Tricarboxylic Acid Cycle (TCA), Krebs Cycle - PowerPoint PPT Presentation

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Tricarboxylic Acid Cycle (TCA), Krebs Cycle

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Tricarboxylic Acid Cycle (TCA), Krebs Cycle Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO2 Some ATP is produced – PowerPoint PPT presentation

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Title: Tricarboxylic Acid Cycle (TCA), Krebs Cycle


1
Tricarboxylic Acid Cycle (TCA), Krebs Cycle
  • Occurs totally in mitochondria
  • Pyruvate (actually acetate) from glycolysis is
    degraded to CO2
  • Some ATP is produced
  • More NADH is made
  • NADH goes on to make more ATP in electron
    transport and oxidative phosphorylation
  • Traffic circle, comp. entering leaving

2
Tricarboxylic Acid Cycle (TCA),
3
Oxidative Decarboxylation of Pyruvate
  • Pyr. from aerobic glycolysis
  • is transported to cross inner
  • mitochondrial membrane
  • by specific transporter.
  • In the matrix, pyr. is
  • irreversibly decarboxylated
  • by a multienzyme complex
  • Five coenzymere needed
  • See figure

4
Oxidative Decarboxylation of Pyruvate
  • Pyr is converted to acetyl CoA by pyr
    dehydrogenase (pyr DH) complex , which is a
    multienzyme complex.
  • pyr dehydrogenase complex is not part of TCA
    cycle proper, but is a mojor source of acetyl
    CoA.
  • The irreversibility of the reaction explains why
    glucose can not be formed from acetyl CoA in
    gluconeogenesis.

5
Oxidative Decarboxylation of Pyruvate
  • pyr dehydrogenase complex is composed of three
    enzymes
    pyr decarboxylase (E1)
    - dihydrolipoyl transacylase (E2)
    - dihydrolipoyl
    dehydrogenase (E3)
  • Each catalyzed a part of the overall reaction
  • In addition to two regulatory enzymes protein
    kinase and phosphoprotein phosphatase.

6
Oxidative Decarboxylation of Pyruvate
  • Coenzymes Pyr DH complex contains 5 coenzyme
    which act as a carriers or oxidant for
    intermediates.
  • (1) Thiamine pyrophosphate
  • (2)Lipoic acid
  • (3) CoA
  • (4) FAD
  • (5) NAD

7
Mechanism of Pyr. decarboxylase
8
Regulation of Pyr. Dehydrogenase Complex
  • Allosteric activation of kinase Phosphatase
  • - Cyclic AMP-independent protein kinase (
    activated)?activates phosphorylated E1 ( inactive
    ) inhibits dephosphorylated ( active ) ?
    inhibit Pyr DH.
  • protein kinase allosterically activated by ATP,
    acetyl CoA, NADH ( high energy signals)? inhibit
    Pyr DH (turned off).
  • protein kinase allosterically inactivated by NAD
    CoA, ( low energy signals)? activate Pyr DH
    (turned ).
  • Pyr is a potent inhibitor of kinase, if pyr
    concentration is elevated so E1 is active
  • Ca is strong activator of Phosphatase,
    stimulating E1 activity ( skeletat muscle
    contraction)

9
Regulation of Pyr. Dehydrogenase Complex
10
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11
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12
Reactions of TCA
  • Synthesis of citrate from acetyl CoA and
    oxaloacetate (OAA)
  • Irreversible, catalyzed by citrate synthase.
  • Aldol condensation reaction.
  • citrate synthase is inhibited by ATP, NADH,
    succinyl CoA fatty acyle CoA.
  • Function of citrate It provides a source of
    acetyl CoA for fatty acid synthesis it inhibits
    PFK1

13
Reactions of TCA
  • (3) Isomerisation of citrate to isocitrate by
    aconitase ( reversible reaction), It is inhibited
    by fluroacetate, a compound used for rat
    poisoning(fluroacetate is converted to
    flurocitrate which is a potent inhibitor for
    aconitase)
  • (4) Oxidative Decarboxylation of isocitrate
    irreversible oxidative phosphorylation, by
    isocitrate DH to give ? -Ketoglutarate, NADH
    CO2
  • -It is rate limiting step
  • -isocitrate DH is activated by ADP and Ca 2
    inhibited by ATP, NADH

