The Citric Acid Cycle

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Lesson Learning Outcomes
Upon the completion of this chapter, students should be able to:  Explain the steps of the citric acid cycle.  Differentiate between citric acid cycle and glyoxylate cycle.  Relate citric acid cycle as energy source.

The Central Role of the Citric Acid Cycle


3 processes play central roles in aerobic metabolism.
 The citric acid cycle.  Electron transport .  Oxidative phosphorylation.



Metabolism consists of:
 Catabolism: the oxidative breakdown of nutrients.  Anabolism: the reductive synthesis of biomolecules.



The citric acid cycle is amphibolic that is, it plays a role in both catabolism and anabolism. It is the central metabolic pathway.

Relationship of TCA Cycle to Catabolism

Amino acids, fatty acids and glucose can all produce acetyl-CoA in stage 1 of catabolism. In stage 2, acetyl-CoA enters the citric acid cycle. Stage 1 and 2 produce reduced electron carriers. In stage 3, the electrons enter the electron transport chain, which then produces ATP.

Where does the Citric Acid Cycle Take Place?


In eukaryotes, the cycle takes place in the mitochondrial matrix.

Features of Citric Acid Cycle
• Pyruvate produced by glycolysis
is transformed by oxidative decarboxylation into acetyl-CoA in the presence of coenzyme A.

• Acetyl-CoA enters citric acid cycle by react with oxaloacetate to produce citrate. • The reactions of the citric acid cycle include two other oxidative decarboxylation, which transform citrate into succinate. • The cycle is complete by regenaration of oxaloacetate from succinate in a multistep process that includes two other oxidation reactions. Pyruvate + 4NAD+ + FAD + GDP + Pi + 2H2O  3CO2 + 4NADH + FADH2 + GTP + 4H+

• The cycle is strongly exergonic.

Pyruvate is Converted to Acetyl-CoA


Pyruvate dehydrogenase complex is responsible for the conversion of pyruvate to CO2 and the acetyl portion of acetyl-CoA. Five enzymes in complex: 1. 2. 3. 4. 5.



Pyruvate dehydrogenase. Dihydrolipoyl transacetylase. Dihydrolipoyl dehydrogenase. Pyruvate dehydrogenase kinase. Pyruvate dehydrogenase phosphatase.

Pyruvate is Converted to Acetyl-CoA


Step 1: Pyruvate loses CO2 and hydroxyethyl TPP (HETTP) is formed. O CH3 CCOO - + T PP Pyruvate pyruvate dehydrogenase OH CO 2 + CH3 CH- TPP Hydroxyethyl-TPP



Step 2: Requires lipoic acid.
 The active form of lipoic acid is bound to the

enzyme by an amide bond to the amino group of a lysine.
COOH S S Lipoic acid reduction oxidation HS COOH SH Dihydrolipoic acid

Pyruvate is Converted to Acetyl-CoA


Step 3: The acetyl group is transferred to the sulfhydryl group of coenzyme A. O O C-N H- Enz SH CoA -SH + CH3 C-S Coenzyme A Dihydrolipoamide dihydrolipoyl transacylase O O CoA -S-CCH3 Acetyl-CoA + HS SH Dihydrolipoamide C-N H- Enz

Pyruvate is Converted to Acetyl-CoA


Step 4: Oxidation of dihydrolipoamide.
O C-N H- Enz HS SH Dihydrolipoamide N AD + N AD H O C-N H- Enz S S Lipoamide

Mechanism of the Pyruvate Dehydrogenase Complex

Summary


The two-carbon unit needed at the start of the citric acid cycle is obtained by converting pyruvate to acetyl-CoA. This conversion requires the three primary enzymes of the pyruvate dehydogenase complex, as well as, the cofactors TPP, FAD, NAD+, and lipoic acid. The overall reaction of the pyruvate dehydogenase complex is the conversion of pyruvate, NAD+, and CoA-SH to acetyl-CoA, NADH + H+, and CO2.





Individual Reactions of the Citric Acid Cycle
1.


Formation of Citrate.

Condensation of acetyl-CoA with oxaloacetate to form citrylCoA. The condensation is followed by the hydrolysis of citrylCoA to give citrate and CoA-SH.  G°’ = -32.8 kJ•mol-1, therefore, the reaction is exergonic.



Reaction is catalyzed by citrate synthase, an allosteric enzyme that is inhibited by NADH, ATP, and succinyl-CoA.

Individual Reactions of the Citric Acid Cycle
2. 

Isomerization of...
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