Energy Production Through the Kreb’s Cycle

Energy is essential to cellular function and we can get this energy by metabolizing carbohydrates, proteins, and fats. The Kreb's Cycle (also known as the TCA Cycle & Citric Acid Cycle) is a critical component for macronutrient metabolism and energy conversion for all 3 of these nutrients. The complete metabolism for each of them must, at some point, go through the Kreb's Cycle. For a more indepth discussion of this pathway, keep reading.

The Kreb's cycle takes place in the mitochondria of the cell. It was named for the chemist and Nobel Prize winner (1953), Hans Krebs. This cycle is a series of chemical intermediates that are transformed to another intermediate by enzymes specific to that step in the cycle. Each step is catalyzed by a specific enzyme. The cycle starts with oxaloacetate and ends with oxaloacetate. The cycle produces 1 ATP, 3 NADH, and 1 FADH2 per turn. If you recall from glycolysis, two pyruvates are produced per molecule of glucose. Pyruvate is converted to acetyl CoA which enters the Kreb's cycle. Therefore, one molecule of glucose eventually creates 2 turns of the krebs cycle.

Kreb's Cycle EnergyThe 2-carbon acetyl portion of acetyl CoA is oxidized to 2 CO2 molecules during the cycle.

Some amino acids can enter at different steps in the Kreb's cycle. During the metabolism of odd chain fatty acids, one three carbon molecule remains at the end. It enters the Kreb's cycle at the Succinyl CoA step. Thus, the Kreb's cycle is very important for energy production from all food supplies.

Also, keep in mind that I have divided these steps based on a number of sources. Different sources divide these steps differently. They may even add other intermediates. I have tried to keep these steps as simple as possible and only expand on the areas that are important in understanding the process. Others may argue that other areas are also important and they may be right but this is my site and not theirs. Again, I hope this helps.

The first step in the Krebs Cycle is the formation of citrate from the combination of oxaloacetate and Acetyl CoA. The acetyl group from acetyl CoA is added to oxaloacetate forming citrate via the enzyme citrate synthase. The CoA from acetyl CoA leaves as CoASH. Not much else occurs at this step. Citrate inhibits citrate synthase (product inhibition). So does succinyl CoA by competitive inhibition.

Citrate is converted to isocitrate by the action of aconitase. Again, not much occurs here.

Isocitrate DH acts on isocitrate, converting it to α-ketoglutarate, producing an NADH and CO2 in the process. The carbon that forms CO2 comes from the acetyl group that enters the cycle. This is our first yield from the Kreb's cycle. The removal of carbon dioxide is termed oxidative decarboxylation (if anyone cares!).

NADH inhibits isocitrate DH (product inhibition). NADH product inhibition provides control over three steps in the Kreb's cycle. Since there are only 4 controlled steps in Kreb's, NADH is an important control mechanism. This step is also controlled (enhanced) by increased ADP and calcium.

This is a pretty big and important step. The α-ketoglutarate DH complex acts upon α-ketoglutarate ultimately forming Succinyl CoA. This enzyme complex is described in fair detail in the pyruvate to acetyl CoA step. However, it should be noted that the α-ketoglutarate DH complex is just one of a family of enzymes that oxidatively decarboxylate these a-keto acids. There is an oxidative decarboxylation occuring here (the 2nd carbon from the acetyl entering the Kreb's). In other words, CO2 is released. CoASH is needed and NADH is also produced. Some amino acids (BCAA's) and the 3-carbon molecule remaining after beta oxidation of odd chain fatty acids enter the Kreb's Cycle at this step by being acted upon by this enzyme complex.

NADH inhibits this enzyme complex (as described previously). As NADH concentrations increase, the Kreb's cycle slows down.

All of the remaining intermediates in the Kreb's cycle are four carbon molecules.

This step produces NADH and allows other energy sources (such as AA's and fatty acids) to enter here.

The CoASH that went into step 4 comes off here. Succinate thiokinase acts upon succinyl CoA removing the CoASH and forming succinate. The energy from its release fuels the formation of GTP. Some would say that the GTP fuels the conversion of ADP to ATP (that's where we get the ATP discussed in the overview).

Two pairs of electrons from the acetyl group of acetyl CoA remain even though the carbons have been removed as carbon dioxide. The remaining steps in the Kreb's cycle are transferred to NAD+ and FAD and ultimately reforming oxaloacetate.

In this step,  succinate DH acts upon succinate forming fumarate and converting FAD to FADH2. The FAD accepts one of the pairs of electrons that remain. Now only one pair of electrons from the original acetyl group remain in fumarate.

Succinate DH resides within the inner mitochondrial membrane. It binds FAD fairly tightly. All of the other enzymes involved in the Kreb's cycle are located in the mitochondrial matrix.

The only thing that happens in this step is that water is added to fumarate. The enzyme fumarase adds a hydroxyl group and a proton (from the water) to fumarate converting it to malate.

This is the final step of the Kreb's cycle. It is the final step because the intermediate that we added acetyl CoA to, oxaloacetate, is reformed. The final pair of electrons from the original acetyl group are donated to NAD+ forming NADH. The enzyme that catalyzes the reaction is malate DH.

NADH inhibits this step.

In case I haven't mentioned it earlier, there are five co-enzymes needed for the Kreb's cycle to function properly. They have been mentioned in the steps but I didn't specifically point them out (as I will do now). They are: NAD+, FAD, thiamine pyrophosphate, lipoate (lipoic acid), and CoA.