14
Reactions of TCA
  • (5) Oxidative Decarboxylation of ?
    -Ketoglutarate by ? -Ketoglutarate DH to give
    succinyle CoA (similar to pyr DH),
  • Release of 2nd NADH CO2
  • ? -Ketoglutarate DH need coenzymes
    TPP,NAD,FAD,CoA lipoic acid.
  • ? -Ketoglutarate DH is inhibited by ATP,NADH,
    GTP succinyle CoA. And activated by Ca 2 .
  • However it is not regulated by the
    phosphorylation and de phosphorylation reaction
    that describe in Pyr DH

15
Reactions of TCA
  • (5) Cleavage of succinyle CoA Cleavage of
    (high-energy thioester dound) succinyle CoA to
    succinate by succinate thiokinase.
  • It is coupled by release of GTPwhich
    inter-converted by nucleoside diphosphate kinase
    reaction
  • Substrate level phosphorylation.
  • succinyle CoA can be produced from Proponyle CoA
    ( metabolism of fatty acids)

16
Reactions of TCA
  • (6) Oxidation of succinate to fumarate by
    succinate DH, producing FADH2
  • (7) Hydration of fumarate to malate by fumarase
  • (8)Oxidation of malate By malate DH
  • To OAA 3nd NADH.

17
Regulation of TCA Cycle
18
Intermediates for Biosynthesis
  • ? -Ketoglutarate is transaminated to make
    glutamate, which can be used to make purine
    nucleotides, Arg and Pro
  • Succinyl-CoA can be used to make porphyrins
  • Fumarate and oxaloacetate can be used to make
    several amino acids and also pyrimidine
    nucleotides
  • mitochondrial citrate can be exported to be a
    cytoplasmic source of acetyl-CoA (?F.A in fed
    state) and oxaloacetate ?glucose in fast state

19
Biosynthetic Anaplerotic reactions
20
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21
Anaplerotic Reactions (filling up reactions)
  • PEP carboxylase - converts PEP to oxaloacetate
  • Pyruvate carboxylase - converts pyruvate to
    oxaloacetate
  • Malic enzyme converts pyruvate to malate
  • See fig. Reactions from1-5 is anaplerotic i.e.
    filling up reactions

22
Membrane Transport System
  • The inner mitochondrial membrane is impermeable
    to the most charged and hydrophilic substances.
    However it contains numerous transport proteins
    that permit the passage of specific molecules.
  • 1- ATP-ADP transport, see oxid-phospho,
  • Transporter for ADP Pi from cytosol into
    mitochondria by specialized carriers ( adenine
    nucleotide carrier) which transport ADP from
    cytosol into mitochondria, while exporting ATP
    from matrix back into the cytosol .

23
Membrane Transport System
  • Transport of reducing equivalents from cytosol
    into mitochondria using The inner mitochondrial
    membrane lacks an NADH transport proteins, NADH
    produced in cytosol cannot directly penetrate
    into mitochondria. However two electron of NADH
    ( called reducing equivalents) are transported by
    using shuttle.
  • 1. glycerophosphate shuttle ( results in
    synthesis of 2 ATP for each cytosolic NADH
    oxidized )
  • 2. malate-aspartate shuttle ( results in
    synthesis of 3 ATP in the mitochondrial matrix
    for each cytosolic NADH oxidized )

24
Membrane Transport System
25
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26
Pyruvate DH deficiency.
  • Pyruvate DH deficiency is the most common
    biochemical cause of congenital lactic acidosis.
  • Pyruvate ? cannot to acetyl CoA but to lactate
  • The most sever form cause neonatal death.
  • The moderate form cause psychomotor retardation
    with damage in cerebral cortx, basal ganglia and
    brain stem and death.
  • The third form cause episodic ataxia.

27
Energy produced from TCA
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