Structural Biochemistry/Protein function/Allosteric Regulation

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General information[edit]

Allosteric regulation is the regulation of activities of an enzyme or a protein caused by the binding of regulators at the site other than the active site of the enzyme or protein. Therefore, it causes the active site to change in shape and prevents the binding of the substrate. In that way, the activity of an enzyme is affected. The term "allosteric" comes from the Greek "allo" which means "other"; "steric" means "space." Example of allosteric regulations includes the feedback from downstream products, the feed forward from upstream substrates. An allosteric protein is a protein with multiple ligand-binding sites such that ligand binding at one site affects ligand binding at another, this is known as cooperative binding.

As we have known, an enzyme can convert itself between active and inactive conformations. In the present of regulator, for example, an inhibitor, fewer enzymes are available for free binding of substrates. However, as the inhibitor releases, the enzyme turns back to its original shape and the active site is available for substrate to bind and form product. The substrates form weak bonds with the active site and specificity of binding depends on the precise arrangement of atoms.

Allosteric activation and inhibition[edit]

In the cell, the allosteric enzyme, which mostly have two or more subunits, can oscillate from active form to inactive form. Depends on which state of the enzyme, regulators can be used to stabilize the enzyme's conformation; the binding of an activator at regulator site can stabilize the active form of that allosteric enzyme while the binding of an inhibitor stabilizes the inactive form of the enzyme. The subunits of an allosteric enzyme fit together in a way that a conformational change in one subunit is transmitted to all others. through this interaction, a single activator or inhibitor molecule that binds to one regulatory site will affect the active sites of all subunits. In the cell, activators and inhibitors dissociate when at low concentrations which then allows the enzyme to oscillate again. This fluctuation of regulators can cause a sophisticated pattern of response in the activity of cellular enzymes. One example of this is the products of ATP hydrolysis which play a major role in balancing the flow of traffic between anabolic and catabolic pathways depending on their effects on key enzymes. For example, ATP binds to several catabolic enzymes allosterically which lowers their affinity for substrate and as a result inhibits their activity while ADP acts as an activator of the same enzyme. So if ATP production lags behind its use, ADP accumulates and activate these key enzymes that speed up catabolism, producing more ATP. If the supply exceeds demand however, catabolism slows down as ATP molecules accumulate and bind to enzymes, inhibiting them. In this way, allosteric enzymes control the rates of key reaction in metabolic pathways.

  • All enzymes must be tightly regulated to perform essential chemical reaction life.

Cooperativity[edit]

When the ennzyme can switch back and forth inactive and active form, the active form is not really stable and not always ready for substrates to bind. Copperativity involves the binding of one substrate to one active site (as the enzyme is in an active form)of one subunit triggers and "locks" all the other subunits in their active form in the way that the active form of the enzyme is stabilized, allowing more substrates to bind to other active site of other subunits.


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Cooperativity Models[edit]

There are two models that describe and give explanation of the cooperativity binding of ligands. The first model is the concerted model (MWC model) states that there are only two possible forms in which protein can exist. It is either T (tense) or R (relaxed) state. The process of the addition of ligands shifts the protein from T state to R state. In the example of the hemoglobin protein, the deoxy form is in T state, but the addition of the oxygen ligands to the active sites of the protein, transfers hemoglobin into the oxy form which corresponds to the R state. Concerted Model.jpeg

For the T state, because it is "deoxy", the affinity (the ability for the ligand to bind into the protein) is low, therefore there would be a high concentration of oxygen needed to be saturated. Because the R state is in the fully oxygenated form, it has a higher affinity for oxygen to bind to the protein. However, the model would only be in either the T state or the R state, or else it would not be cooperative.
The second model is the sequential model states that the process of addition of ligands to the active site does not completely convert T model to the R model. In example of hemoglobin, when three active sites of the protein are occupied by oxygen ligands, the hemoglobin molecule binds oxygen much more powerfully (appx. Three times) compare to the deoxy model. Each of these two models has advantages and disadvantages; the use of both models at the same time is the best way to approach the precise analysis. Allosteric enzymes do not obey the Michaelis-Menten equation. The graph will look like a shape "s", this indicates that the velocity of the reaction depends on the concentration of the substrate.

Feedback inhibition[edit]

Feedback inhibition occurs when an end product synthesized after a chain of anabolic pathways becomes an inhibitor that binds at allosteric site of the first enzyme that made this end product and affects the shape of the enzyme. Thus the enzyme no longer can bind the substrate at its active site. The metabolic pathway is then switch off and can no longer produce the end products that were the same as the inhibitor that bind to the allosteric site. This can be used as a method of metabolic control.
Feedback Inhibition.jpeg
In the above image, the substrate first attaches itself to the Enzyme 1's active site, and the active site turns the substrate into a shape that is the same as the Enzyme 2's active site. This continues until the substrate turns into a product. The feedback inhibition starts when the product binds to the Enzyme 1's allosteric site, changing the shape of Enzyme 1's active site. Because the active site for Enzyme 1 has changed, the substrate that used to bind to Enzyme 1 can no longer bind to the enzymes anymore. Other kinds of substrate may be able to bind to the changed Enzyme, but may not be able to bind to Enzyme 2's active site.

Feedback inhibition usually takes place in organism’s cells, and the inhibition manages the chemical reactions within the cell. Additionally, it can be found in synthesis of amino acid and cholesterol.

In amino acids, the pathways of biosynthesis are regulated by feedback inhibition, where one of the enzymes that participated in the reaction is allosterically inhibited by the final product. The feedback inhibition can be used to stop a synthesis reaction if there are too many products being formed by the synthesis. For instance, as the glutamine synthetase in E.coli continues to increase, the cumulative feedback inhibition would bind to an enzyme’s allosteric site, thus changing the enzyme’s formal form, and the glutamine cannot be made.

References[edit]

Berg, Jeremy, Lubert Stryer, and John l. Tymoczko. Biochemistry, 6th Edition.

Cherrr, Mastering Biology, 1st edition