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Chapter 05 Enzyme Inhibition and Inactivation 1 Chapter 05 Enzyme Inhibition and Inactivation 1

FIGURE 5. 1 Schematic depiction of epidermal growth factor (EGF) and its receptor, activation of FIGURE 5. 1 Schematic depiction of epidermal growth factor (EGF) and its receptor, activation of which leads to cell growth and proliferation. In its activated state, the EGFR normally functions in a dimeric form, as shown. Adapted from Pawson, T. ; Jorgensen, C. Signal Transduction by Growth Factor Receptors (Chapter 11) In The Molecular Basis of Cancer, 3 rd ed. Mendelsohn, J. ; Howley, P. M. ; Israel, M. A. ; Gray, J. W. ; Thompson, C. B. (Eds. ), Elsevier, 2008, pp. 155– 168. Copyright © 2014 Elsevier Inc. All rights reserved. 2

FIGURE 5. 2 (A) Schematic drawing of the interactions of erlotinib (5. 13) with the FIGURE 5. 2 (A) Schematic drawing of the interactions of erlotinib (5. 13) with the active site of EGFR kinase. Modified image from Pose. View (University of Hamburg, Germany) created from Protein Data Bank ID 1 M 17. EGFR residue numbering corresponds to that in PDB 2 ITX. (B) Threedimensional structure of erlotinib (green) bound to EGFR kinase (selected residues shown in blue). Data from Protein Data Bank ID 1 M 17 modified using Accelrys DS Viewer software. (PDB ID: 1 M 17). Stamos, J. , Sliwkowski, M. X. , Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4 -anilinoquinazoline inhibitor. J. Biol. Chem. 2002, 277, 46265– 46272. Copyright © 2014 Elsevier Inc. All rights reserved. 3

FIGURE 5. 3 Schematic drawing of the interactions of stable ATP analog AMP-PNP (5. 14) FIGURE 5. 3 Schematic drawing of the interactions of stable ATP analog AMP-PNP (5. 14) with the active site of EGFR kinase. Modified image from Pose. View (University of Hamburg, Germany) created from Protein Data Bank ID 2 ITX. PDB ID: 2 ITX (Yun, C. -H. , Boggon, T. J. , Li, Y. , Woo, S. , Greulich, H. , Meyerson, M. , Eck, M. J. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 2007, 11, 217– 227. ) Copyright © 2014 Elsevier Inc. All rights reserved. 4

FIGURE 5. 4 Ribbon representations of the structure of the Abl kinase domain (green) in FIGURE 5. 4 Ribbon representations of the structure of the Abl kinase domain (green) in complex with (A) PD 173955 and (B) imatinib (originally known as STI-571). The protein strand colored in (A) and blue in (B) is the “activation loop” of the kinase; the arrow points to the N -methylpiperazine portion of imatinib. Adapted by permission from the American Association for Cancer Research: Nagar, B. et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD 173955 and imatinib (STI-571). Cancer Res. 2002, 62, 4236– 4243. Copyright © 2014 Elsevier Inc. All rights reserved. 5

FIGURE 5. 5 Hypothetical interactions of enalaprilat with ACE Copyright © 2014 Elsevier Inc. All FIGURE 5. 5 Hypothetical interactions of enalaprilat with ACE Copyright © 2014 Elsevier Inc. All rights reserved. 6

FIGURE 5. 6 Hypothesized transition state structure for the reaction catalyzed by bovine PNP; structure FIGURE 5. 6 Hypothesized transition state structure for the reaction catalyzed by bovine PNP; structure of forodesine (5. 36). Copyright © 2014 Elsevier Inc. All rights reserved. 7

FIGURE 5. 7 Hypothesized transition state structure for the reaction catalyzed by human PNP; structure FIGURE 5. 7 Hypothesized transition state structure for the reaction catalyzed by human PNP; structure of DADMe-Immun. H; BCX 4208; 5. 37. Copyright © 2014 Elsevier Inc. All rights reserved. 8

