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Metabolic fate of
Glu-6-P, Pyruvate & Acetyl CoA.
TCA cycle/ Krebs cycle / Citric acid cycle
Dr. Santhosh Kumar N
Associate Professor of Biochemistry
“Believe yourself ”
Have a great day to all
2
Glycogenesis
Glycolysis Gluconeogenesis
HMP
shunt
Glycogenolysis 1
2
3
4a
4b
Fate of Glu-6-P
Gly, Ala, val, Pro, Ser, Asp, Arg ,
Glu, Cys, Thr, His, Met , Gln, Asp
Glucose
Cori cycle
Acetaldehyde
Ethanol
TCA
Cycle
1
2 3
4
5
6 7
Fate of Pyruvate
Pyruvate Dehydrogenase Complex
E1. Pyruvate dehydrogenase
E2: Dihydrolipoamide transacetylase
E3: Dihydrolipoamide dehydrogenase
PDH Complex
Tri-carboxylic acid (TCA cycle) /
Krebs cycle
/ Citric acid cycle
• The citric acid cycle is the central metabolic hub of the cell.
• It is the gateway to the aerobic metabolism of any molecule that can be
transformed into an acetyl group or dicarboxylic acid.
• The aerobic processing of glucose starts with the complete oxidation to CO2.
• This oxidation takes place in the citric acid cycle, a series of reactions known as
the “tricarboxylic acid (TCA) cycle” or the “Krebs cycle”.
TCA cycle is the final common pathway for the oxidation
of fuel molecules – amino acids, carbohydrates & fatty
acids that enter the cycle as acetyl CoA
The enzymes of citric acid cycle are located in the
mitochondrial matrix.
Fluoro acetate
NADH, Arsenate,
Succinyl-CoA
10ATPs ADP
Malonate
+Pi
Energetics of TCA cycle
Isocitrate dehydrogenase (NADH+H+ =2.5ATPs) +2.5 ATP
α-Ketoglutarate Dehydrogenase (NADH+H+) + 2.5ATP
Succinyl Thiokinase [1GTP = 1ATP)] + 1 ATPs
Succinate Dehydrogenase [FADH2 = 1.5 ATP)] + 1.5 ATPs
Malate Dehydrogenase (NADH+H+) +2.5 ATP
one molecule of acetyl CoA produced no. of ATPs in TCA cycle 10 ATPs
Regulation of TCA cycle
• α-ketoglutarate dehydrogenase is inhibited by NADH, Succinyl-CoA and
Arsenate.
• Aconitase enzyme is inhibited by fluoro acetate
• The key enzymes of the TCA cycle are also regulated allosterically by Ca2+, ATP
and ADP.
Significance of the TCA Cycle
• Final common oxidative pathway and integration of major metabolic
pathways
• It is the source of reduced coenzymes that provide the substrate for the
respiratory chain
• Provides the precursors for the building blocks of many molecules such as
amino acids, Nucleotide bases (Purines & Pyrimidines) and Porphyrin
• It act as a link b/w catabolic & anabolic pathways (amphibolic role)
Anabolic role of TCA cycle
It provides the intermediates for the synthesis of many compounds
Anaplerotic reaction of TCA cycle
• filling up reactions which supply intermediates of TCA cycle .
1
2
3
4
5
6
Malate DH
Amphibolic nature of TCA cycle
ATPs
Fatty Acids
Amino Acids
Glucose
Conversion of food to energy to run cellular processes
ATP servers as the energy currency of the cells
Pathways Total ATPs
A. Glycolysis 7 ATPs
B. Oxidative decarboxylation of 2 pyruvate to 2 Acetyl CoA [2 x NADH] 5 ATPs
C. TCA cycle (2 moles of acetyl CoA involved 2x10) 20ATPs
one molecule of glucose produced total ATPs 32 ATPs
Energetics on complete oxidation of glucose:
Acetyl CoA
Synthesis of
Cholesterol
Acetylation reactions
(Detoxification)
Synthesis of Melatonin
Formation of Acetylcholine
Formation of
Ketone Bodies
Oxidation of TCA cycle
Denovo synthesis of FA
HMG -CoA
PYRUVATE
Acetylation of amino- sugars ,
glycoprotein
Ketogenic
a.a’s
β-Oxidation
of FA
Cytoplasmic
Synthase &
Reductase
Mitochondrial
Synthase &
lyase
Fate of Acetyl CoA
Dreams Don’t’ work,
Unless YOU DO

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2. TCA cycle and fate of pyruvate & acetyl CoA.pptx

