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Cell_Biology_Alberts_610	Cell_Biology_Alberts	of the enzyme, [Eo], and the concentration of the substrate, [S]? When enzyme and substrate are frst mixed, the concentration [ES] will rise rapidly from zero to a so-called steady-state level, as illustrated below. E + S E + P ES k1 k–1 kcat V = kcat [ES]	Cell_Biology_Alberts. of the enzyme, [Eo], and the concentration of the substrate, [S]? When enzyme and substrate are frst mixed, the concentration [ES] will rise rapidly from zero to a so-called steady-state level, as illustrated below. E + S E + P ES k1 k–1 kcat V = kcat [ES]
Cell_Biology_Alberts_611	Cell_Biology_Alberts	At this steady state, [ES] is nearly constant, so that or, since the concentration of the free enzyme, [E], is equal to [Eo] – [ES], Rearranging, and defning the constant Km as we get or, remembering that V = kcat [ES], we obtain the famous Michaelis–Menten equation As [S] is increased to higher and higher levels, essentially all of the enzyme will be bound to substrate at steady state; at this point, a maximum rate of reaction, Vmax , will be reached where V = Vmax = kcat [Eo]. Thus, it is convenient to rewrite the Michaelis–Menten equation as rate of ES formation k1 [E][S] rate of ES breakdown k–1 [ES] + kcat [ES] = k1 k–1 + kcat [ES] = [E][S] = [Eo] – [ES] [S] k1 k–1 + kcat k1 k–1 + kcat Km + [S] kcat [Eo][S] [ES] = [Eo][S] Km + [S] V = Km + [S] Vmax [S]V = THE DOUBLE-RECIPROCAL PLOT A typical plot of V versus [S] for an enzyme that follows Michaelis–Menten kinetics is shown below. From this plot, neither the value of Vmax nor of Km is immediately clear.	Cell_Biology_Alberts. At this steady state, [ES] is nearly constant, so that or, since the concentration of the free enzyme, [E], is equal to [Eo] – [ES], Rearranging, and defning the constant Km as we get or, remembering that V = kcat [ES], we obtain the famous Michaelis–Menten equation As [S] is increased to higher and higher levels, essentially all of the enzyme will be bound to substrate at steady state; at this point, a maximum rate of reaction, Vmax , will be reached where V = Vmax = kcat [Eo]. Thus, it is convenient to rewrite the Michaelis–Menten equation as rate of ES formation k1 [E][S] rate of ES breakdown k–1 [ES] + kcat [ES] = k1 k–1 + kcat [ES] = [E][S] = [Eo] – [ES] [S] k1 k–1 + kcat k1 k–1 + kcat Km + [S] kcat [Eo][S] [ES] = [Eo][S] Km + [S] V = Km + [S] Vmax [S]V = THE DOUBLE-RECIPROCAL PLOT A typical plot of V versus [S] for an enzyme that follows Michaelis–Menten kinetics is shown below. From this plot, neither the value of Vmax nor of Km is immediately clear.
Cell_Biology_Alberts_612	Cell_Biology_Alberts	THE SIGNIFICANCE OF Km, kcat, and kcat /Km As described in the text, Km is an approximate measure of substrate affnity for the enzyme: it is numerically equal to the concentration of [S] at V = 0.5 Vmax. In general, a lower value of Km means tighter substrate binding. In fact, for those cases where kcat is much smaller than k–1, the Km will be equal to Kd, the dissociation constant for substrate binding to the enzyme (Kd = 1/Ka; see Figure 3–44). We have seen that k cat is the turnover number for the enzyme. At very low substrate concentrations, where 20 0 0 2 4 6 8 40 60 80 [S] mmole/liter To obtain Vmax and Km from such data, a double-reciprocal [S] << Km, most of the enzyme is free. Thus we can think of [E] = [Eo], so that the Michaelis–Menten equation becomes V = kcat/Km [E][S]. Thus, the ratio kcat/Km is equivalent to the rate constant for the reaction between free enzyme and free substrate. A comparison of kcat/Km for the same enzyme with different substrates, or for two enzymes	Cell_Biology_Alberts. THE SIGNIFICANCE OF Km, kcat, and kcat /Km As described in the text, Km is an approximate measure of substrate affnity for the enzyme: it is numerically equal to the concentration of [S] at V = 0.5 Vmax. In general, a lower value of Km means tighter substrate binding. In fact, for those cases where kcat is much smaller than k–1, the Km will be equal to Kd, the dissociation constant for substrate binding to the enzyme (Kd = 1/Ka; see Figure 3–44). We have seen that k cat is the turnover number for the enzyme. At very low substrate concentrations, where 20 0 0 2 4 6 8 40 60 80 [S] mmole/liter To obtain Vmax and Km from such data, a double-reciprocal [S] << Km, most of the enzyme is free. Thus we can think of [E] = [Eo], so that the Michaelis–Menten equation becomes V = kcat/Km [E][S]. Thus, the ratio kcat/Km is equivalent to the rate constant for the reaction between free enzyme and free substrate. A comparison of kcat/Km for the same enzyme with different substrates, or for two enzymes
Cell_Biology_Alberts_613	Cell_Biology_Alberts	the ratio kcat/Km is equivalent to the rate constant for the reaction between free enzyme and free substrate. A comparison of kcat/Km for the same enzyme with different substrates, or for two enzymes with their different substrates, is widely used as a measure of enzyme effectiveness. For simplicity, in this Panel we have discussed enzymes that have only one substrate, such as the lysozyme enzyme described in the text (see p. 144). Most enzymes have two substrates, one of which is often an active carrier	Cell_Biology_Alberts. the ratio kcat/Km is equivalent to the rate constant for the reaction between free enzyme and free substrate. A comparison of kcat/Km for the same enzyme with different substrates, or for two enzymes with their different substrates, is widely used as a measure of enzyme effectiveness. For simplicity, in this Panel we have discussed enzymes that have only one substrate, such as the lysozyme enzyme described in the text (see p. 144). Most enzymes have two substrates, one of which is often an active carrier
Cell_Biology_Alberts_614	Cell_Biology_Alberts	SOME ENZYMES ARE DIFFUSION LIMITED The values of kcat, Km, and kcat /Km for some selected molecule—such as NADH or ATP. A similar, but more complex, analysis is used to determine the kinetics of such enzymes—allowing the order of substrate binding and the presence of covalent intermediates along the pathway to be revealed.	Cell_Biology_Alberts. SOME ENZYMES ARE DIFFUSION LIMITED The values of kcat, Km, and kcat /Km for some selected molecule—such as NADH or ATP. A similar, but more complex, analysis is used to determine the kinetics of such enzymes—allowing the order of substrate binding and the presence of covalent intermediates along the pathway to be revealed.
