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Enzyme regulation

Cofactors and coenzymes. Reversible, irreversible, competitive, and noncompetitive inhibitors. Allosteric enzymes. Feedback inhibition.


The cells of your body are capable of making many different enzymes, and at first you might think: great, let’s crank all of those enzymes up and metabolize as fast as possible! As it turns out, though, you really don’t want to produce and activate all of those enzymes at the same time, or in the same cell.
Needs and conditions vary from cell to cell and change in individual cells over time. For instance, stomach cells need different enzymes than fat storage cells, skin cells, blood cells, or nerve cells. Also, a digestive cell works much harder to process and break down nutrients during the time that follows a meal as compared with many hours after a meal. As these cellular demands and conditions changes, so do the amounts and functionality of different enzymes.
Because enzymes guide and regulate the metabolism of a cell, they tend to be carefully controlled. In this article, we’ll take a look at factors that can affect or control enzyme activity. These include pH and temperature (discussed in the active site article), as well as:
  • Regulatory molecules. Enzyme activity may be turned "up" or "down" by activator and inhibitor molecules that bind specifically to the enzyme.
  • Cofactors. Many enzymes are only active when bound to non-protein helper molecules known as cofactors.
  • Compartmentalization. Storing enzymes in specific compartments can keep them from doing damage or provide the right conditions for activity.
  • Feedback inhibition. Key metabolic enzymes are often inhibited by the end product of the pathway they control (feedback inhibition).
In the rest of this article, we'll examine these factors one at a time, seeing how each can affect enzyme activity.

Regulatory molecules

Enzymes can be regulated by other molecules that either increase or reduce their activity. Molecules that increase the activity of an enzyme are called activators, while molecules that decrease the activity of an enzyme are called inhibitors.
There are many kinds of molecules that block or promote enzyme function, and that affect enzyme function by different routes.

Competitive vs. noncompetitive

In many well-studied cases, an activator or inhibitor's binding is reversible, meaning that the molecule doesn't permanently attach to the enzyme. Some important types of drugs act as reversible inhibitors. For example, the drug tipranivir, which is used to treat HIV, is a reversible inhibitor.1 It blocks activity of a viral enzyme that helps the virus make more copies of itself.
Reversible inhibitors are divided into groups based on their binding behavior. We won't discuss all of the types here, but we will look at two important groups: competitive and noncompetitive inhibitors.
  • An inhibitor may bind to an enzyme and block binding of the substrate, for example, by attaching to the active site. This is called competitive inhibition, because the inhibitor “competes” with the substrate for the enzyme. That is, only the inhibitor or the substrate can be bound at a given moment.
  • In noncompetitive inhibition, the inhibitor doesn't block the substrate from binding to the active site. Instead, it attaches at another site and blocks the enzyme from doing its job. This inhibition is said to be "noncompetitive" because the inhibitor and substrate can both be bound at the same time.
Competitive and non-competitive inhibitors can be told apart by how they affect an enzyme's activity at different substrate concentrations.
  • If an inhibitor is competitive, it will decrease reaction rate when there's not much substrate, but can be "out-competed" by lots of substrate. That is, the enzyme can still reach its maximum reaction rate given enough substrate. In that case, almost all the active sites of almost all the enzyme molecules will be occupied by the substrate rather than the inhibitor.
  • If an inhibitor is noncompetitive, the enzyme-catalyzed reaction will never reach its normal maximum rate even with a lot of substrate. This is because the enzyme molecules with the noncompetitive inhibitor bound are "poisoned" and can't do their job, regardless of how much substrate is available.
On a graph of reaction velocity (y-axis) at different substrate concentrations (x-axis), you can tell these two types of inhibitors apart by the shape of the curves:
_Image credit: "Enzymes: Figure 3," by OpenStax College, Biology, CC BY 3.0._
Not familiar with this type of graph? No worries! The basics of enzyme kinetics graphs article has a step-by-step walkthrough.

Allosteric regulation

Allosteric regulation, broadly speaking, is just any form of regulation where the regulatory molecule (an activator or inhibitor) binds to an enzyme someplace other than the active site. The place where the regulator binds is called the allosteric site.
_Image modified from "Enzymes: Figure 4," by OpenStax College, Biology, CC BY 3.0._
Pretty much all cases of noncompetitive inhibition (along with some unique cases of competitive inhibition) are forms of allosteric regulation.
However, some enzymes that are allosterically regulated have a set of unique properties that set them apart. These enzymes, which include some of our key metabolic regulators, are often given the name of allosteric enzymes2. Allosteric enzymes typically have multiple active sites located on different protein subunits. When an allosteric inhibitor binds to an enzyme, all active sites on the protein subunits are changed slightly so that they work less well.
There are also allosteric activators. Some allosteric activators bind to locations on an enzyme other than the active site, causing an increase in the function of the active site. Also, in a process called cooperativity, the substrate itself can serve as an allosteric activator: when it binds to one active site, the activity of the other active sites goes up.3 This is considered allosteric regulation because the substrate affects active sites far from its binding site.

