Figure 10.1: Pyruvate Oxidation and the TCA Cycle (2023)

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    Pyruvate oxidation and the TCA cycle

    An overview of pyruvate metabolism and the TCA cycle

    Under the right conditions, pyruvate can be further oxidized. One of the most studied oxidation reactions involving pyruvate is the two-part reaction involving NAD+and a molecule called coenzyme A, often abbreviated as "CoA". This reaction oxidizes pyruvate, resulting in the loss of one carbon through decarboxylation and the formation of a new molecule called acetyl-CoA. The resulting acetyl-CoA can enter multiple biosynthetic pathways for larger molecules or go through another central metabolic pathway called the citric acid cycle, sometimes called the Krebs cycle or the tricarboxylic acid (TCA) cycle. The remaining two carbon atoms of the acetyl group can be further oxidized or reused as a precursor to build various other molecules. We will discuss these scenarios below.

    Different fates of pyruvate and other end products of glycolysis

    The glycolysis module ended with the end products of glycolysis: 2 molecules of pyruvate, 2 molecules of ATP and 2 molecules of NADH. This module and the fermentation module explore what the cell can do with the pyruvate, ATP and NADH produced.

    Losy ATP i NADH

    In general, ATP can be used or combined with various cellular functions, including biosynthesis, transport, replication, etc. We will see many such examples throughout the course.

    However, what to do with NADH depends on the conditions under which the cell is growing. In some cases, the cell chooses to rapidly recycle NADH back to NAD+. This is done through a process called fermentation where the electrons originally taken from the glucose derivatives are returned to downstream products via a further Red/Ox transfer (described in more detail in the Fermentation module). Alternatively, NADH can be recycled back to NAD+by donating electrons to the so-called electron transport chain (this is covered in the module on respiration and electron transport).

    The fate of cellular pyruvate

    • Pyruvate can be used as a terminal electron acceptor (directly or indirectly) in fermentation reactions and is discussed in the fermentation module.
    • Pyruvate can be excreted from the cell as a waste product.
    • Pyruvate can be further oxidized to extract more free energy from this fuel.
    • Pyruvate can serve as a valuable intermediary between some major carbon processing pathways

    Further oxidation of pyruvate

    In respiring bacteria and archaea, pyruvate is further oxidized in the cytoplasm. In aerobic respiration eukaryotic cells, the pyruvate molecules produced at the end of glycolysis are transported to the mitochondria, which are the sites of cellular respiration and contain oxygen-consuming electron transport chains (ETC in the respiration and electron transport module). Organisms from all three layers of life have similar mechanisms for further oxidation of pyruvate to CO2. First, pyruvate is decarboxylated and covalently boundCoenzyme Away to... yesThioesterbonds, forming a molecule calledAcetylo-CoA. Although acetyl-CoA may enter several other biochemical pathways, let us now consider its role in triggering a circuit known astricarboxylic acid cycle, is also calledTCA-Zyklus, AgeThe citric acid cycleLubKrebs cycle. This process is detailed below.

    Conversion of pyruvate to acetyl-CoA

    Pyruvate oxidizes NAD in a multistep reaction catalyzed by the enzyme pyruvate dehydrogenase+, decarboxylated and covalently bound to the coenzyme A molecule viathioester vesa. The release of carbon dioxide is important here, this reaction often leads to the so-calledloss of cell mass as CO2diffuse or be transported out of the cell and become a waste product. In addition, the NAD molecule+it is reduced to NADH per oxidized pyruvate molecule. Remember: they existtwopyruvate molecules, produced at the end of glycolysis for each metabolized glucose molecule; So when these two pyruvate molecules are oxidized to acetyl-CoA, two of the original six carbon atoms turn into waste.

    proposal for discussion

    We already talked about the formation of the thioester bond in the second lesson unit and lecture. Where was it exactly? What was the energetic significance of this connection? What are the similarities and differences between this example (thioester formation from CoA) and the previous example of this chemistry?