Cell_Biology_Alberts_615	Cell_Biology_Alberts	plot is often used, in which the Michaelis–Menten equation has merely been rearranged, so that 1/V can be plotted versus 1/ [S]. 1/V= + 1/ Vmax Km Vmax [S] 1 123468 1 Vmax 0.01 0.02 0.03 0.04 slope = KM / Vmax 1/V (second/µmole) enzymes are given below: Because an enzyme and its substrate must collide before they can react, kcat /Km has a maximum possible value that is limited by collision rates. If every collision forms an enzyme–substrate complex, one can calculate from diffusion theory that kcat /Km will be between 108 and 109 sec–1M–1, in the case where all subsequent steps proceed immediately. – 0.25 0 0.25 0.5 0.75 1.0– 0.5 fumarase fumarate 8x102 5x10–6 1.6x108 catalase H2O2 4x107 1 4x107 acetylcholinesterase acetylcholine 1.4x104 9x10–5 1.6x108 enzyme substrate kcat (sec–1) kcat/Km (sec–1M–1) Km (M)	Cell_Biology_Alberts. plot is often used, in which the Michaelis–Menten equation has merely been rearranged, so that 1/V can be plotted versus 1/ [S]. 1/V= + 1/ Vmax Km Vmax [S] 1 123468 1 Vmax 0.01 0.02 0.03 0.04 slope = KM / Vmax 1/V (second/µmole) enzymes are given below: Because an enzyme and its substrate must collide before they can react, kcat /Km has a maximum possible value that is limited by collision rates. If every collision forms an enzyme–substrate complex, one can calculate from diffusion theory that kcat /Km will be between 108 and 109 sec–1M–1, in the case where all subsequent steps proceed immediately. – 0.25 0 0.25 0.5 0.75 1.0– 0.5 fumarase fumarate 8x102 5x10–6 1.6x108 catalase H2O2 4x107 1 4x107 acetylcholinesterase acetylcholine 1.4x104 9x10–5 1.6x108 enzyme substrate kcat (sec–1) kcat/Km (sec–1M–1) Km (M)
Cell_Biology_Alberts_616	Cell_Biology_Alberts	Thus, it is claimed that enzymes like acetylcholinesterase and1 liter/mmole fumarase are “perfect enzymes,” each enzyme having evolved to the point where nearly every collision with its substrate converts the substrate to a product. [S] Km Figure 3–47 enzymatic acceleration of chemical reactions by decreasing the activation energy. There is a single transition state in this example. However, often both the uncatalyzed reaction (A) and the enzyme-catalyzed reaction (B) go through a series of transition states. In that case, it is the transition state with the highest energy (ST and EST) that determines the activation energy and limits the rate of the reaction. (S = substrate; P = product of the reaction; ES = enzyme–substrate complex; EP = enzyme– product complex.) Because this tight binding greatly lowers the energy of the transition state, the enzyme greatly accelerates a particular reaction by lowering the activation energy that is required (Figure 3–47).	Cell_Biology_Alberts. Thus, it is claimed that enzymes like acetylcholinesterase and1 liter/mmole fumarase are “perfect enzymes,” each enzyme having evolved to the point where nearly every collision with its substrate converts the substrate to a product. [S] Km Figure 3–47 enzymatic acceleration of chemical reactions by decreasing the activation energy. There is a single transition state in this example. However, often both the uncatalyzed reaction (A) and the enzyme-catalyzed reaction (B) go through a series of transition states. In that case, it is the transition state with the highest energy (ST and EST) that determines the activation energy and limits the rate of the reaction. (S = substrate; P = product of the reaction; ES = enzyme–substrate complex; EP = enzyme– product complex.) Because this tight binding greatly lowers the energy of the transition state, the enzyme greatly accelerates a particular reaction by lowering the activation energy that is required (Figure 3–47).
Cell_Biology_Alberts_617	Cell_Biology_Alberts	Because this tight binding greatly lowers the energy of the transition state, the enzyme greatly accelerates a particular reaction by lowering the activation energy that is required (Figure 3–47). Figure 3–48 compares the spontaneous reaction rates and the corresponding enzyme-catalyzed rates for five enzymes. Rate accelerations range from 109 to 1023. Enzymes not only bind tightly to a transition state, they also contain precisely positioned atoms that alter the electron distributions in the atoms that participate directly in the making and breaking of covalent bonds. Peptide bonds, for example, can be hydrolyzed in the absence of an enzyme by exposing a polypeptide to either a strong acid or a strong base. Enzymes are unique, however, in being able to use acid and base catalysis simultaneously, because the rigid framework of the protein constrains the acidic and basic residues and prevents them from combining with each other, as they would do in solution (Figure 3–49).	Cell_Biology_Alberts. Because this tight binding greatly lowers the energy of the transition state, the enzyme greatly accelerates a particular reaction by lowering the activation energy that is required (Figure 3–47). Figure 3–48 compares the spontaneous reaction rates and the corresponding enzyme-catalyzed rates for five enzymes. Rate accelerations range from 109 to 1023. Enzymes not only bind tightly to a transition state, they also contain precisely positioned atoms that alter the electron distributions in the atoms that participate directly in the making and breaking of covalent bonds. Peptide bonds, for example, can be hydrolyzed in the absence of an enzyme by exposing a polypeptide to either a strong acid or a strong base. Enzymes are unique, however, in being able to use acid and base catalysis simultaneously, because the rigid framework of the protein constrains the acidic and basic residues and prevents them from combining with each other, as they would do in solution (Figure 3–49).
Cell_Biology_Alberts_618	Cell_Biology_Alberts	The fit between an enzyme and its substrate needs to be precise. A small change introduced by genetic engineering in the active site of an enzyme can therefore have a profound effect. Replacing a glutamic acid with an aspartic acid in one enzyme, for example, shifts the position of the catalytic carboxylate ion by only 1 Å (about the radius of a hydrogen atom); yet this is enough to decrease the activity of the enzyme a thousandfold.	Cell_Biology_Alberts. The fit between an enzyme and its substrate needs to be precise. A small change introduced by genetic engineering in the active site of an enzyme can therefore have a profound effect. Replacing a glutamic acid with an aspartic acid in one enzyme, for example, shifts the position of the catalytic carboxylate ion by only 1 Å (about the radius of a hydrogen atom); yet this is enough to decrease the activity of the enzyme a thousandfold.