Cofactors and coenzymes

Many enzymes don’t work optimally, or even at all, unless bound to other non-protein helper molecules called cofactors. These may be attached temporarily to the enzyme through ionic or hydrogen bonds, or permanently through stronger covalent bonds.Common cofactors include inorganic ions such as iron (Fe2+) and magnesium (Mg2+). For example, the enzyme that builds DNA molecules, DNA polymerase, requires magnesium ions to function.4
Coenzymes are a subset of cofactors that are organic (carbon-based) molecules. The most common sources of coenzymes are dietary vitamins. Some vitamins are precursors to coenzymes and others act directly as coenzymes. For example, vitamin C is a coenzyme for several enzymes that take part in building the protein collagen, a key part of connective tissue.
Image modified from OpenStax Biology.

Enzyme compartmentalization

Enzymes are often compartmentalized (stored in a specific part of the cell where they do their job) -- for instance, in a particular organelle. Compartmentalization means that enzymes needed for specific processes can be kept in the places where they act, ensuring they can find their substrates readily, don't damage the cell, and have the right microenvironment to work well.
For instance, digestive enzymes of the lysosome work best at a pH around 5.0, which is found in the acidic interior of the lysosome (but not in the cytosol, which has a pH of about 7.2). Lysosomal enzymes have low activity at the pH of the cytosol, which may serve as "insurance" for the cell: even if a lysosome bursts and spills its enzymes, the enzymes will not begin digesting the cell, because they will no longer have the right pH to function.5

Feedback inhibition of metabolic pathways

In the process of feedback inhibition, the end product of a metabolic pathway acts on the key enzyme regulating entry to that pathway, keeping more of the end product from being produced.
This may seem odd – why would a molecule want to turn off its own pathway? But it’s actually a clever way for the cell to make just the right amount of the product. When there’s little of the product, the enzyme will not be inhibited, and the pathway will go full steam ahead to replenish the supply. When there’s lots of the product sitting around, it will block the enzyme, preventing the production of new product until the existing supply has been used up.
Image credit: OpenStax Biology.
Typically, feedback inhibition acts at the first committed step of the pathway, meaning the first step that’s effectively irreversible. However, feedback inhibition can sometimes hit multiple points along a pathway as well, particularly if the pathway has lots of branch points. The pathway steps regulated by feedback inhibition are often catalyzed by allosteric enzymes.6
For example, the energy carrier molecule ATP is an allosteric inhibitor of some of the enzymes involved in cellular respiration, a process that makes ATP to power cellular reactions. When there is lots of ATP, this feedback inhibition keeps more ATP from being made. This is useful because ATP is an unstable molecule. If too much ATP were made, much of it might go to waste, spontaneously breaking back down into its components (ADP and Pi).
ADP, on the other hand, serves as a positive allosteric regulator (an allosteric activator) for some of the same enzymes that are inhibited by ATP. For instance, ADP may act by binding to an enzyme and changing its shape so that it becomes more active.7
Thanks to this pattern of regulation, when ADP levels are high compared to ATP levels, cellular respiration enzymes become very active and will make more ATP through cellular respiration.

Want to join the conversation?

  • aqualine ultimate style avatar for user Zhang, Luyan
    Allosteric regulation confuses me a lot. I don't really get it even after I watched the video on Khan Academy (MCAT) . Can anyone explain it to me briefly?
    (12 votes)
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    • female robot grace style avatar for user tyersome
      I'll try an analogy — let me know if this helps.

      Imagine that an enzyme is like tiny sculpture made from a wire twisted into a very complicated, but somewhat loose structure.
      The substrate is another much smaller sculpture that fits into a gap in the first sculpture — let's say it fits perfectly.
      Now think of hanging a weight off another part of the sculpture — the whole structure shifts a bit under the strain and now the substrate sculpture doesn't fit! In this situation the weight would be analogous to an allosteric inhibitor.

      You could also imagine a similar scenario, but with the substrate fitting poorly until you added a weight — in this case the weight would be analogous to an allosteric activator.
      (69 votes)
  • leafers seed style avatar for user Hannah Stadelmann
    What is an allosteric activator?
    (3 votes)
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  • duskpin ultimate style avatar for user Sidra
    whats the difference between non competitive inhibition and allosteric regulation(involving inhibitor)? .its all so confusing
    (2 votes)
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    • blobby green style avatar for user kalid.dalu14
      Allosteric regulation and noncompetitive inhibitor bind to site other than active site but allosteric regulation change the conformation of enzyme and making the reaction less effective while the noncompetitive inhibitor, like mention in the reading just poison the enzyme so reaction does not take place at all.
      (12 votes)
  • old spice man blue style avatar for user Nithya Shenoy
    In school, we conducted an experiment where a small piece of paper dipped in a liver solution was dropped into a test tube filled with hydrogen peroxide. After a few seconds, the liver juice coated paper rose to the the top. Why did it act in that way?
    (4 votes)
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    • blobby green style avatar for user austin.langley
      This is because the liver cells contain enzymes called catalase which speed up the breaking down of hydrogen peroxide into water and oxygen. When the reaction happens, oxygen is released and it pushes the piece of paper up to the surface along with it. This reaction happens faster or slower depending on the concentration of the liver juice you soaked the paper with.
      (9 votes)
  • starky tree style avatar for user Jaival
    The information about noncompetitive inhibitors contradicts what Sal said in his videos: "Competitive Inhibition" and "Noncompetitive Inhibition"

    What is described here as noncompetitive inhibition, Sal explains as allosteric. Sal has an entirely new definition for noncompetitive inhibition, describing it as a phenomena where the inhibitor and substrate can both bind.

