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Feedback Inhibition Biol 724 - Biosystems Control of Enzymes in Metabolic Pathways Feedback Inhibition The first example of feedback inhibition identified in a metabolic pathway concerned the inhibition of the first enzyme in the biosynthetic pathway to the amino acid isoleucine. Threonine deaminase is specifically and strongly inhibited by isoleucine. The structurally similar amino acids leucine and valine are not effective inhibitors of the enzyme. Feedback loops on the first enzyme of a pathway are a common structural feature of metabolism. Enzyme-1 Enzyme-2 Enzyme-3 Enzyme-4 Substrate Intermediate-1 Intermediate-2 Intermediate-3 Product Inhibition Biosynthetic pathways are often branched - the early part of the pathway leads ultimately to two or more end products: Intermediate-2 Intermediate-3 Product-1 Substrate Intermediate-1 Intermediate-4 Intermediate-5 Product-2 The regulation of branched pathways has to cope with differential variations in the net demand for the different end products. There are two basic models for feedback control in such branched pathways - nested and sequential feedback. -ve Intermediate-2 Intermediate-3 Product-1 -ve Substrate Intermediate-1 -ve Intermediate-4 Intermediate-5 Product-2 -ve Nested feedback inhibition in a branched metabolic pathway. -ve Intermediate-2 Intermediate-3 Product-1 Substrate Intermediate-1 -ve Intermediate-4 Intermediate-5 Product-2 -ve Sequential feedback inhibition in a branched metabolic pathway. Sequential feedback inhibition in the pathways synthesizing the aromatic amino acids tryptophan, tyrosine and phenylalanine in Bacillus subtilis. The final common intermediate of this pathway is a mixture of chorismate and prephenate. These intermediates can inhibit the first step in their synthesis, the joining of phosphoenolpyruvate and the 4-carbon sugar erythrose 4-phosphate. In contrast, none of the aromatic amino acids inhibit this step. Each of them specifically inhibits the first step of its own branch. Sequential systems like this are regarded as being reliable in that they generally behave as required when the source and end product metabolites vary. Nested feedback inhibition can be subdivided into several types: 1. Enzyme Multiplicity A method of ensuring that the inhibited step in a common pathway responds to each of the end products, without any one of them having too powerful an effect is to have separate isoenzymes, each of which is inhibited by just one of the end products. This is seen in the synthesis of threonine and lysine from aspartate in E. coli where there are separate aspartate kinase isoenzymes inhibited by each product. 2. Concerted Feedback Inhibition Concerted feedback inhibition is a form of nested feedback inhibition where the enzyme in the common pathway is not inhibited by either of the products separately. Inhibition by one requires that the other be present. -ve Intermediate-2 Intermediate-3 Product-1 Substrate Intermediate-1 -ve Intermediate-4 Intermediate-5 Product-2 -ve If the inhibition by the product in excess were stronger than necessary, the consequent tendency of the concentration of the other product to drop would be limited by its fall causing a weakening of the inhibition by the one in excess. This type of inhibition occurs in threonine and lysine synthesis in Bacillus polymyxa, which does not have the multiple aspartate kinase isoenzymes seen in E. coli. 3. Cumulative Feedback Inhibition This is nested feedback inhibition where the inhibition of the common enzyme in the presence of both end products is greater than that caused by either separately; however, this greater inhibition is exactly that expected from the combination of the effects of each when they act independently. This is the case for glutamine synthase from E. coli. Glutamine is the common nitrogen-containing metabolite of a number of diverging pathways. Each of the end products of these pathways has a separate inhibition site on the enzyme, each of which separately causes only partial inhibition even at saturating concentrations of the inhibitor. However, together the effects are cumulative causing almost complete inhibition. 