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Tricarboxylic Acid Cycle (TCA), Krebs Cycle. Occurs totally in mitochondria Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is produced More NADH is made NADH goes on to make more ATP in electron transport and oxidative phosphorylation

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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

  • More NADH is made

  • NADH goes on to make more ATP in electron transport and oxidative phosphorylation

  • Traffic circle, comp. entering & leaving


Tricarboxylic Acid Cycle (TCA),


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 coenzyme’re needed

    See figure


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.


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.


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


Mechanism of Pyr. decarboxylase


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)


Regulation of Pyr. Dehydrogenase Complex


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


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


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


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)


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.


Regulation of TCA Cycle


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


Biosynthetic & Anaplerotic reactions


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


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 .


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 )


Membrane Transport System


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.


Energy produced from TCA


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