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Types of enzyme inhibition
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- 3. Competitive Inhibition ■ Competitiveinhibition involves a molecule, other than the substrate, binding to the enzyme’s active site. ■ The molecule (inhibitor) is structurally and chemically similar to the substrate (hence able to bind to the active site). ■ The competitive inhibitor blocks the active site and thus prevents substrate binding. ■ As the inhibitor is in competition with the substrate, its effects can be reduced by increasing substrate concentration.
- 4. - This isa type of Reversible Inhibition,where the excess substrate abolishes the inhibition. - In such inhibition both the ES and EI (Enzyme-Inhibitor) complexes are formed during the reaction. - The amounts of ES and EI will depend on, 1. Affinity between enzyme and substrate/inhibitor. 2. Actual Concentrations (amounts) of substrate and inhibitor present 3. Time of preincubation of enzyme with the substrate or inhibitor.
- 5. - In competitiveinhibition, an inhibitor that resembles the normal substrate binds to the enzyme, usually at the active site, and prevents the substrate from binding. At any given moment, the enzyme may be bound to the inhibitor, the substrate, or neither, but it cannot bind both at the same time. - During competitive inhibition, the inhibitor and substrate compete for the active site. The active site is a region on an enzyme to which a particular protein or substrate can bind. The active site will thus only allow one of the two complexes to bind to the site, either allowing a reaction to occur or yielding it.
- 6. - Increasing thesubstrate concentration would diminish the "competition" for the substrate to properly bind to the active site and allow a reaction to occur. - When the substrate is of higher concentration than the concentration of the competitive inhibitor, it is more probable that the substrate will come into contact with the enzyme's active site than with the inhibitor.
- 7. Competitive Inhibition inBiological Systems - Penicillin, for example, is a competitive inhibitor that blocks the active site of an enzyme that many bacteria use to construct their cell walls. - Penicillin functions by interfering with the synthesis of cell walls of reproducing bacteria. It does so by inhibiting an enzyme transpeptidase that catalyzes the last step in bacterial cell-wall biosynthesis. The defective walls cause bacterial cells to burst. Human cells are not affected because they have cell membranes, not cell walls.
- 8. - Prostaglandin aremade in large amounts as a response to pain and can cause inflammation. Essential fatty acids form the prostaglandins when this was discovered, it turned out that these were actually very good inhibitors to prostaglandins. - These fatty acids inhibitors have been used as drugs to relieve pain because they can act as the substrate, and bind to the enzyme, and block prostaglandins.
- 9. Non-competitive Inhibition - Inthis inhibitor binds at a site other than the active site of the enzyme. It reduces the rate of reaction by changing the conformation of the enzyme. Features: -Inhibitor has no structural resemblance to the Substrate (So no competition for binding) - Increasing the Substrate conc. does not reduce this Inhibition -Inhibitor and substrate binds at different site - Reaction is slowed down but not halted
- 11. Types : Reversible Noncompetitive inhibition : If the inhibitor can be removed from its site of binding without affecting the activity of the enzyme, it is called as Reversible-Non-competitive Inhibition. Irreversible Non competitive inhibition : If the inhibitor can be removed only at the loss of enzymatic activity, it is known as Irreversible Non-competitive Inhibition. The inhibitor combines with the enzymes by forming a covalent bond and then the reaction becomes irreversible.
- 12. Kinetics of Non- Competitive Enzyme Inhibition The velocity (Vmax) is reduced With a noncompetitive inhibitor, the reaction can never reach its normal Vmax, regardless of how much substrate we add. A subset of the enzyme molecules will always be “poisoned” by the inhibitor, so the effective concentration of enzyme is reduced and hence the Vmax. But Km value is not changed The unchanged Km reflects that the inhibitor doesn't affect binding of enzyme to substrate, just lowers the concentration of usable enzyme.
