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20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
20. kreb's cycle
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20. kreb's cycle

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  • 1. CITRIC ACID CYCLE = TCA CYCLE = KREBS CYCLE   TCA = tricarboxylic acid cycle Definition: -- Acetate in the form of acetyl-CoA, is derived from pyruvate and other metabolites, and is oxidized to CO2 in the citric acid cycle.
  • 2. ********************************************************* *  One high energy compound is produced for each cycle.  The electrons from the TCA cycle are made available to an electron transport chain in the form of three NADH and one FADH2 and ultimatelyenergy is provided for oxidative phosphorylation. ************************************************* *
  • 3. ************************************************ The citric acid cycle is central to all respiratory oxidation, oxidizing acetyl-CoA from glucose, lipid and protein catabolism in aerobic respiration to maximize energy gain. The cycle also supplies some precursors for biosynthesis. All enzymes are in the mitochondrial matrix or inner mitochondrial membrane ************************************************
  • 4. The three stages of cellular respiration: Stage 1. Acetyl CoA production − from glucose, fatty acids and amino acids Stage 2. Acetyl CoA oxidation = TCA Cycle = yielding reduced electron carriers Stage 3. Electron transport and oxidative phosphorylation − oxidation of these carriers and production of ATP ************************************************* *
  • 5. Many catabolic pathways yield acetyl CoA for the TCA cycle glycogen  glucose lactate pyruvate fatty acids  amino acids  Acetyl-CoA TCA
  • 6. Space filled Acetyl CoA Acetyl HS-CoA
  • 7. Conversion of pyruvate to acetyl-CoA -- A major Stage 1 setup Enzyme = pyruvate dehydrogenase complex  Location = mitochondrial matrix CH3 CH3 C=O + NAD++ HS-CoA C=O +NADH+CO2 COOS-CoA   Pyruvate Acetyl-CoA
  • 8. Irreversible   -- irreversible means acetyl-CoA cannot be converted backward to pyruvate; hence “fat cannot be converted to carbohydrate”
  • 9.    pyruvate dehydrogenase (=E1) has coenzyme = thiamine pyrophosphate (TPP) -- TPP is coenzyme for all decarboxylations of α-keto acids. -- lack of thiamine = beriberi    dihydrolipoyl transacetylase (=E2) has coenzymes lipoate and CoA
  • 10.  dihydrolipoyl dehydrogenase (= E3) has coenzymes FAD and NAD+   TPP  E1 S-S-E2 FAD  E3 N A D+
  • 11. thiamine pyrophosphate (TPP) lipoic acid aka lipoamide
  • 12. Partial reactions of PDH:  introduction of pyruvate onto TPP in E1 hydroxyethyl-TPP  H OO O-C-C-CH3 TPP CO2 H O H-CCH3 E1
  • 13. Transfer to lipoamide of E2 hydroxyethyl-TPP + S S O CH3 C S HS E2 + TPP E2 lipoamide-E2 acetyl-lipoamide-E2 (disulfide,oxidized) (reduced)  Note concurrent oxidation to acetyl
  • 14.  E2 then transfers acetyl to CoA; acetyl-CoA leaves.    E3 uses its bound coenzyme FAD to oxidize lipoamide back to disulfide and generating FADH2.    FAD is recovered from FADH2 via reducing NAD to NADH.  An NADH is generated.
  • 15. Regulation of Pyruvate Dehydrogenase  Irreversible reaction must be tightly controlled-- three ways 1. Allosteric Inhibition -- inhibited by products: acetyl-CoA and NADH -- inhibited by high ATP 2. Allosteric activation by AMP  Ratio ATP/AMP important
  • 16. 3. Phosphorylation/dephosphorylation   of E1 subunit Pi E1-OH (active) phosphatase activator = insulin indirectly   H2O ATP kinase activator = acetyl-CoA NADH, not cAMP E1-OP ADP (inactive) kinase inhibitors = pyruvate, ADP
  • 17. NADH acetyl CoA NAD+ oxalocitrate synthase MDH acetate l-malate citrate H2O fumarase aconitase H 2O fumarate 2-step FADH2 succinate dehydrogenase isocitrate FAD NAD + succinate TCA IDH NADH CoASH GTP succinate-CoA synthetase CO2 GDP+ Pi succinyl CoA NADH NAD+ CO2 α-ketoglutarate
  • 18. Overall Reaction in the TCA cycle acetyl-CoA + 3NAD+ + FAD + GDP + Pi+2H2O  2CO2 + 3NADH + FADH2 + GTP + 2H+ + CoA Both carbons oxidized  One GTP Three NADH One FADH2
  • 19. - Condensing acetyl-CoA with oxaloacetate nzyme = citrate synthase = ondensing enzyme) acetyl CoA =C-SCoA CH3 H2O + =C-COOCH2 COO- oxaloacetate COO- + CoASH CH2 + H+  HO-C-COOCH2 COO- citrate
  • 20. Condensation of acetyl  committing step in TCA cycle  highly exergonic, driven largely by cleavage of thiol ester bond of acetyl CoA
  • 21. 2 - Citrate isocitrate via cis-aconitate Enzyme = aconitase CH2-COO- -H2O CH2COO +H2O CH2-COOHOC-COOC-COO H-C-COOCH2-COOH-C-COOHOC-COOcitrate cis - aconitate isocitrate -- aconitate never leaves the enzyme -- a dehydration, hydration -- asymmetric enzyme yields stereopecificity
  • 22. - Oxidation of isocitrate to α -ketoglutarate nzyme = isocitrate dehydrogenase COOCOOCH2 NAD+ NADH CH2 + CO2 HC-COOCH2 OCH O=C COOCOO- isocitrate α-ketoglutarat
  • 23. -- two isoforms of isocitrate dehydrogenase. One uses NAD+; other NADP+ -- first oxidation in TCA cycle. Result is a reduction to NADH or NADPH. -- energy is later derived from these electron carrying molecules. -- loss of first CO2 -- Note OH to =O
  • 24. 4- Oxidation of α -ketoglutarate to succinyl-CoA and CO2 Enzyme = α - ketoglutarate dehydrogenase complex α-ketoglutarate succinyl CoA   COOCOO- + CO2 CH2 NAD+ NADH CH2 CH2 CH2 O=C O=C COOSCoA + CoA-SH
  • 25.  second oxidation in TCA cycle; another NADH is produced  loss of second of two CO2  highly exergonic, ∆G°′ = -33.5 kJ/mole  reaction similar to pyruvate to acetyl-CoA; the enzyme is similar to pyruvate dehydrogenase complex
  • 26. 5- Succinyl CoA to succinate Enzyme = succinyl CoA synthetase   succinyl-CoA COO+ GDP + Pi CH2 + CoA-SH + CH2 GTP COOsuccinate   -- substrate level phosphorylation -- GTP is equivalent to ATP; GTP to ATP by nucleoside diphosphokinase
  • 27. -- succinyl phosphate is intermediate. -- overall near equilibrium; ∆G°′ = -2.9 kJ/mole -- succinyl CoA has a strong negative free energy for hydrolysis of its thioester; used to synthesis a GTP.
