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Jr chapter 15
- 1. 15-CO, p.475
- 2. p.476
- 17. p.485
- 18. p.485
Notes de l'éditeur
- FIGURE 15.1 Enzymes regulated by covalent modification are called interconvertible enzymes. The enzymes (protein kinase and protein phosphatase in the example shown here) catalyzing the conversion of the interconvertible enzyme between its two forms are called converter enzymes. In this example, the free enzyme form is catalytically active, whereas the phosphoryl-enzyme form represents an inactive state. The --OH on the interconvertible enzyme represents an --OH group on a specific amino acid side chain in the protein (for example, a particular Ser residue) capable of accepting the phosphoryl group.
- FIGURE 15.2 Proinsulin is an 86-residue precursor to insulin (the sequence shown here is human proinsulin). Proteolytic removal of residues 31 to 65 yields insulin. Residues 1 through 30 (the B chain) remain linked to residues 66 through 87 (the A chain) by a pair of interchain disulfide bridges.
- ANIMATED FIGURE 15.3 The proteolytic activation of chymo- trypsinogen. See this figure animated at http://chemistry.brookscole. com/ggb3
- FIGURE 15.4 The cascade of activation steps leading to blood clotting. The intrinsic and extrinsic pathways converge at factor X, and the final common pathway involves the activation of thrombin and its conversion of fibrinogen into fibrin, which aggregates into ordered filamentous arrays that become crosslinked to form the clot.
- ACTIVE FIGURE 15.5 The isozymes of lactate dehydrogenase (LDH). Active muscle tissue becomes anaerobic and produces pyruvate from glucose via glycolysis (see Chapter 18). It needs LDH to regenerate NAD+ from NADH so that glycolysis can continue. The lactate produced is released into the blood. The muscle LDH isozyme (A4) works best in the NAD+-regenerating direction. Heart tissue is aerobic and uses lactate as a fuel, converting it to pyruvate via LDH and using the pyruvate to fuel the citric acid cycle to obtain energy. The heart LDH isozyme (B4) is inhibited by excess pyruvate so that the fuel won’t be wasted. Test yourself on the concepts in this figure at http://chemistry. brookscole.com/ggb3
- ANIMATED FIGURE 15.6 Cyclic AMP–dependent protein kinase (also known as PKA) is a 150- to 170-kD R2C2 tetramer in mammalian cells. The two R (regulatory) subunits bind cAMP (KD = 3 x 10-8 M); cAMP binding releases the R subunits from the C (catalytic) subunits. C subunits are enzymatically active as monomers. See this figure animated at http://chemistry. brookscole.com/ggb3
- FIGURE 15.7 Sigmoid v versus [S] plot. The dotted line represents the hyperbolic plot characteristic of normal Michaelis–Menten-type enzyme kinetics.
- FIGURE 15.8 Monod–Wyman–Changeux (MWC) model for allosteric transitions. Consider a dimeric protein that can exist in either of two conformational states, R or T. Each subunit in the dimer has a binding site for substrate S and an allosteric effector site, F. The promoters are symmetrically related to one another in the protein, and symmetry is conserved regardless of the conformational state of the protein. The different states of the protein, with or without bound ligand, are linked to one another through the various equilibria. Thus, the relative population of protein molecules in the R or T state is a function of these equilibria and the concentration of the various ligands, substrate (S), and effectors (which bind at FR or FT). As [S] is increased, the T/R equilibrium shifts in favor of an increased proportion of R conformers in the total population (that is, more protein molecules in the R conformational state).
- ANIMATED FIGURE 15.9 The Monod–Wyman–Changeux model. Graphs of allosteric effects for a tetramer (n = 4) in terms of Y, the saturation function, versus [S]. Y is defined as [ligand-binding sites that are occupied by ligand]/ [total ligand-binding sites]. (a) A plot of Y as a function of [S], at various L values. (b) Y as a function of [S], at different c, where c = KR/KT. (When c = 0, KT is infinite.) (Adapted from Monod, J., Wyman, J., and Changeux, J-P., 1965. On the nature of allosteric transitions: A plausible model. Journal of Molecular Biology 12:92.) See this figure animated at http://chemistry.brookscole. com/ggb3
- ACTIVE FIGURE 15.10 Heterotropic allosteric effects: A and I binding to R and T, respectively. The linked equilibria lead to changes in the relative amounts of R and T and, therefore, shifts in the substrate saturation curve. This behavior, depicted by the graph, defines an allosteric “K system.” The parameters of such a system are that (1) S and A (or I) have different affinities for R and T and (2) A (or I) modifies the apparent K0.5 for S by shifting the relative R versus T population. Test yourself on the concepts in this figure at http://chemistry.brookscole.com/ggb3
- FIGURE 15.11 v versus [S] curves for an allosteric “V system.” The V system fits the model of Monod, Wyman, and Changeux, given the following conditions: (1) R and T have the same affinity for the substrate, S. (2) The effectors A and I have different affinities for R and T and thus can shift the relative T/R distribution. (That is, A and I change the apparent value of L.) Assume as before that A binds “only” to the R state and I binds “only” to the T state. (3) R and T differ in their catalytic ability. Assume that R is the enzymatically active form, whereas T is inactive. Because A perturbs the T/R equilibrium in favor of more R, A increases the apparent Vmax. I favors transition to the inactive T state.
