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Regulation of cellular respiration

How cellular respiration can be sped up or slowed down. Key enzymes and feedback inhibition.


You can sometimes have too much of a good thing. For instance, consider ice cream sandwiches. Maybe you really like ice cream sandwiches and buy a bunch of them at the store. If you’re very hungry, that might be a good choice: you can eat them all quickly, before they melt. If you’re only a little hungry, though, that might be a bad choice: most of the sandwiches will melt uneaten, at which point you will have wasted some money.
Cells face a related problem when they break down fuels, such as glucose, to produce ATP. If the cell’s supply of ATP is low, it would do well to break down glucose as quickly as possible, replenishing the ATP it needs to “keep the lights on.” If the supply of ATP is high, on the other hand, it might not be such a good idea to oxidize glucose at top speed. ATP is an unstable molecule, and if it sits around in the cell too long, it’s likely to spontaneously hydrolyze back to ADP. This is like the case of the melted ice cream sandwich: the cell has spent glucose to make ATP, and that ATP ends up going to waste.
It’s important for a cell to carefully match the activity of its fuel breakdown (pathways to its energy needs at a given moment. Here, we'll see how cells turn cellular respiration pathways “up” or “down” in response to ATP levels and other metabolic signals.

Allosteric enzymes and pathway control

How is the activity of a pathway controlled? In many cases, pathways are regulated through enzymes that catalyze individual steps of the pathway. If the enzyme for a particular step is active, that step can take place quickly, but if the enzyme is inactive, the step will happen slowly or not at all. Thus, if a cell wants to control the activity of a metabolic pathway, it needs to regulate the activity of one or more of the enzymes in that pathway.
The primary target for regulation of a biochemical pathway is often the enzyme that catalyzes the pathway’s first committed step (that is, the first step that is not readily reversible). The concept of a committed step can get a little complicated when there are many intersecting metabolic pathways, as in cellular respiration, but this is still a useful idea to keep in mind.
How are the enzymes that control metabolic pathways regulated? A number cellular respiration enzymes are controlled by the binding of regulatory molecules at one or more allosteric sites. (An allosteric site is just a regulatory site other than the active site.) Binding of a regulator to the allosteric site of an enzyme changes its structure, making it more or less active.
The molecules that bind cellular respiration enzymes act as signals, giving the enzyme information about the cell's energy state. ATP, ADP, and NADH are examples of molecules that regulate cellular respiration enzymes. ATP, for instance, is a "stop" signal: high levels mean that the cell has enough ATP and does not need to make more through cellular respiration. This is a case of feedback inhibition, in which a product "feeds back" to shut down its pathway.
Diagram showing feedback inhibition of glycolysis, pyruvate oxidation, and the TCA cycle by the end product of cellular respiration, ATP.

Regulation of glycolysis

Several steps in glycolysis are regulated, but the most important control point is the third step of the pathway, which is catalyzed by an enzyme called phosphofructokinase (PFK). This reaction is the first committed step, making PFK a central target for regulation of the glycolysis pathway as a whole1.
PFK is regulated by ATP, an ADP derivative called AMP, and citrate, as well as some other molecules we won't discuss here.
  • ATP. ATP is a negative regulator of PFK, which makes sense: if there is already plenty of ATP in the cell, glycolysis does not need to make more.
  • AMP. Adenosine monophosphate (AMP) is a positive regulator of PFK. When a cell is very low on ATP, it will start squeezing more ATP out of ADP molecules by converting them to ATP and AMP (ADP + ADP ATP + AMP). High levels of AMP mean that the cell is starved for energy, and that glycolysis must run quickly to replenish ATP2.
  • Citrate. Citrate, the first product of the citric acid cycle, can also inhibit PFK. If citrate builds up, this is a sign that glycolysis can slow down, because the citric acid cycle is backed up and doesn’t need more fuel.
Diagram showing regulation of glycolysis via the enzyme phosphofructokinase (PFK). PFK catalyzes the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate in glycolysis. PFK is inhibited by ATP and citrate and positively regulated by AMP.

