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The citric acid cycle

The citric acid cycle (also known as the Krebs Cycle) is actually a part of the much larger process called cellular respiration, the process where your body harvests energy from the food you eat. Yes, the citric acid cycle has the same citric acid found in oranges and other citrus fruits!
Where does the citric acid cycle fit into cellular respiration?
  1. Glycolysis, where the simple sugar glucose is broken down, occurs in the cytosol.
  2. Pyruvate, the product from glycolysis, is transformed into acetyl CoA in the mitochondria for the next step.
  3. The citric acid cycle, where acetyl CoA is modified in the mitochondria to produce energy precursors in preparation for the next step.
  4. Oxidative phosphorylation, the process where electron transport from the energy precursors from the citric acid cycle (step 3) leads to the phosphorylation of ADP, producing ATP. This also occurs in the mitochondria.
The citric acid cycle captures the energy stored in the chemical bonds of acetyl CoA (processed glucose) 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, ATP (adenosine triphosphate). We can then use that energy to move, breathe, make our hearts beat, and think (among other things)!

How does it happen?

The molecules that enter and circulate through the citric acid cycle are made mostly of carbon atoms. To understand how the citric acid cycle works, we need to follow how the carbon atoms are rearranged through the cycle. Molecules, called electron shuttles, accept the energy released by stepwise rearrangements and the subtraction of carbons in the form of electrons. Electron shuttles are small organic molecules, such as NADstart superscript, start text, plus, end text, end superscript and FADH, that transport high energy electrons to where they need to be by gaining electrons (through “reduction”) and losing electrons (through “oxidation”). The electrons transported by electron shuttles will later be used to generate ATP.
Aside from following how the carbons are rearranged in the cycle, you will also need to know where high energy molecules are formed.
Let’s describe some of our key players in the citric acid cycle:
Energy shuttles:
  1. NADH: An energy 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 electron shuttle is not carrying high energy electrons, meaning it has been oxidized (lost its electrons), it is left with a positive charge and is called NADstart superscript, start text, plus, end text, end superscript.
  2. FADHstart subscript, 2, end subscript: Another energy 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 of FADHstart subscript, 2, end subscript is FAD and happens just like in NADH.
High energy molecules:
  1. ATP: The basic energy currency of the cell. It’s a form of energy that cells can use right away.
  2. GTP: Similar to ATP, GTP can be easily converted to ATP in the cell.
Figure of the 4 step citric acid cycle
Step 1: Glycolysis
A 6-carbon glucose molecule is split into two 3-carbon molecules called pyruvates. Pyruvate is needed in order to create acetyl CoA.
Step 2: The transformation of pyruvate to acetyl CoA
This is a very short step in between glycolysis and the citric acid cycle. The 3-carbon pyruvate molecule made in glycolysis 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 (COstart subscript, 2, end subscript). COstart subscript, 2, end subscript is the waste product that you release when you exhale.
Step 3: The citric acid cycle
The citric acid cycle is called a cycle because the starting molecule, oxaloacetate (which has 4 carbons), is regenerated at the end of the cycle. Throughout the citric acid cycle, oxaloacetate 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 favourable. When a step is favoured, it 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 (see enzyme kinetics). The released energy is captured as the electron shuttles (NADstart superscript, start text, plus, end text, end superscript and FAD) are reduced to NADH and FADHstart subscript, 2, end subscript .
To start the cycle, an enzyme fuses acetyl CoA and oxaloacetate together so that citric acid is formed (a 2-carbon molecule + a 4-carbon molecule = a 6-carbon molecule!). This is the first molecule that is made in the cycle and is where the cycle gets its name. Enzymes then proceed to speed up (or “catalyze”) a sequence of rearrangements that convert the newly made citric acid molecule into a series of slightly different molecules. These enzymes only change the rate that these rearrangements occur, not the outcome.
  1. An enzyme rearranges the atoms in the citric acid molecule (6 carbons) into a new 6-carbon arrangement.
  2. Energy is released when the 6-carbon arrangement is oxidized, causing one carbon to be removed. The removed carbon molecule combines with oxygen to produce COstart subscript, 2, end subscript. Some of the energy, in the form of electrons, is captured in formation of high-energy compound, NADH. (Recall that some of the energy released from the cycle is used to reduce NADstart superscript, start text, plus, end text, end superscript to create NADH.) The high energy electrons that are handed to NADstart superscript, start text, plus, end text, end superscript for reduction come from the oxidation (loss of electrons) from the carbon molecule here.
  3. Next, the same type of reaction happens again. Another carbon is cleaved off the 5-carbon molecule, leaving a 4-carbon molecule and COstart subscript, 2, end subscript, and some of the energy released is used to reduce NADstart superscript, start text, plus, end text, end superscript to NADH.
  4. Rearrangement occurs, allowing the 4-carbon molecule to find a more comfortable configuration (one that doesn’t use require a lot of energy or structural strain, and one that allows each bond to be satisfied). During this rearrangement, non-carbon groups are added to and removed from the molecule. GTP and FADHstart subscript, 2, end subscript are made in these steps.
  5. The 4-carbon molecule rearranges its carbons one last time, producing oxaloacetate. Remember that oxaloacetate will be used again in the next cycle. Once again, some of the energy released is transferred to reduce NADstart superscript, start text, plus, end text, end superscript to NADH.
The products of the citric acid cycle:
From one citric acid cycle, the following products are formed:
  • 1 GTP
  • 3 NADH
  • 1 FADHstart subscript, 2, end subscript
  • 2 COstart subscript, 2, end subscript
  • Regenerated oxaloacetate
The COstart subscript, 2, end subscript that is released during the transformation step (step 2) and the two COstart subscript, 2, end subscript that are made during the citric acid cycle are the same three carbons that came from the initial pyruvate (made at the end of step 1 of cellular respiration). After two rounds of the citric acid cycle, we have completely oxidized one molecule of glucose to COstart subscript, 2, end subscript and captured its energy in a series of steps. These products from the citric acid cycle are made in the mitochondria of your cells..
Step 4: Oxidative phosphorylation
During oxidative phosphorylation, NADH and FADHstart subscript, 2, end subscript are transported to the electron transport chain, where their high energy electrons will ultimately drive synthesis of ATP.