- 14. Clinical Importance 1. Someanticancer drugs : - - inhibit enzymes involved in DNA synthesis - stop DNA production - stop division of more cancer cells 2.Cyanide inhibits cytochrome oxidase. 3. Fluoride will remove magnesium and manganese ion. It inhibits enzyme enolase, and hence the glycolysis process 4. Pepstatin inhibits enzyme pepsin 5. Soybean trypsin inhibitor inhibits enzyme trypsin
- 15. Uncompetitive inhibition - Uncompetitiveinhibition, also known as anti- competitive inhibition, takes place when an enzyme inhibitor binds only to the complex formed between the enzyme and the substrate. Uncompetitive inhibition typically occurs in reactions with two or more substrates or products. - Inhibitor binds at a distant site from the substrate, however an uncompetitive inhibitor binds only to the ES complex. - The inhibitor combines with enzyme-substrate complex rather than with the free enzyme to give inactive enzyme inhibitor complex. - An added substrate increases the Inhibitory effect.
- 16. Mechanism As inhibitor binds,the amount of ES complex is reduced. This reduction in the effective concentration of the ES complex can be explained by the fact that having the inhibitor bound to the ES complex essentially converts it to ESI complex, which is considered a separate complex altogether. This reduction in ES complex decreases the maximum enzyme activity (Vmax), as it takes longer for the substrate or product to leave the active site. The reduction in Km - the substrate concentration at which the enzyme can operate at half of its maximal velocity, often used to approximate an enzyme's affinity for a substrate - can also be linked back to the decrease in ES complex.
- 18. Involvement in cancermechanisms - Uncompetitive mechanisms are involved with certain types of cancer. Human alkaline phosphatases such as CGAP have been found to be over-expressed in certain types of cancers, and those phosphatases often operate via uncompetitive inhibition. - It has also been found that a number of the genes that code for human alkaline phosphatases (TSAPs) are inhibited noncompetitively by amino acids such as leucine and phenylalanine. Implications and uses in biological systems
- 19. Importance in celland organelle membranes - Although this form of inhibition is present in various diseases within biological systems, it does not necessarily only relate to pathologies. It can be involved in typical bodily functions. - For example, active sites capable of uncompetitive inhibition appear to be present in membranes, as removing lipids from cell membranes and making active sites more accessible through conformational changes has been shown to invoke elements resembling the effects of uncompetitive inhibition - In mitochondrial membrane lipids specifically, removing lipids decreases the alpha-helix content in mitochondria and leads to changes in ATPase resembling uncompetitive inhibition.
- 20. Feedback Enzyme Inhibition ●Feedback inhibition is also known as End-Product Inhibition. ● It is a cellular control mechanism in which an enzyme’s activity is inhibited by the enzyme’s end product. ● This mechanism allows cells to regulate how much of an enzyme’s end product is produced. ● Feedback inhibition is usually accomplished through something called an “allosteric site”.
- 21. ● The bindingof the end product to the allosteric site reduces the enzyme activity leading to less or no end product. ● The enzyme activity can increase when the enzyme comes in contact with fewer particles of the end product. ● The result of feedback inhibition is that: 1. It allows to adjust the rate of the reaction depending on how much end product is required 2. It helps in preventing the build up of the end product up to dangerous levels.
- 23. Functions of FeedbackEnzyme Inhibitors ● Prevents Waste: Without feedback inhibition, energy or raw materials that could be used for important cellular functions might be wasted on unnecessary ones. ● Prevents Depletion: ○ Without feedback inhibition, raw materials and energy might be depleted by biochemical processes that don’t stop, even when their end product is not needed. ○ Example is the production of ATP from glucose
- 24. 2. Production ofAmino Acids a. The human body uses twenty different amino acids – the “building blocks” of protein. b. The first unique step in the biochemical pathway for each amino acid – called the “committed step,” because at that point the cell is “committed” to using the raw material to produce the amino acid – is allosterically regulated by the amino acid itself. c. So when there is a lot of taurine in a cell that isn’t being used, for example, that serine will bind to the first enzyme in the pathway that makes more serine. As a result, more serine will not be made until the cell’s serine levels drop. d. In this way, cells ensure that raw materials are available for making the amino acids they need – and that they are not consumed by making amino acids they don’t need.