Cell_Biology_Alberts_619	Cell_Biology_Alberts	To demonstrate how enzymes catalyze chemical reactions, we examine an enzyme that acts as a natural antibiotic in egg white, saliva, tears, and other secretions. Lysozyme catalyzes the cutting of polysaccharide chains in the cell walls of bacteria. The bacterial cell is under pressure from osmotic forces, and cutting even a small number of these chains causes the cell wall to rupture and the cell to burst. A relatively small and stable protein that can be easily isolated in large quantities, lysozyme was the first enzyme to have its structure worked out in atomic detail by x-ray crystallography (in the mid-1960s).	Cell_Biology_Alberts. To demonstrate how enzymes catalyze chemical reactions, we examine an enzyme that acts as a natural antibiotic in egg white, saliva, tears, and other secretions. Lysozyme catalyzes the cutting of polysaccharide chains in the cell walls of bacteria. The bacterial cell is under pressure from osmotic forces, and cutting even a small number of these chains causes the cell wall to rupture and the cell to burst. A relatively small and stable protein that can be easily isolated in large quantities, lysozyme was the first enzyme to have its structure worked out in atomic detail by x-ray crystallography (in the mid-1960s).
Cell_Biology_Alberts_620	Cell_Biology_Alberts	The reaction that lysozyme catalyzes is a hydrolysis: it adds a molecule of water to a single bond between two adjacent sugar groups in the polysaccharide chain, thereby causing the bond to break (see Figure 2–9). The reaction is energetically favorable because the free energy of the severed polysaccharide chain is lower progress of reaction activation energy for catalyzed reaction Figure 3–48 The rate accelerations caused by five different enzymes.	Cell_Biology_Alberts. The reaction that lysozyme catalyzes is a hydrolysis: it adds a molecule of water to a single bond between two adjacent sugar groups in the polysaccharide chain, thereby causing the bond to break (see Figure 2–9). The reaction is energetically favorable because the free energy of the severed polysaccharide chain is lower progress of reaction activation energy for catalyzed reaction Figure 3–48 The rate accelerations caused by five different enzymes.
Cell_Biology_Alberts_621	Cell_Biology_Alberts	(Adapted from A. Radzicka and R. Wolfenden, Science 267:90–93, 1995.) catalysis. (A) The start of the uncatalyzed reaction that hydrolyzes a peptide bond, with blue shading used to indicate electron distribution in the water and carbonyl bonds. (B) An acid likes to donate a proton (H+) to other atoms. By pairing with the carbonyl oxygen, an acid causes electrons to move away from the carbonyl carbon, making this atom much more attractive to the electronegative oxygen of an attacking water molecule. (C) A base likes to take up H+. By pairing with a hydrogen of the attacking water molecule, a base causes base catalyses electrons to move toward the water oxygen, making it a better attacking group for the carbonyl carbon. (D) By having appropriately than the free energy of the intact chain. However, there is an energy barrier to the positioned atoms on its surface, an enzyme reaction, and a colliding water molecule can break a bond linking two sugars only if the polysaccharide molecule	Cell_Biology_Alberts. (Adapted from A. Radzicka and R. Wolfenden, Science 267:90–93, 1995.) catalysis. (A) The start of the uncatalyzed reaction that hydrolyzes a peptide bond, with blue shading used to indicate electron distribution in the water and carbonyl bonds. (B) An acid likes to donate a proton (H+) to other atoms. By pairing with the carbonyl oxygen, an acid causes electrons to move away from the carbonyl carbon, making this atom much more attractive to the electronegative oxygen of an attacking water molecule. (C) A base likes to take up H+. By pairing with a hydrogen of the attacking water molecule, a base causes base catalyses electrons to move toward the water oxygen, making it a better attacking group for the carbonyl carbon. (D) By having appropriately than the free energy of the intact chain. However, there is an energy barrier to the positioned atoms on its surface, an enzyme reaction, and a colliding water molecule can break a bond linking two sugars only if the polysaccharide molecule
Cell_Biology_Alberts_622	Cell_Biology_Alberts	However, there is an energy barrier to the positioned atoms on its surface, an enzyme reaction, and a colliding water molecule can break a bond linking two sugars only if the polysaccharide molecule is distorted into a particular shape—the transition state—in which the atoms around the bond have an altered geometry and electron distribution. Because of this requirement, random collisions must supply a very large activation energy for the reaction to take place. In an aqueous solution at room temperature, the energy of collisions almost never exceeds the activation energy. The pure polysaccharide can therefore remain for years in water without being hydrolyzed to any detectable degree.	Cell_Biology_Alberts. However, there is an energy barrier to the positioned atoms on its surface, an enzyme reaction, and a colliding water molecule can break a bond linking two sugars only if the polysaccharide molecule is distorted into a particular shape—the transition state—in which the atoms around the bond have an altered geometry and electron distribution. Because of this requirement, random collisions must supply a very large activation energy for the reaction to take place. In an aqueous solution at room temperature, the energy of collisions almost never exceeds the activation energy. The pure polysaccharide can therefore remain for years in water without being hydrolyzed to any detectable degree.
Cell_Biology_Alberts_623	Cell_Biology_Alberts	This situation changes drastically when the polysaccharide binds to lysozyme. The active site of lysozyme, because its substrate is a polymer, is a long groove that holds six linked sugars at the same time. As soon as the polysaccharide binds to form an enzyme–substrate complex, the enzyme cuts the polysaccharide by adding a water molecule across one of its sugar–sugar bonds. The product chains are then quickly released, freeing the enzyme for further cycles of reaction (Figure 3–50).	Cell_Biology_Alberts. This situation changes drastically when the polysaccharide binds to lysozyme. The active site of lysozyme, because its substrate is a polymer, is a long groove that holds six linked sugars at the same time. As soon as the polysaccharide binds to form an enzyme–substrate complex, the enzyme cuts the polysaccharide by adding a water molecule across one of its sugar–sugar bonds. The product chains are then quickly released, freeing the enzyme for further cycles of reaction (Figure 3–50).
Cell_Biology_Alberts_624	Cell_Biology_Alberts	An impressive increase in hydrolysis rate is possible because conditions are created in the microenvironment of the lysozyme active site that greatly reduce the activation energy necessary for the hydrolysis to take place. In particular, lysozyme distorts one of the two sugars connected by the bond to be broken from its normal, most stable conformation. The bond to be broken is also held close to two amino acids with acidic side chains (a glutamic acid and an aspartic acid) that participate directly in the reaction. Figure 3–51 shows the three central steps in this enzymatically catalyzed reaction, which occurs millions of times faster than uncatalyzed hydrolysis.	Cell_Biology_Alberts. An impressive increase in hydrolysis rate is possible because conditions are created in the microenvironment of the lysozyme active site that greatly reduce the activation energy necessary for the hydrolysis to take place. In particular, lysozyme distorts one of the two sugars connected by the bond to be broken from its normal, most stable conformation. The bond to be broken is also held close to two amino acids with acidic side chains (a glutamic acid and an aspartic acid) that participate directly in the reaction. Figure 3–51 shows the three central steps in this enzymatically catalyzed reaction, which occurs millions of times faster than uncatalyzed hydrolysis.
