5.11: Citric Acid Cycle
- Describe the reactions of the citric acid cycle.
- Describe the function of the citric acid cycle and identify the products produced.
Citric Acid Cycle
Acetyl-CoA is a two-carbon molecule that enters a circular pathway of reactions known collectively as the citric acid cycle (or Krebs cycle). The cycle brings about the oxidation of the two carbons of acetyl-CoA to carbon dioxide and water. It was first proposed by Hans Krebs in 1937. He was awarded the 1953 Nobel Prize in Physiology or Medicine. Acetyl-CoA’s entrance into the citric acid cycle is the beginning of stage III of catabolism. The citric acid cycle produces guanosine triphosphate (GTP), three reduced nicotinamide adenine dinucleotide (NADH), reduced flavin adenine dinucleotide (FADH 2 ), and metabolic intermediates required for the synthesis of more ATP molecules.
At first glance, the citric acid cycle appears rather complex. All the reactions, however, are familiar types in organic chemistry: hydration, oxidation, decarboxylation, and hydrolysis. Each reaction of the citric acid cycle is numbered. The two carbon atoms of Acetyl-CoA are highlighted in red. Each intermediate in the cycle is a carboxylic acid, existing as an anion at physiological pH of around 7. All the reactions occur within the mitochondria, which are small organelles within the cells of plants and animals. This part of the cell is known as the powerhouse of the cell since this is where most of the ATP is produced.
Figure \(\PageIndex{1}\): The Citric Acid Cycle
Step 1
In the first reaction, acetyl-CoA enters the citric acid cycle, and the two-carbons of the acetyl group reacts with a four-carbon anion called oxaloacetate, yielding a six-carbon anion called citrate. This step also involves addition of water. Note that this step releases coenzyme A. The reaction is catalyzed by citrate synthase .
Step 2
In this step, aconitase catalyzes the isomerization of citrate to isocitrate. In this reaction, a tertiary alcohol, which cannot be oxidized, is converted to a secondary alcohol, which can be oxidized in the next step. Citrate and isocitrate are isomers.
Step 3
Isocitrate then undergoes a reaction known as oxidative decarboxylation because the 2 o -alcohol is oxidized and the molecule is shortened by one carbon atom with the release of carbon dioxide (decarboxylation). The reaction is catalyzed by isocitrate dehydrogenase , and the product of the reaction is α-ketoglutarate. The oxidizing agent of the 2 o -alcohol is the coenzyme nicotinamide adenine dinucleotide (NAD + ) which is reduced to NADH.
Step 4
The fourth step is another oxidative decarboxylation. This time α-ketoglutarate is converted to succinyl-CoA, and another molecule of NAD + is reduced to NADH. The α-ketoglutarate dehydrogenase catalyzes this reaction.
So far, in the first four steps, two carbon atoms have entered the cycle as an acetyl group, and two carbon atoms have been released as molecules of carbon dioxide. The remaining reactions of the citric acid cycle use the four carbon atoms of the succinyl group to resynthesize a molecule of oxaloacetate, which is the compound needed to combine with an incoming acetyl group and begin another round of the cycle.
Step 5
In the fifth reaction, the energy released by the hydrolysis of the high-energy thioester bond of succinyl-CoA is used to make guanosine triphosphate (GTP) from guanosine diphosphate (GDP) and inorganic phosphate (P i ) in a reaction catalyzed by succinyl-CoA synthetase . This step is the only reaction in the citric acid cycle that directly forms a high-energy phosphate compound GTP. GTP is considered equivalent in energy to ATP.
Step 6
Succinate dehydrogenase then catalyzes the removal of two hydrogen atoms from succinate, forming fumarate. This oxidation-reduction reaction uses flavin adenine dinucleotide (FAD), rather than NAD + , as the oxidizing agent.
Step 7
In step 7, a molecule of water is added to the double bond of fumarate to form malate in a hydration reaction catalyzed by fumarase .
Step 8
One cycle is completed with the oxidation of malate to oxaloacetate, catalyzed by malate dehydrogenase . This is the third oxidation-reduction reaction. It uses NAD + as the oxidizing agent to oxidize the 2 o alcohol in malate to a ketone.
Oxaloacetate can accept two carbons from the reaction with acetyl-CoA, allowing the cycle to begin again.
Summary
The citric acid cycle consists of eight step and are made of familiar types of reactions in organic chemistry: hydration, oxidation, decarboxylation, and hydrolysis. The harvest of the citric acid cycle consists of 3NADH, FADH 2 , and GTP.