Amino Acids, Peptides and Proteins in Organic Chemistry Volume 2

Amino Acids, Peptides and Proteins in Organic Chemistry

Author:
Andrew B. Hughes
Publisher: Wiley-VCH
ISBN No: 978-3-527-32098-1
Release at: 2009
Pages: 695
Edition:
Volume 2 - Modified Amino Acids, Organocatalysis, and Enzymes
File Size: 7 MB
File Type: pdf
Language: English



Content of Amino Acids, Peptides and Proteins in Organic Chemistry



Part One Synthesis and Chemistry of Modified Amino Acids 1
1 Synthesis and Chemistry of a,b-Didehydroamino Acids 3
Uli Kazmaier
1.1 Introduction 3
1.2 Synthesis of DDAAs 3
1.2.1 DDAAs via Eliminations 3
1.2.1.1 DDAAs via b-Elimination 3
1.2.1.1.1 From b-Hydroxy Amino Acids 3
1.2.1.1.2 From b-Thio- and Selenoamino Acids 5
1.2.1.2 Elimination from N-Hydroxylated and -Chlorinated Amino Acids
and Peptides 6
1.2.1.3 DDAAs from a-Oxo Acids and Amides 6
1.2.1.4 DDAAs from Azides 7
1.2.2 DDAAs via C1⁄4C Bond Formation 7
1.2.2.1 DDAAs via Azlactones [5(4H)-Oxazolones] 7
1.2.2.2 DDAAs via Horner–Emmons and Wittig Reactions 8
1.2.2.3 DDAAs via Enolates of Nitro- and Isocyano- and Iminoacetates 10
1.2.3 DDAAs via C–C Bond Formation 12
1.2.3.1 DDAAs via Heck Reaction 12
1.2.3.2 DDAAs via Cross-Coupling Reactions 13
1.3 Reactions of DDAAs 14
1.3.1 Additions to the C1⁄4C Bond 14
1.3.1.1 Nucleophilic Additions 14
1.3.1.2 Radical Additions 15
1.3.1.3 Cycloadditions 17
1.3.1.3.1 [3þ2] Cycloadditions 18
1.3.1.3.2 [4þ2] Cycloadditions 19
1.3.1.4 Catalytic Hydrogenations 19
1.3.2 Halogenations of DDAAs 21
1.4 Conclusions 21
1.5 Experimental Procedures 22
1.5.1 General Procedure for the Two-Step Synthesis of Dehydroisoleucine
Derivatives 22
1.5.2 General Procedure for the Synthesis of a,b-Didehydroamino Acid Esters
by the Phosphorylglycine Ester Method using DBU 22
1.5.3 General Procedure for the Synthesis of a-Chloroglycine Derivatives 23
1.5.4 General Procedure for the Synthesis of Homomeric Dimers 23
1.5.5 General Procedure for the Synthesis of (Z)-g-Alkyl-a,
b-Didehydroglutamates from Imino Glycinates 24
1.5.6 Palladium-Catalyzed Trifold Heck Coupling 25
1.5.7 General Experimental Procedure for Conjugate Addition of Alkyl
iodides to Chiral a,b-Unsaturated Amino Acid Derivatives 25
1.5.8 Bromination of N-tert-Butyloxycarbonyldehydroamino Acids 26
References 26
2 Synthesis and Chemistry of a-Hydrazino Acids 35
Joëlle Vidal
2.1 Introduction 35
2.1.1 a-Hydrazino Acids are Potent Inhibitors of Pyridoxal
Phosphate Enzymes 35
2.1.2 Natural Products Containing the N–N–C–C1⁄4O Fragment 36
2.1.3 Synthetic Bioactive Products Containing the N–N–C–C1⁄4O
Fragment 39
2.1.4 The CO–N–N–C–CO–NH Fragment is a Turn Inducer in
Pseudopeptides 40
2.2 Synthesis 41
2.2.1 Disconnection 1a: Reaction of Hydrazine Derivatives with
Carbon Electrophiles 41
2.2.1.1 Reaction of Hydrazine Derivatives with Enantiopure
a-Halogeno Acids 42