    Figure 10.1: Pyruvate Oxidation and the TCA Cycle (1)

    Illustration 1.After entering the mitochondrial matrix, the multienzyme complex converts pyruvate into acetyl-CoA. In this way, carbon dioxide is released and the NADH molecule is formed.

    proposal for discussion

    Describe the energy flow and energy transfer in this reaction using good vocabulary (e.g. reduced, oxidized, red/ox, endergonic, exergonic, thioester, etc.). You can do equal editing - someone can start the description, another person can correct it, another person can correct it further, and so on.

    In the presence of the right onesterminalni akceptor elektrona,Acetyl-CoA donates its acetyl group (replaces the bond) to a four-carbon molecule, oxaloacetate, forming citrate (called the first compound in the cycle). This cycle is called by various names:The citric acid cycle(for the first formed intermediate - citric acid or citrate),TCA-Zyklus(Because citric acid or citrate and isocitrate are tricarboxylic acids)Krebs cycle, according to Hans Krebs, who in the 1930s first identified the stages in pigeon flight muscles.

    (Video) Pyruvate Oxidation and the Citric Acid Cycle

    The tricarboxylic acid (TCA) cycle.

    In bacteria and archaea, reactions in the TCA cycle usually occur in the cytosol. In eukaryotes, the TCA cycle takes place in the mitochondrial matrix. Almost all (but not all) enzymes of the TCA cycle are water soluble (not membrane soluble), with the exception of succinate dehydrogenase, which is embedded in the inner mitochondrial membrane (in eukaryotes). Unlike glycolysis, the TCA cycle is a closed loop: the final part of the pathway regenerates the compound used in the first step. The eight steps of the cycle are a series of Red/Ox, dehydration, hydration, and decarboxylation reactions that produce two molecules of carbon dioxide, ATP, and reduced forms of NADH and FADH2.

    Figure 2.In the TCA cycle, the acetyl group of acetyl-CoA is attached to a four-carbon oxaloacetate molecule to form a six-carbon citrate molecule. Through a series of steps, citrate is oxidized, releasing two molecules of carbon dioxide for each acetyl group that enters the cycle. Three NADs+The molecules are reduced to NADH, FAD+The molecule is reduced to FADH2and ATP or GTP (depending on cell type) is produced (by phosphorylation at the substrate level). Since the end product of the TCA cycle is also the first reactant, the cycle proceeds continuously in the presence of sufficient reactants.

    Image: "Yikrazuul"/Wikimedia Commons (link)

    (Video) Cellular Respiration (UPDATED)


    In particular, we mention eukaryotes, bacteria, and archaea when discussing the location of the TCA cycle, because many beginning biology students associate the TCA cycle exclusively with the mitochondria. Yes, the TCA cycle takes place in the mitochondria of eukaryotic cells. However, this pathway is not exclusive to eukaryotes; it is also found in bacteria and archaea!

    Stages of the TCA cycle

    Step 1:

    The first step of the cycle is a condensation reaction involving a two-carbon acetyl group of acetyl-CoA with a four-carbon oxaloacetate molecule. The products of this reaction are a six-carbon citrate molecule and free coenzyme A. This step is considered irreversible because it is highly exergonic. In addition, the rate of this reaction is controlled by the ATP negative feedback loop. As the level of ATP increases, the rate of this reaction decreases. When ATP is low, the speed increases. If you haven't already, the reason will soon become obvious.

    Step 2:

    In the second step, citrate loses one water molecule and gains another while citrate is converted to its isomer, isocitrate.

    Step 3:

    In the third step, NAD oxidizes isocitrate+and decarboxylated. Watch out for the coals! This carbon most likely now leaves the cell as waste and is no longer available to build new biomolecules. Oxidation of isocitrate therefore produces a five-carbon molecule, α-ketoglutarate, a CO molecule2and NADH. This step is also regulated by negative feedback from ATP and NADH and positive feedback from ADP.