FIGURE 5. 8 Function of the Zn(II) cofactor in ACE catalysis Copyright © 2014 Elsevier FIGURE 5. 8 Function of the Zn(II) cofactor in ACE catalysis Copyright © 2014 Elsevier Inc. All rights reserved. 9

FIGURE 5. 9 Hypothetical active site of carboxypeptidase A. Adapted with permission from Cushman, D. FIGURE 5. 9 Hypothetical active site of carboxypeptidase A. Adapted with permission from Cushman, D. W. , Cheung, H. S. , Sabo, E. F. , Ondetti, M. A. Biochemistry 1977 16, 5484. Copyright © 1977 American Chemical Society Copyright © 2014 Elsevier Inc. All rights reserved. 10

FIGURE 5. 10 The collected products hypothesis of enzyme inhibition using inhibition of carboxypeptidase A FIGURE 5. 10 The collected products hypothesis of enzyme inhibition using inhibition of carboxypeptidase A as an example Copyright © 2014 Elsevier Inc. All rights reserved. 11

FIGURE 5. 11 Hypothetical binding of carboxyalkanoylproline and mercaptoalkanoylproline derivatives to ACE. Adapted with permission FIGURE 5. 11 Hypothetical binding of carboxyalkanoylproline and mercaptoalkanoylproline derivatives to ACE. Adapted with permission from Cushman, D. W. , Cheung, H. S. , Sabo, E. F. , Ondetti, M. A. Biochemistry 1977 16, 5484. Copyright © 1977 American Chemical Society Copyright © 2014 Elsevier Inc. All rights reserved. 12

FIGURE 5. 12 Lead design for C 2 symmetric inhibitors of HIV protease based on FIGURE 5. 12 Lead design for C 2 symmetric inhibitors of HIV protease based on the structure of the tetrahedral intermediate during hydrolysis of HIV protease Copyright © 2014 Elsevier Inc. All rights reserved. 13

FIGURE 5. 13 Comparison of the structure of penicillins with acyl D-alanyl-D-alanine Copyright © 2014 FIGURE 5. 13 Comparison of the structure of penicillins with acyl D-alanyl-D-alanine Copyright © 2014 Elsevier Inc. All rights reserved. 14

SCHEME 5. 1 Kinetic scheme for competitive enzyme inhibition Copyright © 2014 Elsevier Inc. All SCHEME 5. 1 Kinetic scheme for competitive enzyme inhibition Copyright © 2014 Elsevier Inc. All rights reserved. 15

SCHEME 5. 2 Equilibrium between active and inactive conformations of Abl kinase, where the active SCHEME 5. 2 Equilibrium between active and inactive conformations of Abl kinase, where the active conformation binds to ATP, leading to catalysis of the normal enzymatic reaction; the inhibitor imatinib binds to and stabilizes the inactive form, pulling the equilibrium to the right. Copyright © 2014 Elsevier Inc. All rights reserved. 16

SCHEME 5. 3 Biosynthesis of bacterial dihydrofolic acid Copyright © 2014 Elsevier Inc. All rights SCHEME 5. 3 Biosynthesis of bacterial dihydrofolic acid Copyright © 2014 Elsevier Inc. All rights reserved. 17

SCHEME 5. 4 Dihydropteroate synthase use of sulfamethoxazole in place of para-aminobenzoic acid Copyright © SCHEME 5. 4 Dihydropteroate synthase use of sulfamethoxazole in place of para-aminobenzoic acid Copyright © 2014 Elsevier Inc. All rights reserved. 18

SCHEME 5. 5 Hypothetical mechanism for ACE-catalyzed peptide hydrolysis Copyright © 2014 Elsevier Inc. All SCHEME 5. 5 Hypothetical mechanism for ACE-catalyzed peptide hydrolysis Copyright © 2014 Elsevier Inc. All rights reserved. 19

