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OBJECTIVES

OBJECTIVES. Identify the key steps in citric acid cycle Describe how TCA is regulated Illustrate biomedical importance of TCA Explain energy yield from TCA. CITRIC ACID CYCLE (TCA CYCLE OR KREBS CYCLE) Pyruvate Acetyl- CoA Acetate CO 2.

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OBJECTIVES

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  1. OBJECTIVES • Identify the key steps in citric acid • cycle • Describe how TCA is regulated • Illustrate biomedical importance of • TCA • Explain energy yield from TCA.

  2. CITRIC ACID CYCLE (TCA CYCLE OR KREBS CYCLE) Pyruvate Acetyl-CoAAcetate CO2

  3. CITRIC ACID CYCLE • Oxidizing acetyl-CoA from glucose, • lipid and protein catabolism in • aerobic respiration to maximize • energy gain • The cycle supplies precursors for • biosynthesis

  4. 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 lactatePyruvatefatty acids  amino acidsAcetyl-CoA TCA (Note: AA more than one entry point)

  6. Space filled Acetyl CoA A high energy bond HS-CoA Acetyl

  7. STAGE 1 Pyruvate (PDH) Acetyl-CoA (PYRUVATE DEHYDROGENASE COMPLEX) Location = Mitochondrial matrix CH3CH3 C=O + NAD++ HS-CoA C=O +NADH+CO2 COO- S-CoA PyruvateAcetyl-CoA (A high energy compound)

  8. IRREVERSIBLE Irreversible means acetyl-CoA cannot be converted backward to Pyruvate Hence “fat cannot be converted to carbohydrate”

  9. PYRUVATE DEHYDROGENASE COMPLEX S-- S-- TPP FAD   E1 E2 E3 N A D+

  10. REGULATION OF PYRUVATE DEHYDROGENASE • Irreversible reaction must be tightly • controlled-- three ways • Allosteric Inhibition • Inhibited by products: Acetyl-CoA, NADH • ATP • 2. Allosteric activation • AMP • Ratio ATP/AMP important

  11. 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

  12. 1- CONDENSING ACETYL-COA WITH OXALOACETATE ACETYL COA O=C-SCoACOO- + CoASH CH3 H2O CH2 + H+ +  O=C-COOCITRATE SYNTHASE HO-C-COO- CH2 CH2 COO- COO- OXALOACETATE CITRATE ENZYME:CITRATE SYNTHASE

  13. 2 - CITRATEISOCITRATE VIA CIS-ACONITATE CH2-COO--H2O CH2COO +H2O CH2-COO- HOC-COO- C-COO H-C-COO- CH2-COO- H-C-COO- HOC-COO- CITRATE CIS–ACONITATE ISOCITRATE ENZYME: ACONITASE

  14. 3-OXIDATION OF ISOCITRATE TO -KETOGLUTARATE First oxidation in TCA cycle COO- COO- CH2 NAD+ NADH CH2 + CO2 HC-COO- CH2 HOCH O=C COO- COO- ISOCITRATE -KETOGLUTARATE ENZYME = ISOCITRATE DEHYDROGENASE

  15. ISOCITRATE DEHYDROGENASE • Two isoforms • One uses NAD+; other NADP+ •  Reduction to NADH or to NADPH •  Energy is later derived from these • electron carrying molecules • -- loss of first CO2 • -- Note OH to =O

  16. 4- OXIDATION OF -KETOGLUTARATE TO SUCCINYL-COA AND CO2 Second oxidation in TCA cycle -KETOGLUTARATESUCCINYL COA   COO- COO- + CO2 CH2NAD+ NADH CH2 CH2 CH2 O=C O=C COO-SCoA + CoA-SH ENZYME = - KETOGLUTARATE DEHYDROGENASE COMPLEX

  17. Loss of second of two CO2 • Similar to Pyruvate Acetyl-CoA • Enzyme is similar to • Pyruvate dehydrogenase complex - KETOGLUTARATEDEHYDROGENASE COMPLEX