As mentioned earlier, other molecules (such as fats and amino acids) can enter the Kreb's cycle at different locations to produce energy. For example, during periods of long-duration, low to moderate-intensity exercise (aerobic), beta-oxidation of odd-chain fatty acids may enter the Kreb's at the alpha-ketoglutarate DH step. However, when these products must be synthesized, these intermediates have to be pulled out of the cycle. Citrate and malate may be pulled out of the cycle for product synthesis. This would result in a deficiency of the 4-carbon intermediates. Fortunately, there are reactions that re-supply these intermediates. They are called anaplerotic reactions. An example of one of these reactions is the conversion of pyruvate and carbon dioxide to form oxaloacetate. The enzyme that catalyzes this reaction is pyruvate carboxylase. This enzyme must have biotin in order for it to function properly.

Comments

  1. Hi!

    I’m a microbiology student. Thank you very much for such a simple & insightful explanation for energy production through Krebs cycle.

  2. Joyce Hamilton-Whitson says:

    Just another quick comment… my son, Brian Michael Vaught, also had a mitochondrial myopathy… which is also another reason that the Krebs Cycle always interested me.
    The Krebs Cycle teaches us so much… it\’s crazy how everything intertwines!!!
    Thanks again for your article!!!

  3. Joyce Hamilton-Whitson says:

    Just another quick comment… my son, Brian Michael Vaught, also had a mitochondrial myopathy… which is also another reason that the Krebs Cycle always interested me.
    The Krebs Cycle teaches us so much… it’s crazy how everything intertwines!!!
    Thanks again for your article!!!

  4. Joyce Hamilton-Whitson says:

    I just want to say it always catches my attention when I find articles on the Krebs Cycle…. about 16 years ago I lost my oldest son (at age 7 1/2 years old) to a rare genetic disease called Leigh Syndrome… which involved/involves high levels of lactic acid in all of his body fluids, including his spinal fluid. This increased amount of lactic acid in his spinal fluid deteriorated his brain stem. He also had COX deficiency or \’cytochrome c oxidase\’ deficiency. Which to my understanding meant that he had a deficiency in his respiratory chain. He also suffered from several other problems… but I remember trying to understand the Krebs Cycle better… for reasons of the pyruvate/lactate/lactic acid issues. I got on this site to investigate prolotherapy.. but I ran across this article so I had to stop and read it.
    This is never easy to understand and you almost HAVE TO HAVE a degree to get a lot of it…. but back when we were going through everything with my son… I became much more educated about a lot of things that I would have otherwise never even attempted to \’investigate\’.
    My hat is off to ROB… hang in there and keep digging for your answers for your 10 year old son. He needs you, God knew you would look to find ways to help him… that\’s why you\’re together!!! AND… there\’s way more that you will learn in the process of what you\’re doing other than JUST finding out about the Krebs Cycle.. trust me… although THAT is very very important. Lorenzo\’s Oil was a great movie too… Parents need to get more involved in their children\’s health issues….
    Thanks ADMIN for writing/posting this article!!!!

  5. Suleiman Hadi Imam says:

    My name is Suleiman Hadi Imam, a Microbiology student from Nigeria. I really appreciate this explanation, many thanks

  6. Great review before my AP bio test, many thanks!

  7. Ikpoku Justice says:

    i appreciate your site and how its making science easy. am a biology teacher

  8. Soosiel khadka says:

    Hi admin. I am Soosiel Khadka from Nepal. I am doing Bachelor in Pharmacy from Nepal. I just want to tell you that the way you explain this krebs Cycle is so easy to understand……thank you for providing me this.

  9. dear admin, i dont know if this comment site is also designed for questions, but as a lay person trying to understand a metabolic condition my 10 yr old son has, i found your description of the krebs cycle easy to follow. i’ve been told that my son has a fatty acid oxidation problem which keeps stalling during the krebs cycle. he does however produce large amounts of ketone bodies when unwell for any reason and cannot break these down fast enough for energy for his brain in particular and can therefore becomes very acidotic (he is not diabetic). can you explain how its possible to produce large amounts of ketone bodies from the krebs cycle(?) and yet not produce enough energy (or possible enzymes?) to break down the ketone bodies effectively?

    if a reply is possible, it would be greatly appreciated
    regards
    rob

    • Rob,

      Thanks so much for the comment/question! I’ll do the best I can to help you out. First, it is important to understand that Beta Oxidation (fatty acid metabolism) is completely separate from the Kreb’s Cycle. They both occur in the cytosol of the mitochondria but they are 2 separate processes with different enzyme. But, of course, no man is an island and neither are our metabolic substrates.

      Without knowing more about his actual diagnosis, it sounds like he has a deficiency in A-Ketoglutarate DH. As the fatty acids are oxidized, they often leave a 3-carbon molecule residual (ketone bodies). These ketone bodies are generally easily handled/metabolized throught the Kreb’s cycle and their energy is captured. This occurs at the step where A-ketoglutarate is converted to Succinyl CoA.

      Enzymes are often the rate-limiting steps in metabolic issues and when the demand exceeds the supply problems arise. We see this throughout medicine. Enzyme activity can also have hormonal influence. In the case of diabetes, the insulin/glucagon ratio is such that metabolism favors the oxidation of fatty acids resulting in a large amount of ketone bodies. The enzymes that handle the ketone bodies are generally in proper working order but they simply cannot handle the load.

      In the case of a deficiency of these enzymes, the same acidosis occurs but giving insulin is of little value because it doesn’t address the primary issue. I suspect that there may be some utility in using insulin during an attack because it should decrease fatty acid metabolism – but that is another subject altogether.

      I hope this helps. It makes sense in my head but I’m not sure if I communicated my thoughts adequately. Please let me know if I can be of further assistance. Also, I’d be interested in his actual diagnosis. Your son will definitely be in my prayers!

      Doc

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