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Tricarboxylic Acid Cycle (TCA), Krebs Cycle

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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  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 coenzyme’re 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. 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

  11. 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

  12. 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

  13. 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)

  14. 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.

  15. Regulation of TCA Cycle

  16. 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

  17. Biosynthetic & Anaplerotic reactions

  18. 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

  19. 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 .

  20. 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 )

  21. Membrane Transport System

  22. 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.

  23. Energy produced from TCA

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