    Step 4:

    Step 4 is catalyzed by the enzyme succinate dehydrogenase. In this process, NAD additionally oxidizes α-ketoglutarate+. This oxidation in turn leads to decarboxylation and thus the loss of other carbon as waste.So far, two carbon atoms from acetyl-CoA have entered the cycle and two have left it as CO2.There is no net increase in carbon in this phase that is assimilated from glucose molecules that are oxidized in this phase of metabolism. However, unlike the previous step, succinate dehydrogenase - like pyruvate dehydrogenase before it - combines the free energy of the exergonic Red/Ox reaction and decarboxylation to drive the formation of a thioester bond between the coenzyme A substrate and the succinate (what remains after). decarboxylation). Succinate dehydrogenase is regulated by feedback inhibition of ATP, succinyl-CoA and NADH.

    proposal for discussion

    (Video) Krebs Cylcle Trick How to remember krebs cycle FOREVER!!

    We have seen many steps in this and other signaling pathways that are regulated by allosteric feedback mechanisms. Are there similarities between these steps in the TCA cycle? Why might these be good steps towards regulation?

    proposal for discussion

    The thioester linkage has reappeared! Use the terms we've learned (e.g. reduction, oxidation, conjugation, exergonism, endergonism, etc.) to describe the formation of this bond and its subsequent hydrolysis.

    Step 5:

    In the fifth step, phosphorylation occurs at the substrate level. Here, inorganic phosphate (PI) is added to GDP or ADP to form GTP (equivalent to ATP for our purposes) or ATP. The energy that drives this substrate-level phosphorylation event comes from the hydrolysis of the CoA molecule from succinyl-CoA to succinate. Why is GTP or ATP produced? In animal cells, there are two isozymes (different forms of enzymes that carry out the same reaction) at this stage, depending on the type of animal tissue the cells are in. The isozyme is found in tissues that use large amounts of ATP, such as the heart and skeletal muscles. This isozyme produces ATP. Another enzyme isoenzyme is found in tissues that have a large number of anabolic signaling pathways, such as the liver. This isozyme produces GTP. GTP is energetically equivalent to ATP; However, its use is more limited. In particular, the process of protein synthesis mainly uses GTP. Most bacterial systems produce GTP in this reaction.

    Step 6:

    The sixth step is another Red/Ox reaction where succinate is oxidized by FAD+in fumarate. Two hydrogen atoms go to FAD+, produces FADH2. Difference in reduction potential between fumarate/succinate and NAD+/NADH half-reactions are not sufficient to produce NAD+suitable reagent for oxidation of NAD succinate+in cellular conditions. However, there is a difference in the reduction potential with FAD+/ FADH2Half of the reaction is enough to oxidize the succinate and reduce the FAD+. Unlike NAD+, Hi+it remains attached to the enzyme and transfers electrons directly to the electron transport chain. This process is made possible by the localization of the enzyme that catalyzes this step in the inner mitochondrial membrane or the plasma membrane (depending on whether the organism is eukaryotic or not).

    Step 7:

    In the seventh step, water is added to the fumarate to form malate. The final step of the citric acid cycle regenerates oxaloacetate by oxidizing NAD malate+. This creates another NADH molecule.


    Note that this process (oxidation of pyruvate to acetyl-CoA followed by a "circular" TCA cycle) completely oxidizes 1 molecule of pyruvate, a 3-carbon organic acid, to 3 molecules of CO2. A total of 4 NADH molecules, 1 FADH molecule2In addition, 1 molecule of GTP (or ATP) is produced. For breathing organisms, this is an important way of producing energy, as each molecule contains NADH and FAD2can directly enter the electron transport chain, and as we will soon see, subsequent Red/Ox reactions triggered by this process will indirectly stimulate ATP synthesis. The discussion so far suggests that the TCA cycle is primarily an energy generation pathway; designed to extract as much potential energy as possible from organic molecules or convert it into a form that cells can use: ATP (or equivalent) or an energized membrane. However, -and let's not forget- Another important result of the development of this pathway is the ability to produce more precursor or substrate molecules needed for various catabolic reactions (this pathway provides some of the early building blocks for larger molecules). As we will discuss below, there is a close relationship between carbon metabolism and energy metabolism.


