Energy and Metabolism

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Energy and Metabolism

Energy and Metabolism

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Respiration

Citric Acid Cycle

  • Citric acid cycle is also known as the tricarboxylic acid cycle or Krebs' cycle
  • It occurs in mitochondria
  • It is an aerobic stage which requires oxygen
  • The entry point into the citric acid cycle is acetyl CoA (coenzyme A)
  • During the citric acid cycle the acetyl CoA is fully oxidised to carbon dioxide and water
  • The citric acid cycle also provides intermediates - biosynthesis
  • Two carbon atoms enter the cycle as acetyl CoA
  • They add onto a four carbon unit to give citric acid
  • Two carbon atoms leave the cycle as carbon dioxide
  • The cycle has nine steps
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Citric Acid Cycle

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Energy Yield of the Citric Acid Cycle

  • The citric acid cycle does not produce many molecules of ATP itself
  • It produces NADH and FADH2 which are converted into ATP during the electron transport chain
    • 3 molecules of NADH
    • 1 molecule of FADH2 (flavin adenine dinucleotide)
    • 1 molecule of GTP
  • GTP (guanosine triphosphate) is a high energy molecule
  • The cycle can be divided into a number of parts
    • 6 carbon atoms
    • 5 carbon atoms
    • 4 carbon atoms
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Citric Acid Cycle

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Citric Acid Cycle

Six Carbon Atoms - First Step

  • Oxaloacetate + acetyl CoA --> citrate
  • Acetyl CoA undergoes condensatin with oxaloacetate
  • During the cycle oxaloacetate is recycled

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Six Carbon Atoms - Second Step

  • Citrate --> isocitrate

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Citric Acid Cycle

Six to Five Carbon Atoms

  • Isocitrate + NAD+ --> alpha-ketoglutarate + NADH + CO2
  • In this step the citrate is oxidised

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Six to Five Carbon Atoms

  • This a two step process
  • The intermediate is unstable and spontaneously converts

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Citric Acid Cycle

Five to Four Carbon Atoms

  • alpha-ketoglutarate --> succinyl CoA
  • resemble pyruvate dehydrogenase

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Citric Acid Cycle

Four Carbon Atoms

  • Succinyl CoA --> Succinate + GTP
  • The energy of the thioester bond of succinyl CoA is used to drive the formation of GTP

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Four Carbon Atoms

  • GTP is used in protein synthesis and cell signalling
  • It can also be converted readily to ATP

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Four Carbon Atoms

  • Succinate --> fumarate
  • FAD is the electron receptor rather than NAD+ as there is insufficient energy to reduce NAD+

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Four Carbon Atoms

  • Fumarate --> malate

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Four Carbon Atoms

  • Malate --> oxaloacetate
  • The final step in the cycle regenerates oxaloacetate which can undergo further reaction with acetyl CoA

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Overall Stoichiometry

  • Whilst it does not directly involve oxygen, regeneration of the NAD+ and FAD requires molecular oxygen (see oxidative phosphorylation)
  • Citric acid cycle only works under aerobic conditions
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Control of the Citric Acid Cycle

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Biosynthetic Intermediate

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Glycolysis and Citric Acid Cycle

  • Glycolysis
    • converted glucose to 2 molecules of pyruvate
    • produced 2ATP, 2NADH
  • Pyruvate to acetyl coenzyme A
    • produced 2NADH (per glucose)
  • Citric acid cycle
    • converted acetyl CoA to CO2
    • produced 2GTP, 6NADH, 2FADH2
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Oxidative Phosphorylation

  • Process by which NADH and FADH2 react with oxygen
  • This process releases energy which makes ATP
  • Each molecule of NADH produces 3 of ATP
  • Each molecule of FADH2 produces 2 of ATP
  • Each molecule of glucose when metabolised gives rise to 36 molecules of ATP
  • 32 molecules are formed during oxidative phosphorylation
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Oxidative Phosphorylation

  • Occurs in the Mitochondria

Structure of the Mitochondrion

  • Outer membrane
    • binds the mitochondrion
    • permeable to most small molecules
  • Inner membrane
    • highly folded
    • virtually impermeable to all ions and polar molecules
    • contains specific transport proteins for some molecules such as ADP
    • site of oxidative phosphorylation
  • Matrix
    • bounded by inner membrane
    • site of citric acid cycle and fatty acid oxidation
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Summary of Oxidative Phosphorylation

  • During oxidative phosphorylation protons are pumped out of the mitochondrial matrix
  • This gives a proton (energy) gradient
  • The return of protons to the matrix is coupled to phosphorylation of ADP

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Oxidative Phosphorylation

  • Reaction of NADH and oxygen
  • This is the reduction of molecular oxygen
  • It is the transfer of electrons from NADH to oxygen

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Oxidative Phosphorylation: Electron Transport Chai

  • Electrons are transferred from NADH (or FADH2) to molecular oxygen by the electron transport chain
  • In the electron transport chain there are four protein complexes
    • NADH-ubiquinone oxidoreductase (complex I)
    • Succinate-ubiquinone oxidoreductase (complex II)
    • Ubiquinol-cytochrome C oxidoreductase (complex III)
    • Cytochrome C oxidase (complex IV)
  • There are also two electron carriers
    • ubiquinone
    • cytochrome C
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Oxidative Phosphorylation - Complex 1

