Describe Using Relevant Examples the Principle of Allosteric Regulation - Essay Example

THE PRINCIPLE OF ALLOSTERIC REGULATION By Student’s Name Code+ Course Name Professor’s Name University’s Name City, state Date The Principle of Allosteric Regulation Allosteric regulation, also referred to as allosteric control, is an expression used to outline a situation where the function of a protein or enzyme at one site is affected by the binding of regulators to another site, instead of the active site of the protein or enzyme[Ber111]. It may lead to either stimulation or inhibition of an enzyme’s activity. The molecules that by nature regulate enzyme activity within a cell act as reversible non-competitive inhibitors. Such regulatory molecules alter the shape of an enzyme and the functioning of the enzyme’s active site by binding to another site on the molecule through non-covalent interactions. Nearly all enzymes that are well-known to be allosterically regulated are created from more than one subunit, each containing a polypeptide chain with its active site[Hel91]. The whole complex hovers between two dissimilar shapes, one inactive and the other catalytically active. In the most elementary type if allosteric regulation, an inhibiting or activating regulatory molecule binds to an allosteric or regulatory site, regularly where subunits intersect. When an activator binds to an allosteric site, it stabilizes the shape that possesses the functional active sites. On the other hand, when the inhibitor binds to an allosteric site, it stabilizes the inactive form of the enzyme. The fuse together of the allosteric enzyme subunits is very perfect because whenever one subunit changes shape, this change is transmitted to all the subunits[Wil10]. Because of this interaction between the subunits, a single inhibitor or activator molecule that binds to an allosteric site will have an impact on the active sites of every subunit. Allosteric control is a very critical mechanism of cellular regulation. There are two significant roles played by the allosteric enzymes in the cells: catalyzing reactions in metabolic pathways and controlling the rates of the metabolic pathways[Hau10]. Within the cell, inhibitors and activators disassociate once at low concentrations, and this enables the enzyme to oscillate again. The fluctuations of the inhibitors and activators regulators may result in a complex pattern of response in the enzyme’s activity. A good example of this is the ATP hydrolysis products which play a key role in maintaining the flow balance of traffic between catabolic and anabolic pathways subject to their effects on crucial enzymes[BuZ11]. For instance, ATP allosterically binds to a number of catabolic enzymes lowering their affinity for substrate and thus inhibiting their activity. On the other hand, ADP acts as an activator of the same enzyme. Therefore, when ATP falls back its use, accumulation of ADP occurs, and it activate these enzymes that accelerate catabolism, and this enable the production of more ATP. However, when the supply surpasses demand, catabolism will slow down because ATP molecules will accumulate and bind to the enzymes, causing inhibition to them. ADP, ATP, and other affiliated molecules also have an effect upon key enzymes in anabolic pathways[Ric07]. In this context, allosteric enzymes play a key role in controlling the rates of major reaction in metabolic pathways. Each and every enzyme needs to be thoroughly regulated to carry out important chemical reaction life. Feedback inhibition is a good example of allosteric regulation in which the end product of a metabolic pathway is an allosteric inhibitor of the leading enzyme in the pathway and successfully terminates the operations of the pathway when the product starts to accumulate[Goo08]. The feedback inhibition can be illustrated as shown in the Figure 1 below. As indicated in figure 1, feedback inhibition takes place if a final product synthesized after a series of anabolic pathways turn into an inhibitor that binds to an allosteric site of the leading enzyme that produced this final product and affects the enzyme's shape. Therefore, the enzyme is not capable of binding the substrate at its active site. The metabolic pathway is then shut down and cannot produce the final products that were similar to the inhibitor that bind to the allosteric site. Feedback inhibition may be used as a metabolic control method. A clear illustration of feedback inhibition process is as shown in Figure 2 below. Figure 1: Feedback Inhibition: Product E is an allosteric inhibitor of enzyme #1 (regulatory enzyme). Source: Blaber, (2001) In Figure 2, the substrate