Cell_Biology_Alberts_625	Cell_Biology_Alberts	Other enzymes use similar mechanisms to lower activation energies and speed up the reactions they catalyze. In reactions involving two or more reactants, the active site also acts like a template, or mold, that brings the substrates together in the proper orientation for a reaction to occur between them (Figure 3–52A). As we saw for lysozyme, the active site of an enzyme contains precisely positioned can perform both acid catalysis and base catalysis at the same time.	Cell_Biology_Alberts. Other enzymes use similar mechanisms to lower activation energies and speed up the reactions they catalyze. In reactions involving two or more reactants, the active site also acts like a template, or mold, that brings the substrates together in the proper orientation for a reaction to occur between them (Figure 3–52A). As we saw for lysozyme, the active site of an enzyme contains precisely positioned can perform both acid catalysis and base catalysis at the same time.
Cell_Biology_Alberts_626	Cell_Biology_Alberts	Figure 3–50 The reaction catalyzed by lysozyme. (A) The enzyme lysozyme (E) catalyzes the cutting of a polysaccharide chain, which is its substrate (S). The enzyme first binds to the chain to form an enzyme–substrate complex (ES) and then catalyzes the cleavage of a specific covalent bond in the backbone of the polysaccharide, forming an enzyme–product complex (EP) that rapidly dissociates. Release of the severed chain (the products P) leaves the enzyme free to act on another substrate molecule. (B) A space-filling model of the lysozyme molecule bound to a short length of polysaccharide chain before cleavage (Movie 3.8). (B, courtesy of Richard J. Feldmann; PDB code: 3AB6.) This substrate is an oligosaccharide of six sugars, The fnal products are an oligosaccharide of four sugars labeled A through F. Only sugars D and E are shown in detail. (left) and a disaccharide (right), produced by hydrolysis.	Cell_Biology_Alberts. Figure 3–50 The reaction catalyzed by lysozyme. (A) The enzyme lysozyme (E) catalyzes the cutting of a polysaccharide chain, which is its substrate (S). The enzyme first binds to the chain to form an enzyme–substrate complex (ES) and then catalyzes the cleavage of a specific covalent bond in the backbone of the polysaccharide, forming an enzyme–product complex (EP) that rapidly dissociates. Release of the severed chain (the products P) leaves the enzyme free to act on another substrate molecule. (B) A space-filling model of the lysozyme molecule bound to a short length of polysaccharide chain before cleavage (Movie 3.8). (B, courtesy of Richard J. Feldmann; PDB code: 3AB6.) This substrate is an oligosaccharide of six sugars, The fnal products are an oligosaccharide of four sugars labeled A through F. Only sugars D and E are shown in detail. (left) and a disaccharide (right), produced by hydrolysis.
Cell_Biology_Alberts_627	Cell_Biology_Alberts	In the enzyme–substrate complex (ES), the The Asp52 has formed a covalent bond between enzyme forces sugar D into a strained the enzyme and the C1 carbon atom of sugar D. conformation. The Glu35 in the enzyme is The Glu35 then polarizes a water molecule (red ), positioned to serve as an acid that attacks the so that its oxygen can readily attack the C1 adjacent sugar–sugar bond by donating a proton carbon atom and displace Asp52. (H+) to sugar E; Asp52 is poised to attack the C1 carbon atom.	Cell_Biology_Alberts. In the enzyme–substrate complex (ES), the The Asp52 has formed a covalent bond between enzyme forces sugar D into a strained the enzyme and the C1 carbon atom of sugar D. conformation. The Glu35 in the enzyme is The Glu35 then polarizes a water molecule (red ), positioned to serve as an acid that attacks the so that its oxygen can readily attack the C1 adjacent sugar–sugar bond by donating a proton carbon atom and displace Asp52. (H+) to sugar E; Asp52 is poised to attack the C1 carbon atom.
Cell_Biology_Alberts_628	Cell_Biology_Alberts	atoms that speed up a reaction by using charged groups to alter the distribution of electrons in the substrates (Figure 3–52B). And as we have also seen, when a substrate binds to an enzyme, bonds in the substrate are often distorted, changing the substrate shape. These changes, along with mechanical forces, drive a substrate toward a particular transition state (Figure 3–52C). Finally, like lysozyme, many enzymes participate intimately in the reaction by transiently forming a covalent bond between the substrate and a side chain of the enzyme. Subsequent steps in the reaction restore the side chain to its original state, so that the enzyme remains unchanged after the reaction (see also Figure 2–48). Tightly Bound Small Molecules Add Extra Functions to Proteins	Cell_Biology_Alberts. atoms that speed up a reaction by using charged groups to alter the distribution of electrons in the substrates (Figure 3–52B). And as we have also seen, when a substrate binds to an enzyme, bonds in the substrate are often distorted, changing the substrate shape. These changes, along with mechanical forces, drive a substrate toward a particular transition state (Figure 3–52C). Finally, like lysozyme, many enzymes participate intimately in the reaction by transiently forming a covalent bond between the substrate and a side chain of the enzyme. Subsequent steps in the reaction restore the side chain to its original state, so that the enzyme remains unchanged after the reaction (see also Figure 2–48). Tightly Bound Small Molecules Add Extra Functions to Proteins
Cell_Biology_Alberts_629	Cell_Biology_Alberts	Tightly Bound Small Molecules Add Extra Functions to Proteins Although we have emphasized the versatility of enzymes—and proteins in general—as chains of amino acids that perform remarkable functions, there are many instances in which the amino acids by themselves are not enough. Just as humans The reaction of the water molecule (red) completes the hydrolysis and returns the enzyme to its initial state, forming the fnal enzyme– product complex (EP).	Cell_Biology_Alberts. Tightly Bound Small Molecules Add Extra Functions to Proteins Although we have emphasized the versatility of enzymes—and proteins in general—as chains of amino acids that perform remarkable functions, there are many instances in which the amino acids by themselves are not enough. Just as humans The reaction of the water molecule (red) completes the hydrolysis and returns the enzyme to its initial state, forming the fnal enzyme– product complex (EP).
Cell_Biology_Alberts_630	Cell_Biology_Alberts	The reaction of the water molecule (red) completes the hydrolysis and returns the enzyme to its initial state, forming the fnal enzyme– product complex (EP). Figure 3–51 events at the active site of lysozyme. The top left and top right drawings show the free substrate and the free products, respectively, whereas the other three drawings show the sequential events at the enzyme active site. Note the change in the conformation of sugar D in the enzyme–substrate complex; this shape change stabilizes the oxocarbenium ion-like transition states required for formation and hydrolysis of the covalent intermediate shown in the middle panel. It is also possible that a carbonium ion intermediate forms in step 2, but the covalent intermediate shown in the middle panel has been detected with a synthetic substrate (Movie 3.9). (See D.J. Vocadlo et al., Nature 412:835–838, 2001.)	Cell_Biology_Alberts. The reaction of the water molecule (red) completes the hydrolysis and returns the enzyme to its initial state, forming the fnal enzyme– product complex (EP). Figure 3–51 events at the active site of lysozyme. The top left and top right drawings show the free substrate and the free products, respectively, whereas the other three drawings show the sequential events at the enzyme active site. Note the change in the conformation of sugar D in the enzyme–substrate complex; this shape change stabilizes the oxocarbenium ion-like transition states required for formation and hydrolysis of the covalent intermediate shown in the middle panel. It is also possible that a carbonium ion intermediate forms in step 2, but the covalent intermediate shown in the middle panel has been detected with a synthetic substrate (Movie 3.9). (See D.J. Vocadlo et al., Nature 412:835–838, 2001.)
