Enzyme feedback inhibition, figure

Figure 9-4. Sites of feedback inhibition in a branched biosynthetic pathway. Si-Sj are intermediates in the biosynthesis of end products A-D. Straight arrows represent enzymes catalyzing the indicated conversions. Curved arrows represent feedback loops and indicate sites of feedback inhibition by specific end products.

Figure 9-5. Multiple feedback inhibition in a branched biosynthetic pathway. Superimposed on simple feedback loops (dashed, curved arrows) are multiple feedback loops (solid, curved arrows) that regulate enzymes common to biosynthesis of several end products.

Fig. 2.2. Feedback inhibition of a metabolic pathway. In feedback inhibition, the final product, E, of a metabolic path acts as an inhibitor of an early reaction in a cycle, which in the figure leads eventually to the formation of E with the aid of enzymes El, E2, etc. E acts as an effector on the enzymes El and E2 to inhibit their activity.

FIGURE 6-28 Feedback inhibition. The conversion of L-threonine to L-isoleucine is catalyzed by a sequence of five enzymes (E, to E5). Threonine dehydratase (E,) is specifically inhibited allosterically by L-isoleucine, the end product of the sequence, but not by any of the four intermediates (A to D). Feedback inhibition is indicated by the dashed feedback line and the symbol at the threonine dehydratase reaction arrow, a device used throughout this book. 

The most responsive regulation of amino acid synthesis takes place through feedback inhibition of the first reaction in a sequence by the end product of the pathway. This first reaction is usually irreversible and catalyzed by an allosteric enzyme. As an example, Figure 22-21 shows the allosteric regulation of isoleucine synthesis from threonine (detailed in Fig. 22-15). The end product, isoleucine, is an allosteric inhibitor of the first reaction in the sequence. In bacteria, such allosteric modulation of amino acid synthesis occurs as a minute-to-minute response. 

Heterotropic effectors The effector may be different from the substrate, in which case the effect is said to be heterotropic. For example, consider the feedback inhibition shown in Figure 5.17. The enzyme that converts A to B has an allosteric site that binds the end-product, E. If the concentration of E increases (for example, because it is not used as rapidly as it is synthesized), the initial enzyme in the pathway is inhibited. Feedback inhibition provides the cell with a product it needs by regulating the flow of substrate molecules through the pathway that synthesizes that product. [Note Heterotropic effectors are commonly encountered, for example, the glycolytic enzyme phosphofructokinases allosterically inhibited by citrate, which is not a substrate for the enzyme (see p. 97).]... 

Probably the most common and widespread control mechanisms in cells are allosteric inhibition and allosteric activation. These mechanisms are incorporated into metabolic pathways in many ways, the most frequent being feedback inhibition. This occurs when an end product of a metabolic sequence accumulates and turns off one or more enzymes needed for its own formation. It is often the first enzyme unique to the specific biosynthetic pathway for the product that is inhibited. When a cell makes two or more isoenzymes, only one of them may be inhibited by a particular product. For example, in Fig. 11-1 product P inhibits just one of the two isoenzymes that catalyzes conversion of A to B the other is controlled by an enzyme modification reaction. In bacteria such as E. coli, three isoenzymes, which are labeled I, II, and III in Fig. 11-3, convert aspartate to (3-aspartyl phosphate, the precursor to the end products threonine, isoleucine, methionine, and lysine. Each product inhibits only one of the isoenzymes as shown in the figure. 

Figure 11-3 Feedback inhibition of enzymes involved in the biosynthesis of threonine, isoleucine, methionine, and lysine in E. coli. These amino acids all arise from L-aspartate, which is formed from oxaloacetate generated by the biosynthetic reactions of the citric acid cycle (Fig. 10-6). Allosteric inhibition. Q Repression of transcription of the enzyme or of its synthesis on ribosomes.