Consider the following:

What types of foods do we need to be eating in order to fuel our citric acid cycles? Our bodies are capable of digesting complex carbs, proteins, and fats to provide energy for the citric acid cycle. Carbs can be broken down into glucose, the first molecule used during glycolysis. Similarly, proteins can be broken down into their basic parts to form acetyl CoA, the molecule that enters the citric acid cycle. Components of many fats can be transformed into acetyl CoA, or converted to glucose so they can enter the citric acid cycle as well. Essentially, all of the different types of food we eat can end up in the citric acid cycle.

Want to join the conversation?

  • leaf green style avatar for user kate
    Why is GTP considered to be the equivalent of ATP?
    (12 votes)
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    • leaf blue style avatar for user Kevin D. Fettel
      Succinyl-CoA is converted to Succinate by succinyl-CoA synthetase. The term synthetase indicates the participation of a nucleoside triphosphate in the reaction. Animal cells have two isozymes of succinyl-CoA synthetase, one specific for ADP and the other for GDP. This is where the ATP (GTP) references are made from.

      Additionally, it is possible that the body can convert between GTP and ATP; albeit this is not part of the TCA cycle. GTP can transfer a phosphoryl group to ADP to form ATP.

      This process is reversible and catalyzed by nucleoside diphosphate kinase. It's important to also note that GTP and ATP are energetically equivalent.
      (25 votes)
  • leafers ultimate style avatar for user Raymond Mitchell
    When FAD+ is oxidized, why does it gain 2 hydrogen electrons instead of one?
    Since NAD=NADH
    (7 votes)
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    • leafers ultimate style avatar for user Jerry J. Français II
      FAD has both an amine and an amide group that have free electron pairs on their respective Nitrogen atoms that are able to form a bond with Hydrogen. This is why FAD is able to pick up two Hydrogen atoms to become FADH2. On the other hand, NAD+ only has one pyridine group (picture benzene with one Nitrogen in place of one Carbon), however, this Nitrogen on the pyridine is charged due to being short one electron as a result of the double-bond from participating in the ring. When a Hydrogen atom is added para to this Nitrogen, electrons are rearranged such that the charge is neutralized.
      (11 votes)
  • piceratops ultimate style avatar for user Jacob Schluns
    In the 'How Does it Happen?' section of the article, FADH is written out. Later on, this oxidized form of FADH_2 is also written as FAD or FAD+. So, between FAD, FAD+, and FADH, is there a preferred choice/ correct choice for the oxidized form of FADH_2 or is it more a personal preference?
    (2 votes)
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    • blobby green style avatar for user Steven Fowkes
      NAD+ is indeed positively charged. The plus sign does indicate a positive charge. This positive charge is balanced by hydride (H-, the reducing form of hydrogen) to make NADH, which is neutral in charge. Plus one (+) added to minus one (-) makes zero (neutral). The plus and minus signs can also refer to the way molecules rotate the polarization of light (right- or left-handedness), but that is not the case here.
      (1 vote)
  • blobby green style avatar for user Gonzalo Coloma Militar
    I thought that there only a 2 net total of ATP produced in glycolysis, given that it invested in 2 ATP with hexokinase and PFK.
    (3 votes)
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  • leafers tree style avatar for user Daniel Ly