Cell_Biology_Alberts_631	Cell_Biology_Alberts	Figure 3–52 Some general strategies of enzyme catalysis. (A) Holding substrates (A) enzyme binds to two (B) binding of substrate (C) enzyme strains the together in a precise alignment. (B) Charge substrate molecules and to enzyme rearranges bound substrate stabilization of reaction intermediates. orients them precisely to electrons in the substrate, molecule, forcing it encourage a reaction to creating partial negative toward a transition (C) Applying forces that distort bonds in the occur between them and positive charges state to favor a reaction substrate to increase the rate of a particular that favor a reaction reaction.	Cell_Biology_Alberts. Figure 3–52 Some general strategies of enzyme catalysis. (A) Holding substrates (A) enzyme binds to two (B) binding of substrate (C) enzyme strains the together in a precise alignment. (B) Charge substrate molecules and to enzyme rearranges bound substrate stabilization of reaction intermediates. orients them precisely to electrons in the substrate, molecule, forcing it encourage a reaction to creating partial negative toward a transition (C) Applying forces that distort bonds in the occur between them and positive charges state to favor a reaction substrate to increase the rate of a particular that favor a reaction reaction.
Cell_Biology_Alberts_632	Cell_Biology_Alberts	employ tools to enhance and extend the capabilities of their hands, enzymes and other proteins often use small nonprotein molecules to perform functions that would be difficult or impossible to do with amino acids alone. Thus, enzymes frequently have a small molecule or metal atom tightly associated with their active site that assists with their catalytic function. Carboxypeptidase, for example, an enzyme that cuts polypeptide chains, carries a tightly bound zinc ion in its active site. During the cleavage of a peptide bond by carboxypeptidase, the zinc ion forms a transient bond with one of the substrate atoms, thereby assisting the hydrolysis reaction. In other enzymes, a small organic molecule serves a similar purpose. Such organic molecules are often referred to as coenzymes. An example is biotin, which is found in enzymes that transfer a carboxylate group (–COO–) from one molecule to another (see Figure 2–40). Biotin participates in these reactions by forming a transient covalent	Cell_Biology_Alberts. employ tools to enhance and extend the capabilities of their hands, enzymes and other proteins often use small nonprotein molecules to perform functions that would be difficult or impossible to do with amino acids alone. Thus, enzymes frequently have a small molecule or metal atom tightly associated with their active site that assists with their catalytic function. Carboxypeptidase, for example, an enzyme that cuts polypeptide chains, carries a tightly bound zinc ion in its active site. During the cleavage of a peptide bond by carboxypeptidase, the zinc ion forms a transient bond with one of the substrate atoms, thereby assisting the hydrolysis reaction. In other enzymes, a small organic molecule serves a similar purpose. Such organic molecules are often referred to as coenzymes. An example is biotin, which is found in enzymes that transfer a carboxylate group (–COO–) from one molecule to another (see Figure 2–40). Biotin participates in these reactions by forming a transient covalent
Cell_Biology_Alberts_633	Cell_Biology_Alberts	is biotin, which is found in enzymes that transfer a carboxylate group (–COO–) from one molecule to another (see Figure 2–40). Biotin participates in these reactions by forming a transient covalent bond to the –COO– group to be transferred, being better suited to this function than any of the amino acids used to make proteins. Because it cannot be synthesized by humans, and must therefore be supplied in small quantities in our diet, biotin is a vitamin. Many other coenzymes are either vitamins or derivatives of vitamins (Table 3–2).	Cell_Biology_Alberts. is biotin, which is found in enzymes that transfer a carboxylate group (–COO–) from one molecule to another (see Figure 2–40). Biotin participates in these reactions by forming a transient covalent bond to the –COO– group to be transferred, being better suited to this function than any of the amino acids used to make proteins. Because it cannot be synthesized by humans, and must therefore be supplied in small quantities in our diet, biotin is a vitamin. Many other coenzymes are either vitamins or derivatives of vitamins (Table 3–2).
Cell_Biology_Alberts_634	Cell_Biology_Alberts	Other proteins also frequently require specific small-molecule adjuncts to function properly. Thus, the signal receptor protein rhodopsin, which is made by the photoreceptor cells in the retina, detects light by means of a small molecule, retinal, embedded in the protein (Figure 3–53A). Retinal, which is derived from vitamin A, changes its shape when it absorbs a photon of light, and this change causes the protein to trigger a cascade of enzymatic reactions that eventually lead to an electrical signal being carried to the brain. Figure 3–53 Retinal and heme. (A) The structure of retinal, the light-sensitive molecule attached to rhodopsin in the eye. The structure shown isomerizes when it absorbs light. (B) The structure of a heme group. The carbon-containing heme ring is red and the iron atom at its center is orange. A heme group is tightly bound to each of the four polypeptide chains in hemoglobin, the oxygen-carrying protein whose structure is shown in Figure 3–19.	Cell_Biology_Alberts. Other proteins also frequently require specific small-molecule adjuncts to function properly. Thus, the signal receptor protein rhodopsin, which is made by the photoreceptor cells in the retina, detects light by means of a small molecule, retinal, embedded in the protein (Figure 3–53A). Retinal, which is derived from vitamin A, changes its shape when it absorbs a photon of light, and this change causes the protein to trigger a cascade of enzymatic reactions that eventually lead to an electrical signal being carried to the brain. Figure 3–53 Retinal and heme. (A) The structure of retinal, the light-sensitive molecule attached to rhodopsin in the eye. The structure shown isomerizes when it absorbs light. (B) The structure of a heme group. The carbon-containing heme ring is red and the iron atom at its center is orange. A heme group is tightly bound to each of the four polypeptide chains in hemoglobin, the oxygen-carrying protein whose structure is shown in Figure 3–19.
