Feedback Regulation Biochemistry PDF

# Feedback Regulation ## Introduction * Enzyme reaction rate (*V₀*) and maximum reaction rate (*V*_max) are affected by the total concentration of enzyme present ([*E*_tot]). * In living cells, [*E*_tot] depends on expression level. * By altering an enzyme's rate of s...

# Feedback Regulation ## Introduction * Enzyme reaction rate (*V₀*) and maximum reaction rate (*V*_max) are affected by the total concentration of enzyme present ([*E*_tot]). * In living cells, [*E*_tot] depends on expression level. * By altering an enzyme's rate of synthesis or degradation, a cell can alter enzyme amount and therefore control (or regulate) enzyme activity. * Regulation of activity through enzyme synthesis and degradation is slow and energetically costly. * Many enzymes are regulated by small molecules or by post-translational modifications, which allow for quick changes in enzyme activity. * This chapter discusses the various ways enzyme activity is regulated outside of enzyme expression. * The first lesson of this chapter details the phenomenon of feedback regulation. * For a deeper exploration of regulation through expression level, see Biology Chapter 2. ## 6.1.01 Overview of Feedback Regulation * One of the fundamental ways an organism regulates an enzyme's net reaction rate is through its substrates or products. * As the products of a reaction accumulate, the need for the reaction to occur generally decreases, so the net reaction rate tends to decrease. * Conversely, if product levels decrease, the net reaction rate typically increases. * This type of self-regulation is an application of the law of mass action and Le Châtelier's principle. * Self-regulation of the net reaction rate, however, applies only to reversible enzymes, which operate near equilibrium. * The rate and direction of irreversible enzymes, on the other hand, are less affected by relative substrate and product concentrations. * Because these enzymes act far from equilibrium, the reverse reaction is unlikely to occur, so a buildup of products will not cause the net rate to change significantly. * To avoid buildup of potentially toxic intermediates or the wasting of resources, irreversible enzymes require separate mechanisms to quickly slow their activity once sufficient product has been made (Figure 6.1). ## 6.1.02 Allosteric Regulation * Allosteric effectors bind enzymes at a site separate from the active site. * The feedback inhibitors described in Concept 6.1.01 and most of the reversible inhibitors described in Lesson 5.4 are examples of small-molecule allosteric inhibitors. * However, allosteric effectors can also stimulate or activate enzymes, and the effectors can be small molecules, large proteins, or any other molecule that binds to the target enzyme (Figure 6.4). ## 6.1.03 Characteristics of Regulated Enzymes * Many metabolic pathways contain multiple enzymes that catalyze irreversible reactions. * These enzymes typically show at least some level of regulation, certain irreversible enzymes are subject to stricter regulation than other irreversible enzymes. * Regulation of these enzymes can come from feedback inhibition, as well as other types of regulation discussed later in this chapter, such as post-translational modifications (Lesson 6.2). * The enzymes that are most regulated tend to act early in a metabolic pathway and commit the metabolites to the pathway. * For example, glycolysis contains three enzymes that catalyze irreversible reactions: hexokinase, phosphofructokinase-1, and pyruvate kinase. Of these, phosphofructokinase-1 (PFK1) is the most tightly regulated. * PFK1 is the third step (ie, third enzyme) of the 10-step glycolytic pathway and is therefore an early step of the process. * If pyruvate kinase (step 10) were feedback inhibited but PFK1 were not, then the metabolites between them would build up. * This would result in wasted energy as those metabolites have been committed to glycolysis (ie, the metabolites are unlikely to proceed down any other useful pathway except for glycolysis), but they cannot finish the pathway. * Although PFK1 is an early step of glycolysis, it is not the first irreversible step. * Hexokinase catalyzes the first step of the glycolytic pathway, but its product (glucose 6-phosphate) can proceed down many pathways (eg, the pentose phosphate pathway, glycogen synthesis [see Unit 4]). * Consequently, although hexokinase catalyzes the first step in glycolysis, the subsequent metabolites are not committed to glycolysis, and hexokinase is a less useful enzyme to target to regulate glycolysis (Figure 6.7). ## 6.1.04 Positive Feedback * In addition to feedback inhibition (also known as negative feedback), another type of feedback regulation, called positive feedback, also exists. * Like feedback inhibition, positive feedback occurs when a product molecule feeds backward to regulate an earlier enzyme. * However, for positive feedback regulation, the product molecule stimulates or activates the enzyme. * Positive feedback regulation is also known as feedback activation. * Feedback activation is used when the presence of a product molecule indicates that more, not less, product is required, as in activation of digestive enzymes such as pepsin or in the clotting cascade (see Figure 6.8). ## 6.1.05 Feedforward Activation * Enzymes are also sometimes controlled by feedforward regulation. * In contrast to feedback regulation, feedforward regulation occurs when a product feeds forward and regulates a later step. * In metabolic pathways, this type of regulation is typically stimulatory and is known as feedforward activation. * Feedforward activation can help minimize buildup of metabolites that have already been committed to a certain pathway. * For example, although PFK1 is the most tightly regulated enzyme of glycolysis because it is the earliest committed enzyme, pyruvate kinase is also an irreversible enzyme that catalyzes a committed step of glycolysis. * To prevent a wasteful buildup of the metabolites between PFK1 and pyruvate kinase, the immediate product of PFK1 (ie, fructose 1,6-bisphosphate) can feed forward to activate pyruvate kinase. * This process of feedforward activation helps to ensure that pyruvate kinase activity is sufficiently high to keep up with PFK1 activity (see Figure 6.9).