  18. 5- SUCCINYL COA TO SUCCINATE succinyl-CoA COO- + GDP + Pi CH2 + CoA-SH + CH2GTP COO- SUCCINATE -- SUBSTRATE LEVEL PHOSPHORYLATION -- GTP is equivalent to ATP; GTP to ATP by NUCLEOSIDE DIPHOSPHOKINASE ENZYME = SUCCINYL COA SYNTHETASE

  19. 6- OXIDATION OF SUCCINATE TO FUMARATE FLAVIN DEPENDENT OXIDATION Third oxidation of TCA cycle, FAD in flavoprotein reduced to FADH2 COO- COO- CH2 + E3-FAD  CH + E3-FADH2 CH2 COO- HC-COO- SUCCINATE FUMARATE Dehydrogenation; note double bond ENZYME = SUCCINATE DEHYDROGENASE

  20. 7- HYDRATION   COO- COO- CH +H2O HOCH HC HCH COO- -H2O COO- FUMARATE L-MALATE ENZYME = FUMARASE

  21. 8- OXIDATION OF MALATE TO OXALOACETATE COO- COO- HO CH NAD+NADH C=O   CH2CH2 COO- COO- MALATE OXALOACETATE FOURTH OXIDATION: another pair of electrons is made available in NADH ENZYME = MALATE DEHYDROGENASE

  22. 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

  23. Overall 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.

  24. What is the maximum yield of high energy ATP in the aerobic catabolism of glucose? Glycolysis: glucose 2pyruvate + 2NADH+2ATP 8 ATPs Pyruvate Dehydrogenase: 2pyruvate  2acetyl CoA + 2NADH 6 ATPs TCA cycle: acetyl CoA2CO2+3NADH+FADH2+GTP 2x12ATPs OVERALL YIELD FROM GLUCOSE 38 ATPs

  25. ENERGY RELATIONSHIPS • This represents 41% conservation of • the potential energy available in • glucose as ATP

  26. REGULATION OF CITRIC ACID CYCLE FOUR WAYS  1- PYRUVATE DEHYDROGENASE -- Inhibited by acetyl-CoA and NADH 2- CITRATE SYNTHASE -- Substrate = oxaloacetate -- limited 3- ISOCITRATE DEHYDROGENASE -- Activated allosterically by ADP -- Inhibited allosterically by NADH 4- a- KETOGLUTARATE DEHYDROGENASE -- Inhibited allosterically by products = succinyl-CoA and NADH

  27. REGULATION OF CITRIC ACID CYCLE • Major regulator is intramitochondrial • NAD+/NADH ratio

  28. REPLACEMENT OF INTERMEDIATES Intermediates are removed for biosynthesis 1- AMPHIBOLICreactions (Removal of intermediates) 2- ANAPLEROTICreactions (Replacing cyclic intermediates)

  29. AMPHIBOLIC PATHWAYS A- TRANSAMINASES oxaloacetateAsp removes 4C -ketoglutarate Glu removes 5C pyruvate Ala removes 6C B- FATTY ACID BIOSYNTHESIS citrate Acetyl CoA and oxaloacetate acetyl CoA can build fatty acids C- HEME BIOSYNTHESIS succinyl CoA+ glycine  Porphyrins

  30. 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

  31. B- MALIC ENZYME Replaces malate-- pyruvate + CO2 +NADPHmalate + NADP+ C- FROM AMINO ACIDS Reversals of transaminations--restores oxaloacetate or a-ketoglutarate with abundant Asp or Glu Glutamate dehydrogenase Glu + NAD(P)+ a-ketoglutarate + NAD(P)H + NH4+

  32. NADH acetyl CoA NAD+oxalo-citrate synthase MDH acetate l-malatecitrate H2O fumaraseaconitase H2O fumarate 2-step FADH2succinate dehydrogenaseisocitrate FAD NAD+ succinateTCAIDH NADH CoASH GTP succinate-CoAsynthetase CO2 GDP+ Pi succinyl CoA NADH NAD+ CO2-ketoglutarate -KGDHCoASH

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