FIGURE 3.3 L-Phenylalanine-mediated feedback inhibition of wild-type Escherichia coli K12 prephenate dehydratase (JN302) and four feedback inhibition-resistant enzyme variants (JN305-JN308). Activity is expressed as a percentage of normal wild-type enzyme activity. 

In this experiment we will examine some of the properties of the aspartate transcarbamylase of Escherichia coli, which is typical of many enzymes subject to feedback inhibition and which has been studied extensively. Aspartate transcarbamylase (ATCase) catalyzes the first reaction unique to the biosynthesis of pyrimidine nucleotides. ATCase is subject to specific inhibition by quite low concentrations of one of its end products, cytidine 5 -triphosphate (CTP). This relationship and two other regulatory interactions important to the control of pyrimidine biosynthesis are summarized in Figure 9-1. 

Figure 9-1 Sites of feedback inhibition in carbamyl phosphate metabolism of E. coli. Note that aspartate trascarbamylase is the first enzyme on the unique pathway to pyrimidine compounds.

Sophisticated regulation can also evolve by duplication of the genes encoding the biosynthetic enzymes. For example, the phosphorylation of aspartate is the committed step in the biosynthesis of threonine, methionine, and lysine. Three distinct aspartokinases catalyze this reaction in E. coli, an example of a regulatory mechanism called enzyme multiplicity. (Figure 24.24). The catalytic domains of these enzymes show approximately 30% sequence identity. Although the mechanisms of catalysis are essentially identical, their activities are regulated differently one enzyme is not subject to feedback inhibition, another is inhibited by threonine, and the third is inhibited by lysine. 

The activity of glutamine synthetase is also controlled by reversible covalent modification —the attachment of an AMP unit by a phosphodiester bond to the hydroxyl group of a specific tyrosine residue in each subunit (Figure 24.26). This adenylylated enzyme is less active and more susceptible to cumulative feedback inhibition than is the deadenylylated form. The covalently attached AMP unit is removed from the adenylylated enzyme by phosphorolysis. The attachment of an AMP unit is the final step in an enzymatic cascade that is initiated several steps back by reactants and immediate products in glutamine synthesis. 

The answer is c. (Murray, pp 375-401. Scriver, pp 2513-2570. Sack, pp 121-138. Wilson, pp 287-320.) The steps of pyrimicfine nucleotide biosynthesis are summarized in the figure below. The first step in pyrimidine synthesis is the formation of carbamoyl phosphate. The enzyme catalyzing this step, carbamoyl phosphate synthetase (1), is feedback-inhibited by UMP through allosteric effects on enzyme structure (not by competitive inhibition with its substrates). The enzyme of the second step, aspartate transcarbamoylase, is composed of catalytic and regulatory subunits. The regulatory subunit binds CTP or ATP TTP has no role in the feedback inhibition of pyrimidine synthesis. Decreased rather than increased activity of enzymes 1 and 2 would be produced by allosteric feedback inhibition. 

Serine is synthesized in a direct pathway from glycerate-3-phosphate that involves dehydrogenation, transamination, and hydrolysis by a phosphatase (Figure 14.6). Cellular serine concentration controls the pathway through feedback inhibition of phosphoglycerate dehydrogenase and phosphoserine phosphatase. The latter enzyme catalyzes the only irreversible step in the pathway. 

In addition, feedback inhibition has two other characteristics that would be unlikely to arise haphazardly in longer pathways there is often very little structural resemblance between the end product that inhibits and the substrate of the inhibited enzyme and the inhibition is usually cooperative. Let us consider what these two properties mean. When inhibition arises for no obvious biological reason, it is usually for an obvious enough chemical reason the substrate and inhibitor are similar enough in terms of chemical structure that the inhibitor can bind to the same site on the enzyme as the one where the substrate binds however, as it lacks some feature necessary for the chemical reaction it does not react but does nothing. A classical example is provided by the enzyme succinate dehydrogenase, which uses succinate as its substrate but is inhibited by malonate (Figure 10.3). Succinate and malonate have almost the same chemical structures, so either is likely to bind to a site intended for... 

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