The Krebs cycle, or citric acid cycle, is a sequence of chemical reactions that take place in the mitochondria of eukaryotic cells as part of cellular respiration. It is also called the tricarboxylic acid cycle, because citric acid has three carboxylic groups in its structure.
This cycle consists of 8 steps. It begins with the reaction of oxaloacetate, with 4 carbons, with activated acetate in the form of acetyl-CoA, to form citrate or citric acid, a six-carbon molecule. In the following steps, citrate loses electrons and two carbon dioxide molecules, transforming back into oxaloacetate, closing the cycle.
The acetyl-CoA that enters the citric acid cycle may come from glycolysis, with glucose being the raw material for this process.
The main function of the citric acid cycle It is capturing the electrons that are released from the molecules when they oxidize (they lose electrons). These electrons are captured by carrier molecules and then transformed into adenosine triphosphate ATP, the energy molecule that the cell uses to perform its functions.
Scheme of the Krebs cycle. Acetyl-CoA: acetyl coenzyme A; NADH: reduced nicotinamide adenine dinucleotide; FADH2: reduced flavin adenine dinucleotide; GTP: guanosine triphosphate; CO2: carbon dioxide
Products of the Krebs cycle
Each Krebs cycle produces:
3 NADH (reduced nicotinamide adenine dinucleotide)1 GTP (guanosine triphosphate)1 FADH2 (reduced flavin adenine dinucleotide)2 carbon dioxide molecules.
Although ATP (adenosine triphosphate) is not directly formed in the Krebs cycle, GTP can be transformed into ATP. Furthermore, the NADH and FADH2 that are formed in the cycle transfer their electrons to the electron transport chain in the mitochondria which, by oxidative phosphorylation, leads to the production of ATP.
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Steps of the Krebs cycle
1. Citrate formation: Acetyl-coenzyme A (acetyl-CoA) combines with oxaloacetate to form citrate and release coenzyme A. The enzyme that catalyzes this reaction is citrate synthase.
2. Formation of isocitrate: citrate is transformed into isocitrate, by the action of the enzyme aconitase.
3. Oxidation of isocitrate to α-ketoglutarate: Isocitrate, with six carbon atoms, loses one carbon in the form of carbon dioxide CO2 and a pair of electrons, to become α-ketoglutarate, with five carbons. The electrons are captured by an NAD+ (oxidized nicotinamide adenine dinucleotide) and converted into NADH (reduced nicotinamide adenine dinucleotide). The enzyme is isocitrate dehydrogenase.
4. Oxidation of α-ketoglutarate to succinyl-CoA and CO2: the five-carbon α-ketoglutarate molecule is oxidized to obtain succinyl-CoA (four carbon atoms), with the release of CO2. An NAD+ molecule is reduced to NADH. The enzyme involved in this reaction is α-ketoglutarate dehydrogenase.
5. Conversion of succinyl-CoA to succinate: Succinyl-CoA is transformed into succinate when it releases the CoA group to form GTP (guanosine triphosphate) from GDP (guanosine diphosphate) and inorganic phosphate. The enzyme that catalyzes this reaction is succinyl-CoA synthetase.
6. Oxidation of succinate to fumarate: Succinate loses two electrons to form fumarate. The electrons in this reaction are captured by the oxidized flavin adenine dinucleotide (FAD) which is reduced to FADH2. The enzyme involved is succinate dehydrogenase.
7. Hydration from fumarate to malate: fumarate gains a water molecule and is transformed into malate, by the action of the enzyme fumarase.
8. Oxidation of malate to oxaloacetate: the last step of the Krebs cycle regenerates oxaloacetate, through the action of malate dehydrogenase. In this reaction, malate is oxidized and gives up two electrons to NAD+, forming NADH.
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References
Alberts, B., Johnson, A., Lewis, J, Raff, M., Roberts, K., Walter, P. (2008) Molecular Biology of the Cell 5th Ed. Garland Science. UK.
Nelson, DL, Cox, MM, Hoskins, AA (2021) Lehninger Principles of Biochemistry. 8th ed. Macmillan Learning. Boston.