  • 28. 6- Oxidation of succinate to fumarate Enzyme = succinate dehydrogenase -- a flavoprotein bound to the inner membrane of the mitochondria   COOCOOCH2 + E-FAD  CH + E-FADH2 CH2 COOHC-COOsuccinate fumarate a dehydrogenation; note double bond
  • 29. -- third oxidation of TCA cycle, FAD in flavoprotein reduced to FADH2  a flavin dependent oxidation   -- electrons are captured here for electron transport chain   -- preview  the subsequent reoxidation of FADH2 will yield 2 ATPs while the reoxidation of NADH will yield 3 ATPs
  • 30. 7- Hydration. Enzyme = fumarase   COOCH HC COO- +H2O fumarate -H2O COOHOCH HCH COO- l-malate
  • 31. 8- Oxidation of malate to oxaloacetate  it’s a cycle! Enzyme = malate dehydrogenase COOCOOHOCH NAD+ NADH C=O HO   CH2 CH2 COOCOOmalate oxaloacetate  recall same rxn in gluconeogenesis    fourth oxidation; another pair of
  • 32.  formation of oxaloacetate close to equilibrium  reaction driven by exergonic synthesis of citrate  oxaloacetate concentration is thereby kept low
  • 33. ==========SUMMARY=========== SUMMARY First Half -- introduction of two carbon atoms and their loss, yielding 2 NADH and a GTP (= ATP)   Second Half -- partial oxidation of succinate to oxaloacetate. Another NADH is produced as well as a reduced FADH2. Oxaloacetate is regenerated for next cycle.
  • 34. Overall Reaction: Reaction acetyl-CoA+3NAD++FAD+GDP+Pi+2H2O 2CO2 + 3NADH + FADH2 +GTP+2H++CoA  one high energy compound made   four pairs of electrons are made available to the respiratory chain and oxidative phosphorylation. These are used to generate most of the ATP needed.
  • 35. What is the maximum yield of high energy ATP in the aerobic catabolism of glucose? Glycolysis: glucose →2pyruvate + 2NADH+2ATP 8 ATPs 2pyruvate → 2acetyl CoA + 2NADH 6 ATPs Pyruvate Dehydrogenase: TCA cycle: acetyl CoA→2CO2+3NADH+FADH2+GTP 2x12ATPs   OVERALL yield from glucose 38 ATPs
  • 36. REGULATION OF CITRIC ACID CYCLE  four ways  1- PYRUVATE DEHYDROGENASE -- Previously discussed  inhibited by acetyl-CoA and NADH 2- CITRATE SYNTHASE -- inhibited by ATP, NADH, acetyl CoA, Succinyl CoA 3- ISOCITRATE DEHYDROGENASE -- activated allosterically by ADP -- inhibited allosterically by NADH, ATP 4- α - KETOGLUTARATE DEHYDROGENASE -- inhibited allosterically by products = succinyl-CoA and NADH
  • 37. Replacement of Intermediates -- intermediates are removed for biosynthesis  1- amphibolic reactions = removal of intermediates.   2- anaplerotic reactions = replacing cyclic intermediates.
  • 38. Amphibolic pathways a- transaminases oxaloacetate  Asp α-ketoglutarate Glu pyruvate  Ala removes 4C removes 5C removes 6C b- fatty acid biosynthesis citrate  acetyl CoA and oxaloacetate acetyl CoA can build fatty acids c- heme biosynthesis succinyl CoA + glycine  porphyrins
  • 39. Anaplerotic reactions   a- pyruvate carboxylase - replaces oxaloacetate- most important, especially in liver and kidney. O CH3-C-COO- + CO2 + ATP  O OOC-CH2C-COO- + ADP + Pi oxaloacetate  Note: same rxn in gluconeogenesis
  • 40. b- malic enzyme - replaces malate -- pyruvate + CO2 + NADPHmalate + NADP+ c- from amino acids  reversals of transaminations -- restores oxaloacetate or α-ketoglutarate with abundant asp or glu  glutamate dehydrogenase glu + NAD(P)+  α-ketoglutarate+ NAD(P)H + NH4+

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