Oxidative Phosphorylation - Complex 1

  • NADH-Q oxidoreductase (NADH dehydrogenase)
  • A large protein complex (>900,000 molecular weight)
  • Contains 42-43 subunits
  • Catalyses the transfer of two electrons from NADH to Q
  • Initially electrons are transferred from NADH to a coenzyme flavin mononucleotide (FMN)
  • Electrons are then transferred to a series of iron-sulphur complexes (22-24 Fe-S, 7 or 8 clusters)
  • Finally electrons are transferred out of this complex to the electron carrier ubiquinone (Q)
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Oxidative Phosphorylation - Complex 1

  • FMN

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Oxidative Phosphorylation - Complex 1

  • Iron-sulphur proteins
  • These proteins contain iron which is complexed to cysteine residues and inorganic sulphur
  • During electron transport these can be oxidised (Fe3+) or reduced (Fe2+) states
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Summary of NADH-Q

  • NADH-Q takes electrons from NADH and transfers them to ubiquinone
  • During this process energy is released

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Summary of NADH-Q

  • The energy released is used to pump protons out of the matrix of the mitochondria
  • The free energy released as electrons pass through NADH-Q is -50kJ/mol
  • This is sufficient to drive the synthesis of ATP (requires -30kJ/mol)
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Oxidative Phosphorylation: Ubiquinone (Coenzyme Q)

  • Electrons are transferred from NADH-Q reductase to ubiquinone
  • Ubiquinone is anchored to the membrane by the isoprenoid unit
  • The length of the isoprenoid unit varies from species to species

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Oxidative Phosphorylation

  • Ubiquinone acts as an electron carrier
  • Ubiquinone accepts electrons from NADH-Q reductase and passes them to cytochrome reductase
  • Reduction of ubiquinone does not cause pumping of protons

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Oxidative Phosphorylation

Oxidative Phosphorylation - Complex 2

  • Succinate-ubiquinone oxidoreductase
    • succinate dehydrogenase complex
  • Catalyses the reduction of ubiquinone
  • Composed of 4 sub-units (1,250,000 molecular weight)
    • 2 sub-units contain FAD + 3 Fe-S clusters
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Oxidative Phosphorylation - Complex 2

  • Succinate-ubiquinone oxidoreductase

  • FADH2 does not have as much reducing power as NADH
  • Each molecule of NADH produces 3ATP
  • Each molecule of FADH2 produces 2ATP
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Oxidative Phosphorylation

Oxidative Phosphorylation - Complex 3

  • Ubiquinol-cytochrome C oxidoreductase
  • This transfers electrons from ubiquinone to cytochrome C
  • Cytochrome reductase acts as an electron pump
    • Oxidation of QH2 results in the transfer of 4H+ across the inner membrane
  • Cytochrome reductase is a protein complex (250,000 molecular weight) which contains a number of catalytically active sites:
    • cytochrome b
    • cytochrome c1
    • an Fe-S cluster
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Oxidative Phosphorylation - Complex 3

  • A cytochrome is defined as an electron-transferring enzyme which contains a haem prosthetic group
  • In cytochrome c1 the haem unit is attached to the protein via cysteine units

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Oxidative Phosphorylation - Complex 3

  • Mechanisms of cytochrome reductase
  • Reduced ubiquinone (QH2) transfers 2 high energy electrons to the cytochrome reductase complex
  • Each of the high energy electrons has a different pathway in the cytochrome reductase
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Oxidative Phosphorylation - Complex 3

First high-energy electron

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Oxidative Phosphorylation - Complex 3

First high-energy electron

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Oxidative Phosphorylation - Complex 3

  • Second high-energy electron
  • Cytochrome b has 2 haem units with slightly different roles. They are not bound covalently to the enzyme

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Oxidative Phosphorylation

  • Cytochrome C
  • Electrons are then transferred to cytochrome C from cytochrome reductase
  • Cytochrome C does not contain a proton pump
  • Cytochrome C is a membrane-bound haem containing enzyme
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Oxidative Phosphorylation

Oxidative Phosphorylation - Complex 4

  • Cytochrome C oxidase
  • Catalsyses the transfer of electrons to molecular oxygen
  • Overall reaction:

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Cytochrome C Oxidase

  • Dimmer of 13-chain subunits (420,000 moleculae weight)
  • It contains 2 haem units and 2 copper ions
  • During the reduction energy is released (-100kJ/mol)
  • The energy released is used to pump protons out of the matrix. Sufficient protons are moved to generate ATP
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So far...

  • The 3 protein complexes
    • NAD-Q reductase
    • Cytochrome reductase
    • Cytochrome oxidase
  • Have pumped protons out of the matrix of the mitochondrion
  • This generates a proton motive force
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Oxidative Phosphorylation

  • Protons flow back into the matrix through an enzyme
  • ATP synthase (complex 5) which couples ADP and phosphate

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ATP Synthase - Complex 5

  • The enzyme contains a transmembrane region and a large head group on the matrix side of the membrane
  • The head group contains the ATP synthesising domain
  • The transmembrane region is the proton channel through which the protons flow

Metabolism of Glucose - Summary

ATP yield per glucose

  • Glycolysis - 2
  • Citric acid cycle - 2
  • Oxidative phosphorylation - 32
  • Total - 36
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Metabolism of Glucose - Summary

Efficiency 

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Metabolism of Glucose - Summary

Location of metabolic activities

  • Glycolysis - cytosol
  • Citric acid cycle - mitochondria
  • Oxidative phosphorylation - mitochondria
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ATP yield per glucose

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