  • 1. Metabolic fate of Glu-6-P, Pyruvate & Acetyl CoA. TCA cycle/ Krebs cycle / Citric acid cycle Dr. Santhosh Kumar N Associate Professor of Biochemistry “Believe yourself ” Have a great day to all
  • 3. Gly, Ala, val, Pro, Ser, Asp, Arg , Glu, Cys, Thr, His, Met , Gln, Asp Glucose Cori cycle Acetaldehyde Ethanol TCA Cycle 1 2 3 4 5 6 7 Fate of Pyruvate
  • 4. Pyruvate Dehydrogenase Complex E1. Pyruvate dehydrogenase E2: Dihydrolipoamide transacetylase E3: Dihydrolipoamide dehydrogenase
  • 6. Tri-carboxylic acid (TCA cycle) / Krebs cycle / Citric acid cycle
  • 7. • The citric acid cycle is the central metabolic hub of the cell. • It is the gateway to the aerobic metabolism of any molecule that can be transformed into an acetyl group or dicarboxylic acid. • The aerobic processing of glucose starts with the complete oxidation to CO2. • This oxidation takes place in the citric acid cycle, a series of reactions known as the “tricarboxylic acid (TCA) cycle” or the “Krebs cycle”.
  • 8. TCA cycle is the final common pathway for the oxidation of fuel molecules – amino acids, carbohydrates & fatty acids that enter the cycle as acetyl CoA The enzymes of citric acid cycle are located in the mitochondrial matrix.
  • 10. Energetics of TCA cycle Isocitrate dehydrogenase (NADH+H+ =2.5ATPs) +2.5 ATP α-Ketoglutarate Dehydrogenase (NADH+H+) + 2.5ATP Succinyl Thiokinase [1GTP = 1ATP)] + 1 ATPs Succinate Dehydrogenase [FADH2 = 1.5 ATP)] + 1.5 ATPs Malate Dehydrogenase (NADH+H+) +2.5 ATP one molecule of acetyl CoA produced no. of ATPs in TCA cycle 10 ATPs
  • 11. Regulation of TCA cycle • α-ketoglutarate dehydrogenase is inhibited by NADH, Succinyl-CoA and Arsenate. • Aconitase enzyme is inhibited by fluoro acetate • The key enzymes of the TCA cycle are also regulated allosterically by Ca2+, ATP and ADP.
  • 12. Significance of the TCA Cycle • Final common oxidative pathway and integration of major metabolic pathways • It is the source of reduced coenzymes that provide the substrate for the respiratory chain • Provides the precursors for the building blocks of many molecules such as amino acids, Nucleotide bases (Purines & Pyrimidines) and Porphyrin • It act as a link b/w catabolic & anabolic pathways (amphibolic role)
  • 13. Anabolic role of TCA cycle It provides the intermediates for the synthesis of many compounds
  • 14. Anaplerotic reaction of TCA cycle • filling up reactions which supply intermediates of TCA cycle . 1 2 3 4 5 6
  • 16. ATPs Fatty Acids Amino Acids Glucose Conversion of food to energy to run cellular processes ATP servers as the energy currency of the cells
  • 17. Pathways Total ATPs A. Glycolysis 7 ATPs B. Oxidative decarboxylation of 2 pyruvate to 2 Acetyl CoA [2 x NADH] 5 ATPs C. TCA cycle (2 moles of acetyl CoA involved 2x10) 20ATPs one molecule of glucose produced total ATPs 32 ATPs Energetics on complete oxidation of glucose:
  • 18. Acetyl CoA Synthesis of Cholesterol Acetylation reactions (Detoxification) Synthesis of Melatonin Formation of Acetylcholine Formation of Ketone Bodies Oxidation of TCA cycle Denovo synthesis of FA HMG -CoA PYRUVATE Acetylation of amino- sugars , glycoprotein Ketogenic a.a’s β-Oxidation of FA Cytoplasmic Synthase & Reductase Mitochondrial Synthase & lyase Fate of Acetyl CoA

Editor's Notes

  1. The PDH complex is comprises of multiple copies of 3 separate enzymes & coenzymes. Pyruvate dehydrogenase (PDH) Dihydrolipoamide S-acetyltransferase (DLAT) Dihydrolipoamide dehydrogenase (DLD). The complex also requires 5 different coenzymes: CoA, NAD+, FAD+, thiamine pyrophosphate (TPP) and lipoic acid 
  2. Reactions of the TCA Cycle Condensation of Acetyl-CoA with oxaloacetate to form citrate by citrate synthase. Citrate is isomerized to isocitrate by the enzyme aconitase. The reaction occurs in two steps, dehydration to cis-aconitate & rehydration to isocitrate. Isocitrate is dehydration to oxalosuccinate initially, then decarboxylation to give α-ketoglutarate by isocitrate dehydrogenase Alpha-ketoglutarate (α-KG) is oxidative decarboxylated to Succinyl -CoA by the α-ketoglutarate dehydrogenase& it generates NADH [equal to 2.5ATPs]. The Succinyl-CoA is converted to succinate by Succinyl-CoA thiokinase. This reaction produces GTP [equal to 1ATP]. Succinate dehydrogenase catalyzes the oxidation of succinate to form fumarate and it generates FADH2 [equal to 1.5 ATPs]. The fumarase catalyzed by the addition of water to fumarate to gives malate. The final enzyme, forwards the reaction of the TCA cycle, the oxidation of malate to oxaloacetate (OAA) by malate dehydrogenase, and this reaction produces NADH [equal to 2.5ATPs]. Finally oxaloacetate is regenerated, thus two carbon atoms form acetyl-coA enter the cycle.
  3. The reactions concerned to replenish or fill up the intermediates of citric acid cycle are called anapleurotic reactions Pyruvate carboxylase catalyses conversion of pyruvate to oxaloacetate Pyruvate is converted to malate by NADP+ dependent Malate dehydrogenase (Malic enzyme) Alpha ketoglutarate is also synthesized from glutamate by glutamate dehydrogenase
  4. Amphibolic nature of the TCA cycle is both catabolic and anabolic in nature Oxaloacetate is precursor for aspartate Alpha ketoglutarate can be transaminated to glutamate Succinyl CoA is used for synthesis of heme Citrate (mitochondrial) is transported to cytoplasm and provides substrate for fatty acid synthesis