2.2.1.2 Reaction of Hydrazine Derivatives with Enantiopure Activated
a-Hydroxy Esters 42
2.2.1.3 Mitsunobu Reaction of Aminophthalimide Derivatives with
Enantiopure a-Hydroxy Esters 43
2.2.1.4 Reaction of Hydrazine Derivatives with Nonracemic Epoxides 43
2.2.1.5 Enantioselective Conjugate Addition of Hydrazines to
a,b-Unsaturated Imides 44
2.2.2 Disconnection 1b: Stereoselective Synthesis using
Azodicarboxylates 44
2.2.2.1 Stereoselective a-Hydrazination of Chiral Carbonyl Compounds
using Azodicarboxylates 45
2.2.2.2 Catalytic Enantioselective a-Hydrazination of Carbonyl Compounds
using Azodicarboxylates 46
2.2.2.3 Stereoselective a-Hydrazination of Chiral a,b-Unsaturated
Carboxylates using Azodicarboxylates 50
2.2.3 Disconnection 2: Synthesis from Chiral Nonracemic a-Amino
Acids 52
2.2.3.1 Schestakow Rearrangement of Hydantoic Acids Prepared from
a-Amino Acids 52
2.2.3.2 Reduction of N-Nitroso-a-Amino Esters 52
2.2.3.3 Amination of a-Amino Acids by Hydroxylamine Derivatives 52
2.2.3.4 Amination of a-Amino Acids by Oxaziridines 53
2.2.4 Disconnections 3, 4, and 5: Syntheses from Hydrazones or
a-Diazoesters 55
2.2.4.1 Catalytic Enantioselective Hydrogenation of Hydrazones 56
2.2.4.2 Stereoselective and Catalytic Enantioselective
Strecker Reaction 56
2.2.4.3 Stereoselective Addition of Organometallic Reagents to
Hydrazones 57
2.2.4.4 Stereoselective or Catalytic Enantioselective Mannich-Type
Reaction with Hydrazones 58
2.2.4.5 Enantioselective Friedel–Crafts Alkylations with Hydrazones 59
2.2.4.6 Diastereoselective Zinc-Mediated Carbon Radical Addition
to Hydrazones 59
2.2.4.7 Catalytic Enantioselective Reaction of a-Diazoesters with Aldehydes
and Subsequent Stereoselective Reduction 59
2.2.5 Piperazic Acid and Derivatives by Cycloaddition Reactions 61
2.2.5.1 Diels–Alder Cycloaddition 61
2.2.5.2 1,3-Dipolar Cycloaddition 62
2.3 Chemistry 63
2.3.1 Cleavage of the N–N Bond 63
2.3.2 Reactivity of the Hydrazino Function 67
2.3.2.1 Reaction of Unprotected a-Hydrazino Acid Derivatives with
Acylating Reagents 67
2.3.2.2 Reaction of N1
-Substituted a-Hydrazino Acid Derivatives with
Acylating Reagents 69
2.3.2.3 Reaction of N2
-Protected a-Hydrazino Acid Derivatives with
Acylating Reagents 69
2.3.2.4 Reaction with Aldehydes and Ketones 69
2.3.3 Reactivity of the Carboxyl Function 73
2.3.4 Synthesis of Heterocycles 74
2.3.4.1 Cyclization Leading to Piperazic Acid Derivatives 74
2.3.4.2 Other Heterocycles 75
2.4 Conclusions 78
2.5 Experimental Procedures 79
2.5.1 (S)-2-hydrazinosuccinic Acid Monohydrate 79
2.5.2 ()-(R)-N1, N2-dibenzyloxycarbonyl-2-hydrazino-2-phenyl Propionic Acid, Methyl Ester 80
2.5.3 (þ)-(R)-N1, N2-Bis(benzyloxycarbonyl)-1-hydrazino-2-oxocyclopentane
Carboxylic Acid, Ethyl Ester 81
2.5.4 ()-L-N-Aminovaline 81
2.5.5 (þ)-L-N-benzyl-N-(tert-butoxycarbonylamino)tryptophan,
Hexylamine Salt 82
2.5.6 (R)-2-(N2

