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The citric acid cycle

Overview and steps of the citric acid cycle, also known as the Krebs cycle or tricarboxylic acid (TCA) cycle.


How important is the citric acid cycle? So important that it has not one, not two, but three different names in common usage today!
The name we'll primarily use here, the citric acid cycle, refers to the first molecule that forms during the cycle's reactions—citrate, or, in its protonated form, citric acid. However, you may also hear this series of reactions called the tricarboxylic acid (TCA) cycle, for the three carboxyl groups on its first two intermediates, or the Krebs cycle, after its discoverer, Hans Krebs.
Whatever you prefer to call it, the citric cycle is a central driver of cellular respiration. It takes acetyl CoA—produced by the oxidation of pyruvate and originally derived from glucose—as its starting material and, in a series of redox reactions, harvests much of its bond energy in the form of NADH, FADH2, and ATP molecules. The reduced electron carriers—NADH and FADH2—generated in the TCA cycle will pass their electrons into the electron transport chain and, through oxidative phosphorylation, will generate most of the ATP produced in cellular respiration.
Below, we’ll look in more detail at how this remarkable cycle works.

Overview of the citric acid cycle

In eukaryotes, the citric acid cycle takes place in the matrix of the mitochondria, just like the conversion of pyruvate to acetyl CoA. In prokaryotes, these steps both take place in the cytoplasm. The citric acid cycle is a closed loop; the last part of the pathway reforms the molecule used in the first step. The cycle includes eight major steps.
In the first step of the cycle, acetyl CoA combines with a four-carbon acceptor molecule, oxaloacetate, to form a six-carbon molecule called citrate. After a quick rearrangement, this six-carbon molecule releases two of its carbons as carbon dioxide molecules in a pair of similar reactions, producing a molecule of NADH each time1. The enzymes that catalyze these reactions are key regulators of the citric acid cycle, speeding it up or slowing it down based on the cell’s energy needs2.
The remaining four-carbon molecule undergoes a series of additional reactions, first making an ATP molecule—or, in some cells, a similar molecule called GTP—then reducing the electron carrier FAD to FADH2, and finally generating another NADH. This set of reactions regenerates the starting molecule, oxaloacetate, so the cycle can repeat.
Overall, one turn of the citric acid cycle releases two carbon dioxide molecules and produces three NADH, one FADH2, and one ATP or GTP. The citric acid cycle goes around twice for each molecule of glucose that enters cellular respiration because there are two pyruvates—and thus, two acetyl CoAs—made per glucose.

Steps of the citric acid cycle

You've already gotten a preview of the molecules produced during the citric acid cycle. But how, exactly, are those molecules made? We’ll walk through the cycle step by step, seeing how NADH, FADH2, and ATP/GTP are produced and where carbon dioxide molecules are released.
Step 1. In the first step of the citric acid cycle, acetyl CoA joins with a four-carbon molecule, oxaloacetate, releasing the CoA group and forming a six-carbon molecule called citrate.
Step 2. In the second step, citrate is converted into its isomer, isocitrate. This is actually a two-step process, involving first the removal and then the addition of a water molecule, which is why the citric acid cycle is sometimes described as having nine steps—rather than the eight listed here3.
Step 3. In the third step, isocitrate is oxidized and releases a molecule of carbon dioxide, leaving behind a five-carbon molecule—α-ketoglutarate. During this step, NAD+ is reduced to form NADH. The enzyme catalyzing this step, isocitrate dehydrogenase, is important in regulating the speed of the citric acid cycle.
Step 4. The fourth step is similar to the third. In this case, it’s α-ketoglutarate that’s oxidized, reducing NAD+ to NADH and releasing a molecule of carbon dioxide in the process. The remaining four-carbon molecule picks up Coenzyme A, forming the unstable compound succinyl CoA. The enzyme catalyzing this step, α-ketoglutarate dehydrogenase, is also important in regulation of the citric acid cycle.
image credit: modified from "Oxidation of pyruvate and citric acid cycle: Figure 2" by OpenStax College, Biology, CC BY 3.0
Step 5. In step five, the CoA of succinyl CoA is replaced by a phosphate group, which is then transferred to ADP to make ATP. In some cells, GDP—guanosine diphosphate—is used instead of ADP, forming GTP—guanosine triphosphate—as a product. The four-carbon molecule produced in this step is called succinate.
Step 6. In step six, succinate is oxidized, forming another four-carbon molecule called fumarate. In this reaction, two hydrogen atoms—with their electrons—are transferred to FAD, producing FADH2. The enzyme that carries out this step is embedded in the inner membrane of the mitochondrion, so FADH2 can transfer its electrons directly into the electron transport chain.
Step 7. In step seven, water is added to the four-carbon molecule fumarate, converting it into another four-carbon molecule called malate.
Step 8. In the last step of the citric acid cycle, oxaloacetate—the starting four-carbon compound—is regenerated by oxidation of malate. Another molecule of NAD+ is reduced to NADH in the process.

