enough energy to make 3 ATP
    – Transport of electrons from FADH2 to O2 releases
    enough energy to make 2 ATP
    Quiz Yourself

    • What are the regulated steps of the TCA cycle?

    • What is the pathway of electrons when NADH is the


    electron donor?

    • How much ATP is made for every FADH2 that


    passes electrons into the ETC?
    Accounting for ATP

    We now have:
    • Glycolysis: 2 ATP and 2 NADH
    • TCA cycle: 2 GTP (ATP), 6 NADH, 2 FADH2
    • How many ATP from 1 glucose?
    • 2 + 6 + 2 +18 + 4 = 32

    How do we make this ATP?


    Oxidative Phosphorylation

    • Oxidative phosphorylation refers to the


    synthesis of ATP using the energy created by
    the electron transport chain

    • Chemiosmotic hypothesis: the theory of how


    the free energy of the ETC is used to produce
    ATP from ADP and Pi
    Chemiosmotic Hypothesis

    • Electron transport is coupled to the transport of H+


    from the matrix to the intermembrane space
    Creation of Proton Gradient

    • As H+ passes across the membrane, two


    gradients are created: electrical and pH
    ATP Synthesis

    • After the protons


    have been
    transported to the
    intermembrane
    side, they reenter
    the matrix
    (because of
    gradients) through
    Complex V
    • This results in the
    synthesis of ATP
    from ADP+Pi
    Site-Specific Inhibitors of ETC

    • Complex I: barbiturates
    • Complex II: carboxin
    • Complex III: antimycin A
    • Complex IV: cyanide
    • Complex V: oligomycin
    Complex I: Barbiturates
    Complex II: Carboxin
    Complex III: Antimycin A
    Complex IV: Cyanide

    Cyanide
    Complex V: Oligomycin
    Uncoupling Mechanism

    • When the ETC is “uncoupled” from oxidative


    phosphorylation, protons leak back across the
    inner mitochondrial membrane into the matrix
    • They do not go through ATP synthase
    (Complex V)
    • This means that ATP is not formed via the
    proton gradient
    • Example: bupivicaine
    Uncoupling of ETC from Ox-Phos
    Quiz Yourself

    • How much ATP do we expect to make from aerobic


    glycolysis?

    • What are the two gradients created by the free


    energy released by the ETC?

    • What is the mechanism of uncoupling?


    Lecture objectives (1 of 2)

    • What is the purpose of the TCA cycle?


    Where does it occur?
    • Name the steps of the TCA cycle (hint:
    CIOOPOHO).
    • What are the regulated steps? What
    enzymes are used? What activates and
    inhibits these enyzmes?
    Lecture objectives (2 of 2)

    • What is the purpose of the Electron Transport Chain?


    Where does it occur?
    • Name the 5 Complexes. What is the pathway of
    electron flow?
    • What is oxidative phosphorylation? How does it
    result in ATP?
    • What is the net ATP production of aerobic glycolysis?
    • Name the inhibitors of the ETC. How does
    uncoupling work?

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