- FIGURE 15.12 The glycogen phosphorylase reaction.
- FIGURE 15.13 The phosphoglucomutase reaction.
- FIGURE 15.14 (a) The structure of a glycogen phosphorylase monomer, showing the locations of the catalytic site, the PLP cofactor site, the allosteric effector site, the glycogen storage site, the tower helix (residues 262 through 278), and the subunit interface. (b) Glycogen phosphorylase dimer.
- (a) The structure of a glycogen phosphorylase monomer, showing the locations of the catalytic site, the PLP cofactor site, the allosteric effector site, the glycogen storage site, the tower helix (residues 262 through 278), and the subunit interface.
- (b) Glycogen phosphorylase dimer.
- FIGURE 15.15 v versus S curves for glycogen phosphorylase. (a) The sigmoid response of glycogen phosphorylase to the concentration of the substrate phosphate (Pi) shows strong positive cooperativity. (b) ATP is a feedback inhibitor that affects the affinity of glycogen phosphorylase for its substrates but does not affect Vmax. (Glucose-6-P shows similar effects on glycogen phosphorylase.) (c) AMP is a positive heterotropic effector for glycogen phosphorylase. It binds at the same site as ATP. AMP and ATP are competitive. Like ATP, AMP affects the affinity of glycogen phosphorylase for its substrates but does not affect Vmax.
- (a) The sigmoid response of glycogen phosphorylase to the concentration of the substrate phosphate (Pi) shows strong positive cooperativity.
- (b) ATP is a feedback inhibitor that affects the affinity of glycogen phosphorylase for its substrates but does not affect Vmax. (Glucose-6-P shows similar effects on glycogen phosphorylase.)
- (c) AMP is a positive heterotropic effector for glycogen phosphorylase. It binds at the same site as ATP. AMP and ATP are competitive. Like ATP, AMP affects the affinity of glycogen phosphorylase for its substrates but does not affect Vmax.
- ACTIVE FIGURE 15.16 The mechanism of covalent modification and allosteric regulation of glycogen phosphorylase. The T states are blue, and the R states blue-green. Test yourself on the concepts in this figure at http://chemistry.brookscole.com/ggb3
- FIGURE 15.17 In this diagram of the glycogen phosphorylase dimer, the phosphorylation site (Ser14) and the allosteric (AMP) site face the viewer. Access to the catalytic site is from the opposite side of the protein. The diagram shows the major conformational change that occurs in the N-terminal residues upon phosphorylation of Ser14. The solid black line shows the conformation of residues 10 to 23 in the b, or unphosphorylated, form of glycogen phosphorylase. The conformational change in the location of residues 10 to 23 upon phosphorylation of Ser14 to give the a (phosphorylated) form of glycogen phosphorylase is shown in yellow. Note that these residues move from intrasubunit contacts into intersubunit contacts at the subunit interface. [Sites on the two respective subunits are denoted, with those of the upper subunit designated by primes (‘).] (Adapted from Johnson, L. N., and Barford, D., 1993. The effects of phosphorylation on the structure and function of proteins. Annual Review of Biophysics and Biomolecular Structure 22:199-232.)
- FIGURE 15.18 The hormone-activated enzymatic cascade that leads to activation of glycogen phosphorylase.
- FIGURE 15.19 The adenylyl cyclase reaction yields 3’,5’-cyclic AMP and pyrophosphate. The reaction is driven forward by subsequent hydrolysis of pyrophosphate by the enzyme inorganic pyrophosphatase.
- FIGURE 15.20 Hormone binding to its receptor creates a hormone : receptor complex that catalyzes GDP-GTP exchange on the -subunit of the heterotrimer G protein (G), replacing GDP with GTP.
- FIGURE 15.21 O2-binding curves for hemoglobin and myoglobin.