SCHEME 5. 6 Hypothetical mechanism for adenosine deaminase-catalyzed hydrolysis of 2′-deoxyadenosine Copyright © 2014 Elsevier SCHEME 5. 6 Hypothetical mechanism for adenosine deaminase-catalyzed hydrolysis of 2′-deoxyadenosine Copyright © 2014 Elsevier Inc. All rights reserved. 20

SCHEME 5. 7 Reaction catalyzed by PNP Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 5. 7 Reaction catalyzed by PNP Copyright © 2014 Elsevier Inc. All rights reserved. 21

SCHEME 5. 8 Hypothetical mechanism for the reaction catalyzed by aspartate transcarbamylase Copyright © 2014 SCHEME 5. 8 Hypothetical mechanism for the reaction catalyzed by aspartate transcarbamylase Copyright © 2014 Elsevier Inc. All rights reserved. 22

SCHEME 5. 9 Proposed mechanism of action of isoniazid Copyright © 2014 Elsevier Inc. All SCHEME 5. 9 Proposed mechanism of action of isoniazid Copyright © 2014 Elsevier Inc. All rights reserved. 23

SCHEME 5. 10 Renin-angiotensin system Copyright © 2014 Elsevier Inc. All rights reserved. 24 SCHEME 5. 10 Renin-angiotensin system Copyright © 2014 Elsevier Inc. All rights reserved. 24

SCHEME 5. 11 HMG-Co. A reductase, the rate-determining enzyme in de novo cholesterol biosynthesis Copyright SCHEME 5. 11 HMG-Co. A reductase, the rate-determining enzyme in de novo cholesterol biosynthesis Copyright © 2014 Elsevier Inc. All rights reserved. 25

SCHEME 5. 12 Intramolecular cyclization of 5. 76, which causes its short pharmacokinetic duration Copyright SCHEME 5. 12 Intramolecular cyclization of 5. 76, which causes its short pharmacokinetic duration Copyright © 2014 Elsevier Inc. All rights reserved. 26

SCHEME 5. 13 Basic kinetic scheme for an affinity labeling agent Copyright © 2014 Elsevier SCHEME 5. 13 Basic kinetic scheme for an affinity labeling agent Copyright © 2014 Elsevier Inc. All rights reserved. 27

SCHEME 5. 14 Peptidyl acyloxymethyl ketones as an example of a quiescent affinity labeling agent SCHEME 5. 14 Peptidyl acyloxymethyl ketones as an example of a quiescent affinity labeling agent Copyright © 2014 Elsevier Inc. All rights reserved. 28

SCHEME 5. 15 Acylation of peptidoglycan transpeptidase by penicillins Copyright © 2014 Elsevier Inc. All SCHEME 5. 15 Acylation of peptidoglycan transpeptidase by penicillins Copyright © 2014 Elsevier Inc. All rights reserved. 29

SCHEME 5. 16 Activation of the β-lactam carbonyl of cephalosporins Copyright © 2014 Elsevier Inc. SCHEME 5. 16 Activation of the β-lactam carbonyl of cephalosporins Copyright © 2014 Elsevier Inc. All rights reserved. 30

SCHEME 5. 17 Biosynthesis of prostaglandins (PGs) from arachidonic acid Copyright © 2014 Elsevier Inc. SCHEME 5. 17 Biosynthesis of prostaglandins (PGs) from arachidonic acid Copyright © 2014 Elsevier Inc. All rights reserved. 31

SCHEME 5. 18 Hypothetical mechanism for acetylation of prostaglandin synthase by aspirin Copyright © 2014 SCHEME 5. 18 Hypothetical mechanism for acetylation of prostaglandin synthase by aspirin Copyright © 2014 Elsevier Inc. All rights reserved. 32

SCHEME 5. 19 Hypothetical nucleophilic aromatic substitution mechanism for arylation of βtubulin Copyright © 2014 SCHEME 5. 19 Hypothetical nucleophilic aromatic substitution mechanism for arylation of βtubulin Copyright © 2014 Elsevier Inc. All rights reserved. 33