    TCA Energy Stories

    Work on creating your own energy stories

    There are some interesting reactions that involve large energy transfers and redistributions of matter. Pick a few. Copy the reaction into your notes and practice constructing an energy story. You now have the tools to discuss energy redistribution in the context of broader ideas and concepts such as exergonism and endergonism. You also have the opportunity to start a discussion about the mechanisms (how these reactions work) by including enzyme catalysts. Go to your teacher and/or assistant and talk to your classmates to see how good you are.

    (Video) KREBS CYCLE MADE SIMPLE - TCA Cycle Carbohydrate Metabolism Made Easy

    Connections to coal flows

    One of the hypotheses we explored in this reading and lecture is the idea that "central metabolism" evolved as a means of creating carbon precursors for catabolic reactions. Our hypothesis also states that during cell development these responses were combined in the glycolysis and TCA cycle signaling pathways to increase their power to the cell. We can assume that aside effectThe cornerstone for the development of this pathway was the generation of NADH from the complete oxidation of glucose - we saw the beginning of this idea when we discussed fermentation. We have already discussed how glycolysis not only yields ATP from substrate-level phosphorylation, but also yields a network of 2 NADH molecules and 6 essential precursors: glucose-6-P, fructose-6-P, 3-phosphoglycerate, phosphoenolpyruvate and Of course pyruvate . While the cell can directly use ATP as an energy source, NADH is a problem and needs to be converted back to NAD+to keep the track balanced. As we can see in detail in the fermentation module, the oldest way that cells deal with this problem is by using the fermentation reaction to regenerate NAD+.

    During the pyruvate oxidation process in the TCA cycle, four other important precursors are produced: acetyl-CoA, α-ketoglutarate, oxaloacetate, and succinyl-CoA. Three CO molecules2are lost, which means a net mass loss for the cell. However, these precursors are substrates for a variety of catabolic reactions, including the production of amino acids, fatty acids, and various cofactors such as chem. This means that the rate of reaction in the TCA cycle depends on the concentrations involvedmetabolic intermediate(more about thermodynamics in class). A metabolic intermediate is a compound that is formed in a reaction (product) and then acts as a substrate for the next reaction. This also means that metabolic intermediates, especially the 4 primary precursors, can be removed at any time for catabolic reactions if necessary, thus altering the thermodynamics of the cycle.

    Not all cells have a functional TCA cycle

    Since all cells require the ability to produce these precursor molecules, one would expect all organisms to have a fully functional TCA cycle. In fact, the cells of many organisms do NOT have all the enzymes needed to complete a complete cycle. However, all cells have the ability to produce the 4 precursors of the TCA cycle mentioned in the previous paragraph. How can cells form progenitor cells and not go through a full cycle? Note that most of these reactions are freely reversible, so if NAD+If oxidation of pyruvate or acetyl-CoA is required, the reverse reactions require NADH. This process is often referred to as the reduction TCA cycle. Initiating these reactions in the opposite direction (relative to the direction discussed above) requires energy, which in this case is carried by ATP and NADH. If ATP and NADH control the pathway in one direction, it is obvious that reverse control requires ATP and NADH as "inputs". Therefore, organisms that do not complete the cycle can still produce the four major metabolic precursors by using previously extracted energy and electrons (ATP and NADH) to perform some key steps in reverse order.

    proposal for discussion

    Why might some organisms not fully develop the TCA oxidative cycle? Remember that the cells in NAD need to maintain balance+on NADH ratio and [ATP]/[AMP]/[ADP] ratios.

    Additional links

    Here are some additional links to videos and sites you may find useful.

    (Video) Krebs Cycle step by step |Citric acid Cycle or TCA|

    Links to Chemwiki

    • Chemwiki TCA cycle - downlink until important content corrections are made to the resource

    Linkovi and Khan Academy

    • Capable of Academy TCA Cycle - Downlink until major content revisions are made to the asset


    1. Easy Trick to learn 'Krebs Cycle' | Funny Mnemonics
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