4. Synergistic Feedback Inhibition Synergistic feedback inhibition is intermediate between concerted and cumulative feedback inhibition. Each end product exhibits some partial inhibition on its own, but the inhibition by both end products together is much greater than would be expected for cumulative inhibition i.e. there is interaction between the separate inhibition sites. Synergistic inhibition is observed in purine biosynthesis on the first enzyme of the common pathway to AMP and GMP. This allosteric enzyme has separate inhibitory sites for AMP and GMP, but both of them together interact to cause greater inhibition than would be expected. Synergistic inhibition in purine biosynthesis. Substrate or ‘Futile’ Cycles A substrate cycle can exist wherever a reaction (or set of reactions) that converts intermediate I1 into I2 is opposed by a second (different) reaction that converts I2 to I1. If both sets of reactions are simultaneously active, then there can be a cyclic flux whereby the I1 that is converted to I2 reverts to I1. Enzyme-1 Substrate Intermediate-1 Intermediate-2 Product Enzyme-2 Both sets of reactions must be intrinsically favourable and for this to be the case, at least one of the sets must be coupled to some other exergonic process (usually phosphorylation by ATP). Hence the cyclic flow leads to no net change other than the dissipation of energy by a net flux through the coupled process that drives the cycle. The substrate cycles of glycolysis/gluconeogenesis The substrate cycles of glycolysis/gluconeogenesis Flight muscle of bumble bees. The fructose 6-phosphate: fructose 1,6-bisphosphate cycle is used by bumble bees to raise the temperature of their flight muscles in cold weather. Insect PFK F 1,6 bisPase (mmol/min/g) (mmol/min/g) Bumble Bee: Worker 56 73 Male 40 77 Queen 26 25 Honey Bee: Worker 30 0.05 Cuckoo Bumble Bee: Male 16 1.8 Queen 16 2.2 Sensitivity of Control It has been proposed that substrate cycles can increase the sensitivity of the regulation of pathway flux by an effector acting on one or both of the pathway enzymes. However, it appears that the conditions under which substrate cycles can generate increased sensitivity are quite restrictive. Condition Glycolytic Flux Fold (mmoles/min/g) Increase Rest 0.03 - 100m Sprint 66 2200 (mainly anaerobic glycolysis) Marathon Run 0.90 30 (glycolysis plus oxidation) If a substrate cycle exists this may explain the dramatic increase in glycolytic flux seen in the sprinter. If flux = 0.03 at rest then: In the sprinter at rest Vf = 0.3 and Vr = 0.27 (i.e. net flux = 0.03) In the marathon runner at rest Vf = 0.04 and Vr = 0.01 (i.e. net flux = 0.03) If at the start of a sprint Vr ~ 0 then. For a sprinter the new net flux = 0.3 For a marathon runner the new net flux = 0.04 i.e. If there is a high rate of cycling at rest then a massive change in flux can occur at the start of a sprint. Marathon runners do not need this massive change in flux. Covalent Modification of Enzymes Irreversible cascades There are many types of post-translational modifications of enzymes. Some of these are irreversible and not primarily mechanisms of control e.g. proteolytic cleavage of inactive precursors (zymogens) is a mechanism for synthesizing and storing potentially hazardous products such as digestive enzymes or blood clotting factors. Activation of blood clotting involves a cascade of zymogens in which each factor, upon activation, proteolytically cleaves the next zymogen in the sequence, until prothrombin is cleaved to thrombin, which cleaves soluble fibrinogen to give the clot-forming fibrin fibres. The sequence shows amplification through using catalysts that create catalysts, and convert the minute initiating signal generated following tissue injury into a major response within a few seconds. However, for the enzymes involved, it is a once-only mechanism as the clotting can only be stopped by their proteolytic inactivation. The blood clotting cascade Cyclic cascades The covalent modifications that play the greatest role in metabolic control are reversible or cyclic, so that the enzyme is interconverted between two forms that differ in activity, either because of effects on the kinetics with respect to substrates or of altered sensitivity to effectors. Summary Enzymes operate in metabolic pathways and overall control of these metabolic pathways can depend upon feedback inhibition of selected enzymes be specific metabolites. Feedback inhibition can be sequential or nested in nature. Nested feedback may be concerted, cumulative or synergistic . The occurrence of ‘substrate’ or ‘futile’ cycles, within metabolic pathways, may have important implications for the overall responsiveness of metabolic pathways to changing demands. Enzyme activity may also be changed by irreversible (e.g. partial proteolysis) or reversible (e.g. phosphorylation/ dephosphorylation) covalent modification..
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