    I'm confused, someone please clear this up for me.
    (3 votes)
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    • duskpin ultimate style avatar for user C4LOwenZ
      I think Sal is right about Competitive Allosteric Inhibition. In CAI, the inhibitor binds to an allosteric site (somewhere on the enzyme that is not an active site) and PREVENTS the substrate from binding in the first place. In non-competitive inhibition, the binding of the inhibitor still allows the binding of the substrate - the catalysis just doesn't work.
      The short answer is: CAI is competitive because only one thing, be it substrate or inhibitor, can bind to the enzyme.Non-competitive inhibition lets two things bind to the enzyme.
      (I think Sal didn't write this article.)
      (6 votes)
  • blobby green style avatar for user Edna Villapando
    Life is a process regulated by enzymes. What might be the sources of these enzymes? If particular enzyme is not available in person's cells, what sequence of events might result to produce it?
    (2 votes)
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    • female robot grace style avatar for user tyersome
      Enzymes are encoded as genes in the DNA — these genes are then transcribed to produce RNA and (for most enzymes§) then translated† to make a protein that has a catalytic activity (i.e. is an enzyme).

      Typically enzymes found within a cell are encoded by the DNA of that cell. However, multicellular organisms are colonized by many different microbes (these may be prokaryotes or other eukaryotes such as fungi) — these microbes often supply enzyme activities that aid the organism. The digestive system of animals is one example of this. In fact, most multicellular organisms depend on their microbiota for survival!

      The process of regulating gene expression is highly complex, but there is KhanAcademy material on this is several places — I recommend starting here:

      §Note: Some enzymes are make of RNA and these RNAs do not get translated.

      †Note: Many proteins undergo post-translational modifications that are essential for them to function.
      (5 votes)
  • starky sapling style avatar for user Anh Le
    what would happen if our bodies do not have inhibitors?
    (3 votes)
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  • blobby green style avatar for user seungjumoon2003
    if a allosteric inhibitor casues distortion of the enzyme's shape so that it cannot function, is it non-competitive or competitive?
    (i looked up many resources ,such as princeton review AP bio,Barrons, internet, but they all weren't clear)
    (3 votes)
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    • leafers tree style avatar for user BButler522
      Being allosteric lets you know that the inhibitor binds somewhere other than the active site, where the substrate binds. The location that the allosteric inhibitor binds is called the allosteric site.

      Because it isn't "competing" for the same binding site as the substrate, you can tell that it is non-competitive as the substrate will still be able to bond at the active site.
      (2 votes)
  • blobby green style avatar for user Colleen Troy
    When discussing cofactors, the article says, "These may be attached temporarily to the enzyme through ionic or hydrogen bonds, or permanently through stronger covalent bonds." I thought however that ionic bonds were much stronger than covalent bonds, but there seem to be contradictions online about this. Message boards typically say covalent is stronger but science websites typically say ionic is stronger. Do you know which bond is usually stronger?
    (3 votes)
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    • marcimus purple style avatar for user l
      Ionic bonds are stronger. It takes more energy to pull the two atoms apart to infinity than it does in a covalent bond. But, that is an energy measured in a vacuum. In the presence of solvent, such as water, this changes drastically. This is because the two atoms in an ionic bond (there is no such thing as a purely ionic or covalent bond, it is just what we call the extremes of different ends of a continuum) once separated make ions. These ions are massively stabilized by the water molecules through non-covalent interactions. What this means in physical terms is that when you break a bond, you not only have to look at the stability of the bond, but also the stability of the products. When the products are very stable, there is a smaller energy difference between the bond and the atoms. So, it is really hard to break a NaCl bond in a vacuum. It is very easy to do it in water. So in biological contexts, always in water, ionic bonds are more suggestions than bonds-a convenient way of describing ion pairs, and are thus much much weaker than a covalent bond that doesn't dissociate in the same way. But in a vacuum, the ionic bond is much harder to break than a simple covalent interaction.
      So in biological contexts, always in water, ionic bonds are more suggestions than bonds-a convenient way of describing ion pairs, and are thus much much weaker than a covalent bond that doesn't dissociate in the same way. But in a vacuum, the ionic bond is much harder to break than a simple covalent interaction.
      found this answer on reddit
      (1 vote)
  • blobby green style avatar for user 3000785
    How do you determine whether an enzyme's activity is enhanced or inhibited by regulatory cell binding?
    (2 votes)
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