Citric Acid Cycle: The Reactions

The Citric Acid Cycle is a metabolic pathway that uses a two-carbon molecule, and a four-carbon molecule to form a six-carbon molecule that is used to produce NADH, carbon dioxide, ATP and FADH2. The cycle involves eight chemical reactions, and at the end, the original four-carbon molecule is produced.

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The citric acid cycle is a series of chemical reactions that takes place in the mitochondrial matrix. This cycle uses acetyl CoA, derived from sugar and fat breakdown, to form ATP, NADH, FADH2, and carbon dioxide. The NADH and FADH2 can be used to form additional ATP through the electron transport chain.

The citric acid cycle goes by many names including the tricarboxylic acid (or TCA) cycle and the Krebs cycle. Citric acid refers to the citrate that is produced in the first step of the pathway. The tricarboxylic acid title gets its name from the three carbon dioxides that are produced for each fully oxidized pyruvate. Krebs refers to Hans Adolf Krebs who identified the full cycle in 1937. He was eventually awarded the Nobel Prize for Physiology or Medicine in 1953 for his discovery.

In the first step of the cycle, an enzyme called citrate synthase joins the two-carbon acetyl group from acetyl CoA with the four-carbon oxaloacetate to form a six-carbon citrate.

In step two, an enzyme called aconitase converts citrate into isocitrate. Next, an isocitrate dehydrogenase enzyme oxidizes isocitrate, a six-carbon molecule, to a five-carbon α-ketoglutarate. The carbon that was lost is released as carbon dioxide and one NADH is also formed. The carbon dioxide that is released was originally part of oxaloacetate and not acetyl CoA.

In the fouth step, an enzyme called α-ketoglutarate dehydrogenase converts α-ketoglutarate into a four-carbon succinyl CoA. Similar to step three, this reaction produces one carbon dioxide and one NADH. In step five, a succinyl CoA synthetase enzyme converts succinyl CoA into succinate. This produces GTP which is converted to ATP.

In step six, an enzyme called succinate dehydrogenase converts succinate into fumarate. This step makes one FADH2. In step seven, a fumarate hydratase enzyme then converts fumarate into malate.

In the final step of the citric acid cycle, a malate dehydrogenase enzyme converts malate back to oxaloacetate. Like all steps involving a dehydrogenase, a coenzyme is produced. Here it is NADH.

The oxaloacetate that was regenerated through the citric acid cycle is now ready to join with another acetyl group and begin the cycle a second time. For every one glucose that is broken down through glycolysis, two pyruvates will be produced. These two pyruvates will produce two acetyl CoAs. So, for every one glucose, two acetyl CoAs will be made and two turns of the citric acid cycle will occur. This means each product of the cycle must be doubled.

A total of four CO2, six NADHs, two FADH2, and two ATPs are made through the citric acid cycle. NADH and FADH2 are electron carriers that can produce more ATPs later in aerobic respiration.

In addition to sugars like glucose, proteins and fats can also provide carbon substrates to fuel the citric acid cycle. Proteins can be broken down into individual amino acids such as alanine, aspartate, and glutamate and converted into intermediates in the cycle. Fatty acids can be broken down into acetyl CoA which then begins the citric acid cycle. This metabolism of sugars, proteins, and fats through the citric acid cycle provides the vital energy necessary to maintain many cellular processes.

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