initially binds itself to the active site of Enzyme 1, and the active site converts the substrate into a shape that is similar to the active site of Enzyme 2. This process carries on till the substrate becomes a product. The feedback inhibition begins when the product attaches itself to the allosteric site of Enzyme 1, altering the shape of active site for Enzyme 1. Since Enzyme 1’s active site has changed, the substrate that was attaching itself to Enzyme 1 cannot attach itself to the enzymes any longer. Other types of substrate are capable of binding to the changed enzyme, although it will be impossible to attach to the active site of Enzyme 2. Figure 2: Feedback Inhibition. Source: Wilson & Walker, (2010) Feedback inhibition normally occurs in the cells of organisms and inhibition controls the chemical reactions within the cell. In addition, it may take place in the synthesis of cholesterol and amino acids[Bla01]. Feedback inhibition regulates the pathways of biosynthesis in amino acids, in which one of the enzymes that took part in the reaction is inhibited by the end product in an allosteric manner. The process may be applied to end a synthesis reaction whenever there are excessively many products being produced by the synthesis. For example, cumulative feedback inhibition can stop the synthesis of glutamine in E. coli by binding to the allosteric site of the enzyme, hence changing the original form of the enzyme and this stops the synthesis of glutamine completely[Hel91]. Whenever an enzyme can change back and forth active and inactive form, the active form cannot be considered stable and is not at all times ready for substrates to attach. Cooperativity is another example of allosteric activation. Cooperativity substrate binding is where the binding of one substrate may result in many other functional substrate binding sites being formed, thus increasing the catalytic activity in all the active sites[Wil10]. Cooperativity is considered as an example of allosteric regulation since binding of the substrate to one active site impacts catalysis in a different active site. There are two main models that provide a description of the cooperativity binding of ligands. The two models are concerted model (MWC model) and sequential model. The concerted model says that protein can only exist in two forms. The two states are tense (T) and relaxed (R) states[Hau10]. According to the model, the addition of ligands changes the protein from tense state to relaxed state. A good example of this model is demonstrated by the hemoglobin protein. The deoxy form of the hemoglobin protein is considered to be in T state; however, addition of oxygen ligands to the protein’s active sites changes it into the oxy form, which is considered to be in R state. Figure 3: Concerted Model. Source: Wilson & Walker, (2010) In deoxy form, or the T state, the affinity is low; hence, a high concentration of oxygen is required to be saturated. Since the oxy or R state is in the completely oxygenated form, it has a higher affinity. This means that the oxygen ligand has a higher affinity to bind into the protein. Nonetheless, this type of model can only be in either the R state or the T state; otherwise it cannot considered to be cooperative[Wil10]. In organs such as lungs or gills, oxygen is at high levels, and thus hemoglobin affinity for oxygen is high as more binding sites are filled. However, in oxygen-deprived tissues, the ejection of an oxygen molecule minimizes the oxygen affinity of the different binding sites, causing oxygen to be released where it is most required[Ber111]. The sequential model says that the addition of ligands into the active sites does not necessarily change T model to the R model[Wil10]. In addition, this model dictates that substrate molecules bind through an induced fit protocol. Generally, if a subunit collides with a substrate molecule in a random manner, the active site creates a glove all over its substrate. Although this induced fit changes a subunit from the T state to R state, it does not necessarily transfer the conformational change to the nearby subunits. On the contrary, substrate binding into one subunit will barely change the structures of other subunits, and thus their binding sites will be more receptive to the substrate[Wil10]. Reference List Ber111: , (Berg, et al., 2011), Hel91: , (Helmstaedt, et al., 2001; Becker, 2001), Wil10: , (Wilson & Walker, 2010), Hau10: , (Haucke, 2010), BuZ11: , (Bu & Callaway, 2011), Ric07: , (Ricketson, et al., 2007; Blaber, 2001), Goo08: , (Goodey & Benkovic, 2008), Bla01: , (Blaber, 2001; Laberge, 2009), Hel91: , (Helmstaedt, et al., 2001), Read More