Cell_Biology_Alberts_635	Cell_Biology_Alberts	Another example of a protein with a nonprotein portion is hemoglobin (see Figure 3–19). Each molecule of hemoglobin carries four heme groups, ring-shaped molecules each with a single central iron atom (Figure 3–53B). Heme gives hemoglobin (and blood) its red color. By binding reversibly to oxygen gas through its iron atom, heme enables hemoglobin to pick up oxygen in the lungs and release it in the tissues. Sometimes these small molecules are attached covalently and permanently to their protein, thereby becoming an integral part of the protein molecule itself. We shall see in Chapter 10 that proteins are often anchored to cell membranes through covalently attached lipid molecules. And membrane proteins exposed on the surface of the cell, as well as proteins secreted outside the cell, are often modified by the covalent addition of sugars and oligosaccharides. Multienzyme Complexes Help to Increase the Rate of Cell Metabolism	Cell_Biology_Alberts. Another example of a protein with a nonprotein portion is hemoglobin (see Figure 3–19). Each molecule of hemoglobin carries four heme groups, ring-shaped molecules each with a single central iron atom (Figure 3–53B). Heme gives hemoglobin (and blood) its red color. By binding reversibly to oxygen gas through its iron atom, heme enables hemoglobin to pick up oxygen in the lungs and release it in the tissues. Sometimes these small molecules are attached covalently and permanently to their protein, thereby becoming an integral part of the protein molecule itself. We shall see in Chapter 10 that proteins are often anchored to cell membranes through covalently attached lipid molecules. And membrane proteins exposed on the surface of the cell, as well as proteins secreted outside the cell, are often modified by the covalent addition of sugars and oligosaccharides. Multienzyme Complexes Help to Increase the Rate of Cell Metabolism
Cell_Biology_Alberts_636	Cell_Biology_Alberts	Multienzyme Complexes Help to Increase the Rate of Cell Metabolism The efficiency of enzymes in accelerating chemical reactions is crucial to the maintenance of life. Cells, in effect, must race against the unavoidable processes of decay, which—if left unattended—cause macromolecules to run downhill toward greater and greater disorder. If the rates of desirable reactions were not greater than the rates of competing side reactions, a cell would soon die. We can get some idea of the rate at which cell metabolism proceeds by measuring the rate of ATP utilization. A typical mammalian cell “turns over” (i.e., hydrolyzes and restores by phosphorylation) its entire ATP pool once every 1 or 2 minutes. For each cell, this turnover represents the utilization of roughly 107 molecules of ATP per second (or, for the human body, about 1 gram of ATP every minute).	Cell_Biology_Alberts. Multienzyme Complexes Help to Increase the Rate of Cell Metabolism The efficiency of enzymes in accelerating chemical reactions is crucial to the maintenance of life. Cells, in effect, must race against the unavoidable processes of decay, which—if left unattended—cause macromolecules to run downhill toward greater and greater disorder. If the rates of desirable reactions were not greater than the rates of competing side reactions, a cell would soon die. We can get some idea of the rate at which cell metabolism proceeds by measuring the rate of ATP utilization. A typical mammalian cell “turns over” (i.e., hydrolyzes and restores by phosphorylation) its entire ATP pool once every 1 or 2 minutes. For each cell, this turnover represents the utilization of roughly 107 molecules of ATP per second (or, for the human body, about 1 gram of ATP every minute).
Cell_Biology_Alberts_637	Cell_Biology_Alberts	The rates of reactions in cells are rapid because enzyme catalysis is so effective. Some enzymes have become so efficient that there is no possibility of further useful improvement. The factor that limits the reaction rate is no longer the enzyme’s intrinsic speed of action; rather, it is the frequency with which the enzyme collides with its substrate. Such a reaction is said to be diffusion-limited (see Panel 3–2, pp. 142–143).	Cell_Biology_Alberts. The rates of reactions in cells are rapid because enzyme catalysis is so effective. Some enzymes have become so efficient that there is no possibility of further useful improvement. The factor that limits the reaction rate is no longer the enzyme’s intrinsic speed of action; rather, it is the frequency with which the enzyme collides with its substrate. Such a reaction is said to be diffusion-limited (see Panel 3–2, pp. 142–143).
Cell_Biology_Alberts_638	Cell_Biology_Alberts	The amount of product produced by an enzyme will depend on the concentration of both the enzyme and its substrate. If a sequence of reactions is to occur extremely rapidly, each metabolic intermediate and enzyme involved must be present in high concentration. However, given the enormous number of different reactions performed by a cell, there are limits to the concentrations that can be achieved. In fact, most metabolites are present in micromolar (10–6 M) concentrations, and most enzyme concentrations are much lower. How is it possible, therefore, to maintain very fast metabolic rates?	Cell_Biology_Alberts. The amount of product produced by an enzyme will depend on the concentration of both the enzyme and its substrate. If a sequence of reactions is to occur extremely rapidly, each metabolic intermediate and enzyme involved must be present in high concentration. However, given the enormous number of different reactions performed by a cell, there are limits to the concentrations that can be achieved. In fact, most metabolites are present in micromolar (10–6 M) concentrations, and most enzyme concentrations are much lower. How is it possible, therefore, to maintain very fast metabolic rates?
Cell_Biology_Alberts_639	Cell_Biology_Alberts	The answer lies in the spatial organization of cell components. The cell can increase reaction rates without raising substrate concentrations by bringing the various enzymes involved in a reaction sequence together to form a large protein assembly known as a multienzyme complex (Figure 3–54). Because this assembly is organized in a way that allows the product of enzyme A to be passed directly to enzyme B, and so on, diffusion rates need not be limiting, even when the concentrations of the substrates in the cell as a whole are very low. It is perhaps not surprising, therefore, that such enzyme complexes are very common, and they are involved in nearly all aspects of metabolism—including the central genetic processes of DNA, RNA, and protein synthesis. In fact, few enzymes in eukaryotic cells diffuse freely in solution; instead, most seem to have evolved binding sites that concentrate them with other proteins of related function in particular regions of the cell, thereby increasing the	Cell_Biology_Alberts. The answer lies in the spatial organization of cell components. The cell can increase reaction rates without raising substrate concentrations by bringing the various enzymes involved in a reaction sequence together to form a large protein assembly known as a multienzyme complex (Figure 3–54). Because this assembly is organized in a way that allows the product of enzyme A to be passed directly to enzyme B, and so on, diffusion rates need not be limiting, even when the concentrations of the substrates in the cell as a whole are very low. It is perhaps not surprising, therefore, that such enzyme complexes are very common, and they are involved in nearly all aspects of metabolism—including the central genetic processes of DNA, RNA, and protein synthesis. In fact, few enzymes in eukaryotic cells diffuse freely in solution; instead, most seem to have evolved binding sites that concentrate them with other proteins of related function in particular regions of the cell, thereby increasing the
Cell_Biology_Alberts_640	Cell_Biology_Alberts	diffuse freely in solution; instead, most seem to have evolved binding sites that concentrate them with other proteins of related function in particular regions of the cell, thereby increasing the rate and efficiency of the reactions that they catalyze (see p. 331).	Cell_Biology_Alberts. diffuse freely in solution; instead, most seem to have evolved binding sites that concentrate them with other proteins of related function in particular regions of the cell, thereby increasing the rate and efficiency of the reactions that they catalyze (see p. 331).