    If a polysaccharide includes monomers other than glucose, are they broken down in a separate pathway than glycolysis? Or are the monosaccharides converted to glucose and then go through the pathway listed here?
    (2 votes)
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    • leafers tree style avatar for user Matt Hagerman
      We can use fructose as an example here (given its notorious status as both a component of HFCS and the "other half" of the disaccharide sucrose).

      To answer your question, fructose is NOT converted to glucose prior to glycolysis. Fructose has a somewhat different metabolic pathway called fructolysis, where the hexose is eventually converted into pyruvate through a series of catalyzed steps. However, the similarities really end there. The pyruvate does enter the Krebs cycle, but those products are directed to glycogen production, not for energetic purposes (like ATP generation).

      Another fun fact is that fructose is metabolized entirely in the liver. One of the hypotheses about why fructose consumption can be unhealthy is that those glycogen stores can build up over time, leading to a "fatty" liver.

      I would assume that all other metabolized monosaccharides follow similar fates, where their metabolic pathways may be similar - but they aren't converted to glucose for glycolysis.
      (4 votes)
  • piceratops seed style avatar for user Nikunj Shah
    So I have read from multiple sources that typically synthases do not require energy input while synthetases do require energy input in order for the reaction to occur. Even in my Kaplan biochemistry review book, it says that succinyl CoA synthetase requires energy input, however one of the products of this reaction is the formation of GTP from GDP and Pi. I was just wondering how this makes any sense, because the name synthetase is supposed to suggest that energy is required, not a byproduct of the reaction.
    (2 votes)
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    • leafers ultimate style avatar for user Nick Tsaftaridis
      The name "Succinyl-CoA synthetase" characterizes the inverse of the reaction that happens here.

      The synthetase actually requires energy in the form of GTP to create succinyl-CoA from succinyl acid and CoA-SH.

      But now, in this pathway, we HAVE succinyl-CoA and want to PRODUCE succinyl acid and CoA-SH, so the enzyme catalyses the inverse reaction, thus producing a high energy bond in the form of GTP.

      Hope this helps!
      (2 votes)
  • blobby green style avatar for user sj1809
    what happens when there isn't enough oxygen to complete the process
    (2 votes)
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  • starky sapling style avatar for user Ariel Brennan
    What molecule do you breathe out that leaves the Kreb cycle?
    (1 vote)
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    • blobby green style avatar for user fultonog
      Carbon dioxide (CO2). It is a combination of carbon from sugars and fibers (C), combined with atmospheric oxygen (O2). Plants in turn use their equivalent of the citric acid cycle (photosynthesis), to cleave carbon from exhaled (Atmospheric) CO2 and they emit oxygen as a waste product (which humans use). Plants and animals consume each other's waste products, creating a symbiotic balance.
      (2 votes)
  • blobby green style avatar for user Shruti Bhattacharyya
    Hey, could you elaborate exactly on how the whole energy-into-electrons thing with the NAD+ molecule works? I'm a little lost here. Thanks a ton.
    (1 vote)
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  • blobby green style avatar for user fultonog
    Is there a net gain of any molecule in the citric acid cycle, aside from carbon dioxide, such as water ?
    (1 vote)
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