Pyruvate oxidation

The next key control point comes after glycolysis, when pyruvate is converted to acetyl CoA. This conversion step is irreversible in many organisms and controls how much acetyl CoA “fuel” enters the citric acid cycle3. The enzyme that catalyzes the conversion reaction is called pyruvate dehydrogenase.
  • ATP and NADH make this enzyme less active, while ADP makes it more active. So, more acetyl CoA is made when energy stores are low.
  • Pyruvate dehydrogenase is also activated by its substrate, pyruvate, and inhibited by its product, acetyl CoA. This ensures that acetyl CoA is made only when it’s needed (and when there's plenty of pyruvate available)4.
Diagram of the regulation of pyruvate oxidation. The enzyme pyruvate dehydrogenase catalyzes the conversion of pyruvate to acetyl CoA. ATP, acetyl CoA, and NADH negatively regulate (inhibit) pyruvate dehydrogenase, while ADP and pyruvate activate it.

Citric acid cycle

Entry into the citric acid cycle is largely controlled through pyruvate dehydrogenase (above), the enzyme that produces acetyl CoA. However, there are two additional steps in the cycle that are subject to regulation. These are the two steps in which carbon dioxide molecules are released, and also the steps at which the first two NADH molecules of the cycle are produced.
  • Isocitrate dehydrogenase controls the first of these two steps, turning a six-carbon molecule into a five-carbon molecule. This enzyme is inhibited by ATP and NADH, but activated by ADP.
  • α-Ketoglutarate dehydrogenase controls the second of these two steps, turning the five-carbon compound from the previous step into a four-carbon compound bound to CoA (succinyl CoA). This enzyme is inhibited by ATP, NADH, and several other molecules, including succinyl CoA itself.
Diagram showing regulation of the citric acid cycle. The conversion of isocitrate to α-ketoglutarate is catalyzed by the enzyme isocitrate dehydrogenase, while the conversion of α-ketoglutarate to succinyl CoA is catalyzed by the enzyme α-ketoglutarate dehydrogenase.
Isocitrate dehydrogenase is inhibited by ATP and NADH and positively regulated by ADP.
α-Ketoglutarate dehydrogenase is inhibited by ATP, NADH, and succinyl CoA.

Putting it all together

There are lots of other regulatory mechanisms for cellular respiration besides the ones we've discussed here. For instance, the speed of the electron transport chain is regulated by levels of ADP and ATP, and many other enzymes are subject to regulation. However, these examples give you a feel for the kind of logic and strategies cells use to regulate metabolic processes.
At each stage, we can see similar elements. For instance, we see feedback inhibition at many stages, at the level of pathways and of individual reactions. Monitoring of the cell's energy state through levels of molecules like ATP, ADP, AMP, and NADH is another common feature.
The diagram below summarizes the key enzymes we’ve discussed, along with some of their most important regulators.
Diagram summarizing the regulation of cellular respiration during glycolysis, pyruvate oxidation, and the citric acid cycle. (This diagram simply combines the preceding three diagrams into one.)

Want to join the conversation?

  • mr pink red style avatar for user Johanna
    So this page and the entire section is on cellular respiration and how it works but what I’m curious is: With all these many tiny molecules bopping into each other and performing all these different and variable reactions inside of a tiny cell, how did biologists / chemists figure this out?

