Citric Acid Cycle

Carbohydrate Metabolism Overview
Overview Metabolism &
Energy Summary
 Elmhurst College
Form Acetyl CoA Citric Acid Cycle Summary Cori Cycle  Chemistry Department
Citric Acid Cycle Reactions Hormone Control    Virtual ChemBook


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Citric Acid Cycle Reactions

Introduction:

Under aerobic conditions the end product of glycolysis is pyruvic acid. The next step is the formation of acetyl coenzyme A(acetyl CoA) - this step is technically not a part of the citric acid cycle, but is shown on the diagram on the top left.

Acetyl CoA, whether from glycolysis or the fatty acid spiral, is the initiator of the citric acid cycle. In carbohydrate metabolism, acetyl CoA is the link between glycolysis and the citric acid cycle.

The initiating step of the citric acid cycle occurs when a four carbon compound (oxaloacetic acid) condenses with acetyl CoA (2 carbons) to form citric acid (6 carbons).

The whole purpose of a "turn" of the citric acid cycle is to produce two carbon dioxide molecules. This general oxidation reaction is accompanied by the loss of hydrogen and electrons at four specific places. These oxidations are connected to the electron transport chain where many ATP are produced.

The reactions for the citric acid cycle are shown in the graphic on the left. These reactions are more familiar than those from glycolysis. Unless the instructor states otherwise, you should study these reactions so that you can: tabulate the ATP and CO2 generated; name the type of reaction at each step; and write the structure of any compound which has been blanked out. You should not memorize these structures but derive them from a knowledge of reaction principles.

Citric Acid Cycle - with white background for printing

Overview of Metabolism



Reaction 1: Synthesis of Citric Acid

Acetyl CoA and oxaloacetic acid condense to form citric acid. The acetyl group CH3COO is transferred from CoA to oxaloacetic acid at the ketone carbon, which is then changed to an alcohol. The net effect is to join a 2 carbon piece with a 4 carbon piece to make citric acid which is 6 carbons. This is just called the synthesis of citric acid.

This reaction is catalyzed by citric acid synthetase.

Reaction 1 - Chime in new window

Link to Chime: Citric Acid Synthetase - Department of Biochemistry,The University of Arizona

Reaction 2: Dehydration of an alcohol

Two steps (Rx. 2 and 3) are required to isomerize the position of the -OH group on citric acid. This first step is a dehydration of an alcohol to make an alkene. The cis-aconitic acid remains bound to the enzyme aconitase in readiness for the next step.

This reaction is catalyzed by aconitase.

Reaction 2 - Chime in new window

 
 

Reaction 3: Hydration to make alcohol

This reaction is a hydration reaction of an alkene to make an alcohol. This hydration does not follow Markovnikov's Rule. The net effect of reactions 2 and 3 has been to move the -OH group from C-3 to C-2, which is isocitric acid.

This reaction is catalyzed by aconitase.

Reaction 3 - Chime in new window

Link to Chime: Aconitase - Department of Biochemistry,The University of Arizona

 

Reaction 4: Oxidation

This is the first oxidation reaction in which an alcohol is converted to a ketone. Two hydrogens and 2 electrons are transferred to NAD+ to NADH + H+. This is the entry point into the electron transport chain.

The product of this reaction, oxalosuccinic acid, remains attached to the isocitrate dehydrogenase for the next step.

This reaction is catalyzed by isocitrate dehydrogenase.

Reaction 4 Chime in new window

 

 Reaction 5: Decarboxylation

This is the first step where a carbon group is lost as carbon dioxide in a decarboxylation reaction. The remaining compound now has 5 carbons and is called alpha-ketoglutaric acid.

This reaction is also catalyzed by isocitrate dehydrogenase.

Reaction 5 Chime in new window

 

 Reaction 6: Oxidation, Decarboxylation, Thiol Ester Synthesis

This complex oxidative decarboxylation is guided by three enzymes in much the same fashion as the formation of acetyl CoA from pyruvic acid. This is actually the only non-reversible step in the entire cycle and prevents the cycle from operating in the reverse direction.

This is the second oxidation reaction in which an alcohol is converted to a ketone. Two hydrogens and 2 electrons are transferred to NAD+ to NADH + H+. This another the entry point into the electron transport chain.

This is the second step where a carbon group is lost as carbon dioxide in a decarboxylation reaction. Essentially, although not the exact same carbons, the two carbons from the acetyl CoA have been converted to carbon dioxide at the end this step/.

The remaining 4 carbon group is attached to the CoA through a thiol ester high energy bond. Notice that the final product, succinyl CoA, has 4 carbons in the succinate group at one end of the CoA molecule.

This reaction is catalyzed by alpha-ketoglutarate dehydrogenase complex.

Reaction 6 Chime in new window

 

 Reaction 7: Hydrolysis of Succinyl CoA;
Synthesis of ATP

The hydrolysis of the thioester bond (exothermic) is coupled with the formation of ATP (Actually guanosine triphosphate is formed first but is further coupled with the ADP to make ATP). This is the only "visible" ATP formed in the entire cycle.

Succinic acid, a 4 carbon acid, is the product of this reaction. This is the start of the return to the beginning of the cycle.

This reaction is catalyzed by succinyl CoA.

Reaction 7 Chime in new window

 

 Reaction 8: Oxidation

This slightly unusual oxidation reaction results in the removal of the hydrogens from saturated alkyl carbons to form an alkene, fumaric acid. The hydrogen acceptor is the coenzyme FAD instead of the more usual NAD+. This will be significant when the ATP is tabulated from the electron transport chain, since this coenzyme is in the enzyme complex 2. Only 2 ATP result from this reaction in the electron transport chain.

This reaction is catalyzed by succinate dehydrogenase.

Reaction 8 Chime in new window

Link to Chime: Succinate dehydrogenase - Department of Biochemistry,The University of Arizona

 

 Reaction 9: Hydration to form an alcohol

This is a simple hydration reaction of an alkene to form an alcohol. Take your pick where you place the -OH group since it must be adjacent to a carboxylic acid group in either case and forms malic acid.

This reaction is catalyzed by fumarase.

Reaction 9 - phosphoenol pyruvic acid Chime in new window

 

 Reaction 10: Oxidation

This is the final reaction in the citric acid cycle. The reaction is the oxidation of an alcohol to a ketone to make oxaloacetic acid. The coenzyme NAD+ causes the transfer of two hydrogens and 2 electrons to NADH + H+. This is a final entry point into the electron transport chain.

This reaction is catalyzed by malate dehydrogenase.

Reaction 10 Chime in new window

Conclusion:

Starting with acetyl Co A with 2 carbons, the citric acid cycle spins these 2 carbons off as two carbon dioxide molecules.