Cell_Biology_Alberts_641	Cell_Biology_Alberts	Eukaryotic cells have yet another way of increasing the rate of metabolic reactions: using their intracellular membrane systems. These membranes can segregate particular substrates and the enzymes that act on them into the same membrane-enclosed compartment, such as the endoplasmic reticulum or the cell nucleus. If, for example, a compartment occupies a total of 10% of the volume of TE2 2 2 1 1 4 4 5 21 4 5 3 3 3 enzyme domains (C) (E) (D) etc.5 nm C acyl carrier domain termination domain (TE) PYRUVATE DEHYDROGENASE COMPLEX FATTY ACID SYNTHASE 3 1 20 nm	Cell_Biology_Alberts. Eukaryotic cells have yet another way of increasing the rate of metabolic reactions: using their intracellular membrane systems. These membranes can segregate particular substrates and the enzymes that act on them into the same membrane-enclosed compartment, such as the endoplasmic reticulum or the cell nucleus. If, for example, a compartment occupies a total of 10% of the volume of TE2 2 2 1 1 4 4 5 21 4 5 3 3 3 enzyme domains (C) (E) (D) etc.5 nm C acyl carrier domain termination domain (TE) PYRUVATE DEHYDROGENASE COMPLEX FATTY ACID SYNTHASE 3 1 20 nm
Cell_Biology_Alberts_642	Cell_Biology_Alberts	Figure 3–54 How unstructured regions of polypeptide chain serving as tethers allow reaction intermediates to be passed from one active site to another in large multienzyme complexes. (A–C) The fatty acid synthase in mammals. (A) The location of seven protein domains with different activities in this 270 kilodalton protein. The numbers refer to the order in which each enzyme domain must function to complete each two-carbon addition step. After multiple cycles of two-carbon addition, the termination domain releases the final product once the desired length of fatty acid has been synthesized. (B) The structure of the dimeric enzyme, with the location of the five active sites in one monomer indicated. (C) How a flexible tether allows the substrate that remains linked to the acyl carrier domain (red) to be passed from one active site to another in each monomer, sequentially elongating and modifying the bound fatty acid intermediate (yellow). The five steps are repeated until the final	Cell_Biology_Alberts. Figure 3–54 How unstructured regions of polypeptide chain serving as tethers allow reaction intermediates to be passed from one active site to another in large multienzyme complexes. (A–C) The fatty acid synthase in mammals. (A) The location of seven protein domains with different activities in this 270 kilodalton protein. The numbers refer to the order in which each enzyme domain must function to complete each two-carbon addition step. After multiple cycles of two-carbon addition, the termination domain releases the final product once the desired length of fatty acid has been synthesized. (B) The structure of the dimeric enzyme, with the location of the five active sites in one monomer indicated. (C) How a flexible tether allows the substrate that remains linked to the acyl carrier domain (red) to be passed from one active site to another in each monomer, sequentially elongating and modifying the bound fatty acid intermediate (yellow). The five steps are repeated until the final
Cell_Biology_Alberts_643	Cell_Biology_Alberts	(red) to be passed from one active site to another in each monomer, sequentially elongating and modifying the bound fatty acid intermediate (yellow). The five steps are repeated until the final length of fatty acid chain has been synthesized. (Only steps 1 through 4 are illustrated here.) (D) Multiple tethered subunits in the giant pyruvate dehydrogenase complex (9500 kilodaltons, larger than a ribosome) that catalyzes the conversion of pyruvate to acetyl CoA. As in (C), a covalently bound substrate held on a flexible tether (red balls with yellow substrate) is serially passed through active sites on subunits (here labeled 1 through 3) to produce the final products. Here, subunit 1 catalyzes the decarboxylation of pyruvate accompanied by the reductive acetylation of a lipoyl group linked to one of the red balls. Subunit 2 transfers this acetyl group to CoA, forming acetyl CoA, and subunit 3 reoxidizes the lipoyl group to prepare it for the next cycle. Only one-tenth of the subunits	Cell_Biology_Alberts. (red) to be passed from one active site to another in each monomer, sequentially elongating and modifying the bound fatty acid intermediate (yellow). The five steps are repeated until the final length of fatty acid chain has been synthesized. (Only steps 1 through 4 are illustrated here.) (D) Multiple tethered subunits in the giant pyruvate dehydrogenase complex (9500 kilodaltons, larger than a ribosome) that catalyzes the conversion of pyruvate to acetyl CoA. As in (C), a covalently bound substrate held on a flexible tether (red balls with yellow substrate) is serially passed through active sites on subunits (here labeled 1 through 3) to produce the final products. Here, subunit 1 catalyzes the decarboxylation of pyruvate accompanied by the reductive acetylation of a lipoyl group linked to one of the red balls. Subunit 2 transfers this acetyl group to CoA, forming acetyl CoA, and subunit 3 reoxidizes the lipoyl group to prepare it for the next cycle. Only one-tenth of the subunits
Cell_Biology_Alberts_644	Cell_Biology_Alberts	to one of the red balls. Subunit 2 transfers this acetyl group to CoA, forming acetyl CoA, and subunit 3 reoxidizes the lipoyl group to prepare it for the next cycle. Only one-tenth of the subunits labeled 1 and 3, attached to the core formed by subunit 2, are illustrated here. This important reaction takes place in the mammalian mitochondrion, as part of the pathway that oxidizes sugars to CO2 and H2O (see page 82). (A–C, adapted from T. Maier et al., Quart. Rev. Biophys. 43:373–422, 2010; D, from J.L.S. Milne et al., J. Biol. Chem. 281:4364–4370, 2006.) the cell, the concentration of reactants in that compartment may be increased by 10 times compared with a cell with the same number of enzyme and substrate molecules, but no compartmentalization. Reactions limited by the speed of diffusion can thereby be speeded up by a factor of 10.	Cell_Biology_Alberts. to one of the red balls. Subunit 2 transfers this acetyl group to CoA, forming acetyl CoA, and subunit 3 reoxidizes the lipoyl group to prepare it for the next cycle. Only one-tenth of the subunits labeled 1 and 3, attached to the core formed by subunit 2, are illustrated here. This important reaction takes place in the mammalian mitochondrion, as part of the pathway that oxidizes sugars to CO2 and H2O (see page 82). (A–C, adapted from T. Maier et al., Quart. Rev. Biophys. 43:373–422, 2010; D, from J.L.S. Milne et al., J. Biol. Chem. 281:4364–4370, 2006.) the cell, the concentration of reactants in that compartment may be increased by 10 times compared with a cell with the same number of enzyme and substrate molecules, but no compartmentalization. Reactions limited by the speed of diffusion can thereby be speeded up by a factor of 10.