    (Hoping for a detailed technical answer…)
    (21 votes)
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  • piceratops ultimate style avatar for user tmollman
    Can someone tell me if cellular respiration is similar to photosynthesis?
    (1 vote)
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    • duskpin ultimate style avatar for user Laurent
      If anything I would say they are both close to being opposite of one another. Cellular respiration takes in carbohydrates for example and break them down to their oxidized form CO2 and harvest the energy stored in the carbs by breaking their bonds to drive our physiological functions (Catabolism). Photosynthesis on the other hand is the process of creating chemical energy from light energy emitted from the sun. In plants another process known as the Calvin cycles uses this chemical energy to reduce a whole bunch of CO2 molecules to generate carbs/sugar/glucose (Anabolism).
      (20 votes)
  • blobby green style avatar for user BriannaDene123
    In this entire Cellular Respiration section, I haven't been able to figure this out: If the anaerobic glycolysis occurs, does pyruvate oxidation and the krebs cycle continue? Or are the last 3 steps only able to occur with aerobic glycolysis?
    (4 votes)
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  • leaf green style avatar for user Cassie Schiller
    Why is it essential that the enzymes that catalyze steps 1 and 2 are not inhibited when ATP concentrations are high?
    (5 votes)
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  • blobby green style avatar for user siddhiad
    how does citrate come out of the mitochondria ?
    (4 votes)
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    • winston baby style avatar for user Ivana - Science trainee
      Citrate - pyruvate shuttle

      Citrate can exchange for malate. The citrate in the cytoplasm can act as a regulator of phosphofructokinase, or as a substrate for ATP citrate lyase, an enzyme that reverses the citrate synthase reaction, and produces acetyl-CoA and oxaloacetate.

      The oxaloacetate produced in the ATP-citrate lyase reaction can be converted to malate. Both the oxaloacetate and malate can be used for a variety of reactions; for malate, one additional reaction, catalyzed by a malic enzyme, results in the formation of NADPH and pyruvate and carbon dioxide. The pyruvate produced by the malic the enzyme can return to the mitochondria to complete the cycle.
      (2 votes)
  • blobby green style avatar for user babalolatobi123
    what are the enzymes names
    (3 votes)
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  • blobby green style avatar for user Quintanilla kathia
    How do the various stages of cellular respiration work together and utilize enzymes to reduce or oxidize molecules to efficiently create ATP energy for the cell?
    (3 votes)
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  • purple pi pink style avatar for user jrtf2001
    I thought ADP was too stable to lose another phosphate group. So, does the cell mistakenly use ADP in place of ATP when it's low on the latter?
    (2 votes)
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    • aqualine tree style avatar for user Don Zhu
      ATP is the most common energy carrier for the cell. Each phosphate that you remove conveys energy but less each level. ATP has more energy than ADP for example. The cell sometimes doesn't need all the energy from ATP -> ADP and thus, ADP -> AMP can be used to drive a reaction. This is why the cell might use ADP. Our enzymes are pretty good at choosing the right energy carrier that leads to the best efficiencies. ADP usually doesn't carry enough energy to power a reaction requiring ATP.
      (3 votes)
  • blobby green style avatar for user Bill
    Biochemistry question: We use citric acid in industry to increase self life etc. of foods. Instead of utilizing citrus fruits scientists have learned we can use microganisms (Asperigillus niger) and harvest their citric acid (that is produced as an intermediate during cellular respiration). These microorganisms are grown in "fermentation tanks". But, these fermentation tanks must supply oxygen to the microorganism so that it can go through cellular respiration (or part of it). So, my question is: why is this process considered fermentation if it includes using oxygen?
    (2 votes)
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    • piceratops ultimate style avatar for user OoZooL Obliterator666
      Certain micro-organisms, such as the Clostridium Botulinium can only use fermentation, and oxygen is actually dangerous to them. A lot of other micro-organisms can perform both aerobic and anaerobic respiration. The type of respiration will depend whether oxygen was supplied to the mixture or deprived of it when the situation mandates itself... I hope that helps...
      (2 votes)
  • hopper cool style avatar for user Michael
    Cells uses biochemical pathways for it's anabolic processes, which there are more steps to create the end product. Can someone tell me why making your process longer be more beneficial to the cell?
    (2 votes)
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    • winston baby style avatar for user Ivana - Science trainee
      That's not the point we are looking at it.

      If you set it that way it looks like making process longer is more beneficial, which usually is not in the cell.

      Cells use longer biochemical pathways for anabolism because usually intermediates of catabolism or anabolism are substrates for other reactions.

      Literally, every molecule has its own place in the network of metabolic reactions. :)

      comment if you have more questions.
      (2 votes)