SCHEME 5. 20 Kinetic scheme for simple mechanism-based enzyme inactivation Copyright © 2014 Elsevier Inc. SCHEME 5. 20 Kinetic scheme for simple mechanism-based enzyme inactivation Copyright © 2014 Elsevier Inc. All rights reserved. 34

SCHEME 5. 21 Metabolism of L-glutamic acid. SSADH, is semialdehyde dehydrogenase Copyright © 2014 Elsevier SCHEME 5. 21 Metabolism of L-glutamic acid. SSADH, is semialdehyde dehydrogenase Copyright © 2014 Elsevier Inc. All rights reserved. 35

SCHEME 5. 22 Hypothetical mechanism for the inactivation of GABA aminotransferase by vigabatrin Copyright © SCHEME 5. 22 Hypothetical mechanism for the inactivation of GABA aminotransferase by vigabatrin Copyright © 2014 Elsevier Inc. All rights reserved. 36

SCHEME 5. 23 Zwitterionic and nonzwitterionic forms of vigabatrin Copyright © 2014 Elsevier Inc. All SCHEME 5. 23 Zwitterionic and nonzwitterionic forms of vigabatrin Copyright © 2014 Elsevier Inc. All rights reserved. 37

SCHEME 5. 24 Polyamine biosynthesis Copyright © 2014 Elsevier Inc. All rights reserved. 38 SCHEME 5. 24 Polyamine biosynthesis Copyright © 2014 Elsevier Inc. All rights reserved. 38

SCHEME 5. 25 Hypothetical mechanism for inactivation of ornithine decarboxylase by eflornithine Copyright © 2014 SCHEME 5. 25 Hypothetical mechanism for inactivation of ornithine decarboxylase by eflornithine Copyright © 2014 Elsevier Inc. All rights reserved. 39

SCHEME 5. 26 Hypothetical mechanism for inactivation of ornithine decarboxylase by αdifluoromethylputrescine Copyright © 2014 SCHEME 5. 26 Hypothetical mechanism for inactivation of ornithine decarboxylase by αdifluoromethylputrescine Copyright © 2014 Elsevier Inc. All rights reserved. 40

SCHEME 5. 27 Hypothetical mechanism for the inactivation of monoamine oxidase by tranylcypromine Copyright © SCHEME 5. 27 Hypothetical mechanism for the inactivation of monoamine oxidase by tranylcypromine Copyright © 2014 Elsevier Inc. All rights reserved. 41

SCHEME 5. 28 Hypothetical mechanism for the inactivation of monoamine oxidase by selegiline Copyright © SCHEME 5. 28 Hypothetical mechanism for the inactivation of monoamine oxidase by selegiline Copyright © 2014 Elsevier Inc. All rights reserved. 42

SCHEME 5. 29 Metabolism of 5 -fluorouracil Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 5. 29 Metabolism of 5 -fluorouracil Copyright © 2014 Elsevier Inc. All rights reserved. 43

SCHEME 5. 30 Hypothetical mechanism for thymidylate synthase (d. RP is deoxyribose phosphate) Copyright © SCHEME 5. 30 Hypothetical mechanism for thymidylate synthase (d. RP is deoxyribose phosphate) Copyright © 2014 Elsevier Inc. All rights reserved. 44

SCHEME 5. 31 Hypothetical mechanism for the inactivation of thymidylate synthase by 5 -fluoro-2′deoxyuridylate Copyright SCHEME 5. 31 Hypothetical mechanism for the inactivation of thymidylate synthase by 5 -fluoro-2′deoxyuridylate Copyright © 2014 Elsevier Inc. All rights reserved. 45

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Table 5. 1 Copyright © 2014 Elsevier Inc. All rights reserved. 127 Table 5. 1 Copyright © 2014 Elsevier Inc. All rights reserved. 127

Table 5. 2 Copyright © 2014 Elsevier Inc. All rights reserved. 128 Table 5. 2 Copyright © 2014 Elsevier Inc. All rights reserved. 128