- 25. ● Prevents dangerousbuild up: ○ The end products of some biochemical pathways can actually be dangerous in high concentrations. ○ Example is cholesterol ● Maintain homeostasis: ○ An essential function of life is the ability to maintain constant internal circumstances in the face of changing environmental circumstances. ○ Some chemical messengers that are involved in maintaining homeostasis are regulated through feedback regulation.
- 26. Examples of FeedbackInhibition 1. Production of ATP a. ATP is created from glucose through various enzymatic reactions in our cells. b. To control the amount of glucose that is broken down to produce ATP, the first enzyme in this breakdown chain is allosterically regulated by ATP. c. If ATP binds to this enzyme, it will not break down further glucose which in turn will allow cells to produce lots of ATP in circumstances where ATP is being used quickly, meaning it is depleted. d. This will then produce little in circumstances where little ATP is needed, leading to a buildup of ATP within the cell. e. In this way our bodies make very efficient use of their energy, storing it in the stable form of glucose until it is needed.
- 27. 3. Production ofCholesterol a. Cholesterol is used in cell membranes, where it helps to maintain the integrity of the cell membrane and facilitate signaling between cells. b. In the case of cholesterol, allosteric regulation is of a transcription factor that leads to more cholesterol-producing enzyme being made. c. When a lot of cholesterol is present in the blood, no new cholesterol-producing enzyme is made, which leads to a fall in cholesterol over time. d. Some cases of dangerously high cholesterol are caused by failure of this feedback inhibition mechanism, resulting in large amounts of cholesterol being made by the liver even though there is already a large amount of cholesterol present in the body.
- 28. Allosteric Enzyme Regulation Itis a type of non-competitive enzyme regulation. Allosteric Inhibition: When an inhibitor binds to the enzyme, all the active sites of the protein complex of the enzyme undergo conformational changes so that the activity of the enzyme decreases. Inhibitor molecules bind to an enzyme at the allosteric site. The binding causes conformational change at the enzyme’s active site which stops binding with the substrate. This prevents the enzyme from lowering the activation energy of the reaction, and the reaction rate is reduced. Allosteric Activation: When an activator binds, it increases the function of active sites and results in increased binding of substrate molecules. Allosteric activators can also bind to the allosteric sites of an enzyme. Once these molecules bind they increase reaction rates of the enzymes. They bind to an allosteric site which induces a conformational change that increases the affinity of the enzyme’s active site for its substrate.
- 30. Allosteric Enzyme Properties Allostericenzymes have an additional site apart from the active/substrate site of a typical enzyme. The substrate-binding site is known as C-subunit or the catalytic subunit and effector binding site is known as R- subunit or regulatory subunit. There can be more than one allosteric sites present in an enzyme molecule.
- 31. They have anability to respond to multiple conditions, that influence the biological reactions The binding molecule is called an effector, it can be inhibitor as well as activator The rate of the reaction vs substrate concentration graph of allosteric enzymes is S-curve as compared to the usual hyperbolic curve
- 32. Allosteric Regulation Mechanism Thereare two types of allosteric regulation on the basis of substrate and effector molecules: Homotropic Regulation: Here, the substrate molecule acts as an effector also. It is mostly enzyme activation and also called cooperativity, e.g. binding of oxygen to haemoglobin. Heterotropic Regulation: When the substrate and effector are different. The effector may activate or inhibit the enzyme, e.g. binding of CO2 to haemoglobin.
- 33. There are twomodels proposed for the mechanism of regulation of allosteric enzymes: Simple Sequential Model- In this model there are still 2 conformations but the subunits can undergo conformational change individually. Concerted Model- In this model an allosteric enzyme can exist in only 2 conformations either active or inactive.
- 34. Examples 1) 2,3-BPG bindsto an allosteric site on hemoglobin,which leads to a decrease in the affinity for oxygen on all subunits. 1) Another example is strychnine (poison), which acts as an allosteric inhibitor of the glycine receptor. Strychnine acts on the allosteric site of the glycine receptor. Its binding lowers the affinity of the glycine receptor for glycine. Thus, strychnine inhibits the action, leading to convulsions.
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