The citric acid cycle (or the Krebs cycle) is one of the steps in cellular respiration and consists of a series of reactions that produces two carbon dioxide molecules, one GTP/ATP, and reduced forms of NADH and FADH2.
The citric acid cycle takes place in the matrix of the mitochondria. It captures the energy stored in the chemical bonds of acetyl-CoA from the products of glycolysis in a step-by-step process, trapping it in the form of high-energy intermediate molecules. The trapped energy from the citric acid cycle is then passed on to oxidative phosphorylation, where it is converted to a usable form of cellular energy, adenosine triphosphate (ATP). Unlike glycolysis, the citric acid cycle is a closed loop: the last part of the pathway regenerates the oxaloacetate molecule used in the first step.
The molecules that enter and move through the citric acid cycle are made mostly of carbon atoms, and these carbon atoms undergo rearrangements throughout the cycle. Electron shuttle molecules accept the energy released by these stepwise rearrangements and the subtraction of carbons in the form of electrons. Electron shuttles are small organic molecules, such as NAD+ and FADH, that transport high energy electrons by gaining electrons (through “reduction”) and losing electrons (through “oxidation”). The electrons transported by electron shuttles represent the high-energy intermediates that are later used to generate ATP.
The eight steps of the cycle are a series of redox, dehydration, hydration, and decarboxylation reactions. This is considered an aerobic pathway because the NADH and FADH2 produced must transfer their electrons to the next pathway in the system, which will use oxygen. If this transfer does not occur, the oxidation steps of the citric acid cycle also do not occur. The citric acid cycle produces very little ATP directly and does not directly consume oxygen.
Before it can be used as a substrate in the citric acid cycle, acetyl-CoA must be made. You’ll recall that in glycolysis, a 6-carbon glucose molecule is split into two 3-carbon molecules called pyruvates. Between glycolysis and the citric acid cycle, the 3-carbon pyruvate molecule loses a carbon to produce a new, 2-carbon molecule called acetyl-CoA. The carbon that is removed takes two oxygens from pyruvate with it, and exits the body as carbon dioxide.
Throughout the citric acid cycle, the starting molecule oxaloacetate (which has 4 carbons) is progressively transformed into several different molecules (as carbon atoms are added to and removed from it), but at the end of the cycle it always turns back into oxaloacetate to be used again. Energy can be captured from this cycle because several of the steps are energetically favorable. This means that the products of the reaction have lower energy than the reactants. The difference in energy between the products and the reactants is the energy that is released when the reaction takes place. The released energy is captured as the electron shuttles are reduced from NAD+ and FADH to NADH and FADH2, respectively.
Two carbon atoms come into the citric acid cycle from each acetyl-CoA molecule, representing four out of the six carbons of one glucose molecule. Two carbon dioxide molecules are released on each turn of the cycle; however, these do not necessarily contain the most recently-added carbon atoms. The two acetyl carbon atoms will eventually be released on later turns of the cycle; thus, all six carbon atoms from the original glucose molecule are eventually incorporated into carbon dioxide.
Take a look at the diagram below showing the entire citric acid cycle. You’ll see that in total, 1 GTP, 3 NADH, 1 FADH2, 2 CO2, and 1 regenerated oxaloacetate molecule are produced during one round of the cycle. Since each glucose molecule produces two pyruvate molecules, one glucose molecule powers two turns of the citric acid cycle, and 6 NADH and 3 FADH2 are produced per glucose. The GTP produced during the citric acid cycle becomes a phosphate donor to ADP to create ATP.
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Key Points
• The citric acid cycle takes place in the matrix of the mitochondria.
• The four-carbon molecule, oxaloacetate, acts as the starting point for the cycle and is regenerated after the eight steps of the citric acid cycle.
• The eight steps of the citric acid cycle are a series of redox, dehydration, hydration, and decarboxylation reactions.
• Acetyl-CoA, produced from pyruvate that is itself produced from glucose in glycolysis, is the starting substrate for the cycle.
• Each turn of the cycle produces 1 GTP or ATP, 3 NADH molecules and 1 FADH2 molecule.
• One glucose molecule produces two pyruvate molecules, meaning one glucose can power two turns of the cycle and produce a total of 6 NADH and 2 FADH2 molecules.
Key Terms
citric acid cycle (or the Krebs cycle): a series of chemical reactions used by all aerobic organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats, and proteins into carbon dioxide
cellular respiration: the metabolic reactions that take place in organisms to convert chemical energy from food intake and oxygen into cellular energy in the form of ATP
GTP: a molecule that is energetically equivalent to ATP
NADH/NAD+: an electron shuttle which delivers high energy electrons to the electron transport chain where they will eventually power the production of 2 to 3 ATP molecules; when this molecule has been oxidized (lost electrons), it is left with a positive charge and is called NAD+
FADH2/FADH: an electron shuttle that carries high energy electrons to the electron transport chain, where they will ultimately drive production of 1 to 2 ATP molecules; the oxidized form is FADH
acetyl-CoA: a molecule that is involved in carbohydrate, lipid, and protein metabolism, and delivers an acetyl group (containing 2 carbons) to the citric acid cycle
oxidative phosphorylation: the final stage of cellular respiration where the combined action of the electron transport chain and chemiosmotic coupling result in ATP production
adenosine triphosphate (ATP): an organic molecule that stores chemical energy and is the main energy source for cells
glycolysis: the chemical process that takes place in the cytosol by which a 6-carbon glucose molecule is split into two 3-carbon molecules called pyruvates
oxaloacetate: a four-carbon molecule that receives an acetyl group from acetyl-CoA to form citrate in the citric acid cycle
electron shuttle: small organic molecules, such as NAD+ and FADH, that transport high energy electrons by gaining electrons (through “reduction”) and losing electrons (through “oxidation”)
redox reaction: a chemical reaction that results in a change in the oxidation states of atoms through electron transfers
dehydration reaction: a reaction in which a molecule of water is lost from a reactant; the reverse of a hydration reaction
hydration reaction: a reaction in which a molecule combines with water
decarboxylation reaction: a chemical reaction in which a carboxyl group is removed from a reactant, releasing carbon dioxide
aerobic: a pathway is considered aerobic if oxygen is required to move the pathway forward.
energetically favorable: a chemical reaction is favorable if the products of the reaction have lower energy than the reactants
glycolysis: the first step in the breakdown of glucose to extract energy for cellular metabolism