Cell_Biology_Alberts_645	Cell_Biology_Alberts	The Cell Regulates the Catalytic Activities of Its Enzymes A living cell contains thousands of enzymes, many of which operate at the same time and in the same small volume of the cytosol. By their catalytic action, these enzymes generate a complex web of metabolic pathways, each composed of chains of chemical reactions in which the product of one enzyme becomes the substrate of the next. In this maze of pathways, there are many branch points (nodes) where different enzymes compete for the same substrate. The system is complex (see Figure 2–63), and elaborate controls are required to regulate when and how rapidly each reaction occurs.	Cell_Biology_Alberts. The Cell Regulates the Catalytic Activities of Its Enzymes A living cell contains thousands of enzymes, many of which operate at the same time and in the same small volume of the cytosol. By their catalytic action, these enzymes generate a complex web of metabolic pathways, each composed of chains of chemical reactions in which the product of one enzyme becomes the substrate of the next. In this maze of pathways, there are many branch points (nodes) where different enzymes compete for the same substrate. The system is complex (see Figure 2–63), and elaborate controls are required to regulate when and how rapidly each reaction occurs.
Cell_Biology_Alberts_646	Cell_Biology_Alberts	Regulation occurs at many levels. At one level, the cell controls how many molecules of each enzyme it makes by regulating the expression of the gene that encodes that enzyme (discussed in Chapter 7). The cell also controls enzymatic activities by confining sets of enzymes to particular subcellular compartments, whether by enclosing them in a distinct membrane-bounded compartment (discussed in Chapters 12 and 14) or by concentrating them on a protein scaffold (see Figure 3–77). As will be explained later in this chapter, enzymes are also covalently modified to control their activity. The rate of protein destruction by targeted proteolysis represents yet another important regulatory mechanism (see Figure 6–86). But the most general process that adjusts reaction rates operates through a direct, reversible change in the activity of an enzyme in response to the specific small molecules that it binds.	Cell_Biology_Alberts. Regulation occurs at many levels. At one level, the cell controls how many molecules of each enzyme it makes by regulating the expression of the gene that encodes that enzyme (discussed in Chapter 7). The cell also controls enzymatic activities by confining sets of enzymes to particular subcellular compartments, whether by enclosing them in a distinct membrane-bounded compartment (discussed in Chapters 12 and 14) or by concentrating them on a protein scaffold (see Figure 3–77). As will be explained later in this chapter, enzymes are also covalently modified to control their activity. The rate of protein destruction by targeted proteolysis represents yet another important regulatory mechanism (see Figure 6–86). But the most general process that adjusts reaction rates operates through a direct, reversible change in the activity of an enzyme in response to the specific small molecules that it binds.
Cell_Biology_Alberts_647	Cell_Biology_Alberts	The most common type of control occurs when an enzyme binds a molecule that is not a substrate to a special regulatory site outside the active site, thereby altering the rate at which the enzyme converts its substrates to products. For example, in feedback inhibition, a product produced late in a reaction pathway inhibits an enzyme that acts earlier in the pathway. Thus, whenever large quantities of the final product begin to accumulate, this product binds to the enzyme and slows down its catalytic action, thereby limiting the further entry of substrates into that reaction pathway (Figure 3–55). Where pathways branch or intersect, there are usually multiple points of control by different final products, each of which works to regulate its own synthesis (Figure 3–56). Feedback inhibition can work almost instantaneously, and it is rapidly reversed when the level of the product falls.	Cell_Biology_Alberts. The most common type of control occurs when an enzyme binds a molecule that is not a substrate to a special regulatory site outside the active site, thereby altering the rate at which the enzyme converts its substrates to products. For example, in feedback inhibition, a product produced late in a reaction pathway inhibits an enzyme that acts earlier in the pathway. Thus, whenever large quantities of the final product begin to accumulate, this product binds to the enzyme and slows down its catalytic action, thereby limiting the further entry of substrates into that reaction pathway (Figure 3–55). Where pathways branch or intersect, there are usually multiple points of control by different final products, each of which works to regulate its own synthesis (Figure 3–56). Feedback inhibition can work almost instantaneously, and it is rapidly reversed when the level of the product falls.
Cell_Biology_Alberts_648	Cell_Biology_Alberts	Figure 3–55 Feedback inhibition of a single biosynthetic pathway. The end product Z inhibits the first enzyme that is unique to its synthesis and thereby controls its own level in the cell. This is an example of negative regulation. Figure 3–56 Multiple feedback inhibition. In this example, which shows the biosynthetic pathways for four different amino acids in bacteria, the red lines indicate positions at which products feed back to inhibit enzymes. Each amino acid controls the first enzyme specific to its own synthesis, thereby controlling its own levels and avoiding a wasteful, or even dangerous, buildup of intermediates. The products can also separately inhibit the initial set of reactions common to all the syntheses; in this case, three different enzymes catalyze the initial reaction, each inhibited by a different product.	Cell_Biology_Alberts. Figure 3–55 Feedback inhibition of a single biosynthetic pathway. The end product Z inhibits the first enzyme that is unique to its synthesis and thereby controls its own level in the cell. This is an example of negative regulation. Figure 3–56 Multiple feedback inhibition. In this example, which shows the biosynthetic pathways for four different amino acids in bacteria, the red lines indicate positions at which products feed back to inhibit enzymes. Each amino acid controls the first enzyme specific to its own synthesis, thereby controlling its own levels and avoiding a wasteful, or even dangerous, buildup of intermediates. The products can also separately inhibit the initial set of reactions common to all the syntheses; in this case, three different enzymes catalyze the initial reaction, each inhibited by a different product.
Cell_Biology_Alberts_649	Cell_Biology_Alberts	Feedback inhibition is negative regulation: it prevents an enzyme from acting. Enzymes can also be subject to positive regulation, in which a regulatory molecule stimulates the enzyme’s activity rather than shutting the enzyme down. Positive regulation occurs when a product in one branch of the metabolic network stimulates the activity of an enzyme in another pathway. As one example, the accumulation of ADP activates several enzymes involved in the oxidation of sugar molecules, thereby stimulating the cell to convert more ADP to ATP.	Cell_Biology_Alberts. Feedback inhibition is negative regulation: it prevents an enzyme from acting. Enzymes can also be subject to positive regulation, in which a regulatory molecule stimulates the enzyme’s activity rather than shutting the enzyme down. Positive regulation occurs when a product in one branch of the metabolic network stimulates the activity of an enzyme in another pathway. As one example, the accumulation of ADP activates several enzymes involved in the oxidation of sugar molecules, thereby stimulating the cell to convert more ADP to ATP.