Products of the citric acid cycle

Let’s take a step back and do some accounting, tracing the fate of the carbons that enter the citric acid cycle and counting the reduced electron carriers—NADH and FADH2—and ATP produced.
In a single turn of the cycle,
  • two carbons enter from acetyl CoA, and two molecules of carbon dioxide are released;
  • three molecules of NADH and one molecule of FADH2 are generated; and
  • one molecule of ATP or GTP is produced.
These figures are for one turn of the cycle, corresponding to one molecule of acetyl CoA. Each glucose produces two acetyl CoA molecules, so we need to multiply these numbers by 2 if we want the per-glucose yield.
Two carbons—from acetyl CoA—enter the citric acid cycle in each turn, and two carbon dioxide molecules are released. However, the carbon dioxide molecules don’t actually contain carbon atoms from the acetyl CoA that just entered the cycle. Instead, the carbons from acetyl CoA are initially incorporated into the intermediates of the cycle and are released as carbon dioxide only during later turns. After enough turns, all the carbon atoms from the acetyl group of acetyl CoA will be released as carbon dioxide.

Where’s all the ATP?

You may be thinking that the ATP output of the citric acid cycle seems pretty unimpressive. All that work for just one ATP or GTP?
It’s true that the citric acid cycle doesn’t produce much ATP directly. However, it can make a lot of ATP indirectly, by way of the NADH and FADH2 it generates. These electron carriers will connect with the last portion of cellular respiration, depositing their electrons into the electron transport chain to drive synthesis of ATP molecules through oxidative phosphorylation.

Want to join the conversation?

  • aqualine seed style avatar for user PrincessDeen101
    Is there a difference between ATP and GTP?
    (13 votes)
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    • leafers ultimate style avatar for user William H
      ATP is adenosine triphosphate, or adenine (the DNA base) with a ribose (the sugar) attached which makes it adenosine, then with three phosphate groups added. GTP is all the same stuff, except for Guanine substituted in for Adenine.
      (61 votes)
  • piceratops seed style avatar for user VINI
    Explain why citric acid cycle can't operate in the absence of oxygen?
    (16 votes)
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    • blobby green style avatar for user Ali Sasani
      Cooper is right...

      Once the ETC stops oxidizing NADH to NAD+ there is no longer any NAD+ available for the Krebs cycle to reduce back to NADH and the cycle comes to a halt. Therefore, the Krebs cycle is actually regulated by the availability of NAD+

      It is true that the Fermentation process an contribute to NAD+ regeneration but remember that under anaerobic condition most of the cell's pyruvate is being sent to the Fermentation pathway... and even when NAD+ is regenerated during Fermentation, there will be much less Pyruvate (I'm trying to avoid words like "none") entering the Kreb's Cycle.

      All this being said, yes technically it can but it would not be contributing to the overall goal (ETC) so the ATP production will be significantly less.
      (23 votes)
  • blobby green style avatar for user Mohammad mahdy yousefi
    How kerebs found this cycle?
    (5 votes)
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    • piceratops ultimate style avatar for user Darmon
      Krebs was working on the problem of finding the chemicals that act as intermediaries in cellular respiration. He discovered that when he added certain chemicals to pigeon breast muscle cells, their oxygen consumption would increase, thus indicating that more respiration reactions were taking place. These chemicals are the same ones we now identify as those making up the Kreb's Cycle. :)
      (20 votes)
  • leafers ultimate style avatar for user Devon Dryer
    Which provides more energy output, 1 ATP molecule or 1 GTP molecule?
    (7 votes)
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  • blobby green style avatar for user fiky95
    I was wondering whether it's necessary to remember the formula of each compound? Thank you! :)
    (3 votes)
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    • leafers ultimate style avatar for user William H
      Most basic biology classes, even AP bio don't require you to know the exact structure, although you might want to know their basic structure such as oh this is glucose with a phosphate group attached, this is a molecule with an extra proton, since most questions in that topic will revolve around that.
      (12 votes)
  • leaf green style avatar for user BSnailer
    Going from Malate to Oxaloacetic Acid 2 hydrogen ions are hydrolyzed but only one NADH is formed. Where did the other Hydrogen Ion go?
    (5 votes)
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    • male robot donald style avatar for user Maxime
      NAD+ needs 2 electrons en 1 proton to make NADH.
      The oxidation of malate transfers these products to NAD+. There is indeed a remaining H+ ion that is released in the matrix as a proton. That way the charge is kept on both ends of the reaction.
      This also happens with the other times that NADH is formed (releasing a proton) but there the proton was released beforehand when the carboxyl group was created.
      (4 votes)
  • orange juice squid orange style avatar for user Martin
    Can GTP serve the same functions as ATP?
    (3 votes)
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  • duskpin sapling style avatar for user Gale
    If using this for CLEP bio should I memorize this cycle and equation?
    (3 votes)
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    • piceratops ultimate style avatar for user FrozenPhoenix45
      Having taken the CLEP Biology exam, I would recommend it. You may not come across it, but it can't hurt. I had a few questions regarding this, but I can't remember whether I needed the equation memorized. I still memorized it though, because I would rather know it and not need it than not know it and need it.
      (5 votes)
  • blobby green style avatar for user caominh11122000
    In the picture "Oxidation of pyruvate and citric acid cycle", in step 3 and 4, I saw there are 2 H+ ions produced but I'm not sure where they came from. I think there should be no spare H+ ion in step 3 and 4.
    (4 votes)
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  • leaf green style avatar for user Thatmysticchick
    Synthethases are ligase enzymes and differ from synthases in that they use energy in the reaction derived from a nucleoside triphosphate. I’m aware the nomenclature has changed to using synthases for the same purpose but that’s recent. I REALLY WANT TO UNDERSTAND how the enzyme responsible for the PRODUCTION of GTP/ATP (the only one for that matter) is a SYNTHETASE given that they USE gtp/atp, NOT PRODUCE. Please and Thank you very much in advance!
    (4 votes)
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