-benzoylhydrazino)-2-(4-dimethylaminophenyl)
Acetonitrile 83
2.5.7 tert-Butoxycarbonylamino-(4-dimethylamino-2-methoxy-phenyl)-acetic
Acid Ethyl Ester by Reduction using SmI2 84
2.5.8 (R)-1,2-bis(benzyloxycarbonyl)piperazine-3-carboxylic Acid 84
References 86

3 Hydroxamic Acids: Chemistry, Bioactivity, and Solution-
and Solid-Phase Synthesis 93
Darren Griffith, Marc Devocelle, and Celine J. Marmion
3.1 Introduction 93
3.2 Chemistry, Bioactivity, and Clinical Utility 93
3.2.1 Chemistry 93
3.2.2 Bioactivity and Clinical Utility 95
3.2.2.1 Hydroxamic Acids as Siderophores 95
3.2.2.2 Hydroxamic Acids as Enzyme Inhibitors 97
3.2.2.2.1 MMP Inhibitors 98
3.2.2.2.2 HDAC Inhibitors 102
3.2.2.2.3 PGHS Inhibitors 104
3.3 Solution-Phase Synthesis of Hydroxamic Acids 106
3.3.1 Synthesis of Hydroxamic Acids Derived from Carboxylic
Acid Derivatives 106
3.3.1.1 From Esters 107
3.3.1.2 From Acid Halides 108
3.3.1.3 From Anhydrides 109
3.3.1.4 From [1.3.5]Triazine-Coupled Carboxylic Acids 110
3.3.1.5 From Carbodiimide-Coupled Carboxylic Acids 111
3.3.1.6 From Acyloxyphosphonium Ions 111
3.3.1.7 From Carboxylic Acids Coupled with other Agents 113
3.3.2 Synthesis of Hydroxamic Acids from N-acyloxazolidinones 114
3.3.3 Synthesis of Hydroxamic Acids from gem-Dicyanoepoxides 115
3.3.4 Synthesis of Hydroxamic Acids from Aldehydes 115
3.3.5 Synthesis of Hydroxamic Acids from Nitro Compounds 116
3.3.6 Synthesis of Hydroxamic Acids via a Palladium-Catalyzed
Cascade Reaction 116
3.3.7 Synthesis of N-Formylhydroxylamine (Formohydroxamic Acid) 117
3.3.8 Synthesis of Reverse or Retro-Hydroxamates 117
3.3.9 Synthesis of Acylhydroxamic Acids 120
3.4 Solid-Phase Synthesis of Hydroxamic Acids 121
3.4.1 Acidic Cleavage 122
3.4.1.1 O-Tethered Hydroxylamine 122
3.4.1.1.1 Cleavage with 30–90% TFA 122
3.4.1.1.2 Super Acid-Sensitive Linkers 124
3.4.1.2 N-Tethered Hydroxylamine 126
3.4.1.3 Other Methods of Solid-Phase Synthesis of Hydroxamic Acids
based on an Acidic Cleavage 126
3.4.2 Nucleophilic Cleavage 128
3.4.2.1 Other Methods 129
3.5 Conclusions 130
3.6 Experimental Procedures 130
3.6.1 Synthesis of 3-Pyridinehydroxamic Acid 130
3.6.2 Synthesis of O-benzylbenzohydroxamic Acid 131
3.6.3 Synthesis of N-methylbenzohydroxamic Acid 131
3.6.4 Synthesis of Isobutyrohydroxamic Acid 132
3.6.5 Synthesis of O-benzyl-2-phenylpropionohydroxamic Acid 132
3.6.6 Synthesis of Methyl 3-(2-quinolinylmethoxy)benzeneacetohydroxamic
Acid 133
3.6.7 Synthesis of the Chlamydocin Hydroxamic Acid Analog,
cyclo(L-Asu(NHOH)–Aib-L-Phe–D-Pro) 133
3.6.8 Synthesis of O-benzyl-4-methoxybenzohydroxamic Acid 134
3.6.9 Synthesis of O-benzylbenzohydroxamic acid 134
3.6.10 Synthesis of a 4-chlorophenyl Substituted-a-bromohydroxamic
acid 134
3.6.11 Synthesis of 4-Chlorobenzohydroxamic Acid 135
3.6.12 Synthesis of Acetohydroxamic Acid 135
3.6.13 Synthesis of N-hydroxy Lactam 136
3.6.14 Synthesis of O-tert-butyl-N-formylhydroxylamine 136
3.6.15 Synthesis of Triacetylsalicylhydroxamic Acid 137
References 137
4 Chemistry of a-Aminoboronic Acids and their Derivatives 145
Valery M. Dembitsky and Morris Srebnik
4.1 Introduction 145
4.2 Synthesis of a-Aminoboronic Acids 146
4.3 Synthesis of a-Amidoboronic Acid Derivatives 146
4.4 Asymmetric Synthesis via a-Haloalkylboronic Esters 151
4.5 Synthesis of Glycine a-Aminoboronic Acids 154
4.6 Synthesis of Proline a-Aminoboronic Acids 155
4.7 Synthesis of Alanine a-Aminoboronic Acids 162
4.8 Synthesis of Ornithine a-Aminoboronic Acids 164
4.9 Synthesis of Arginine a-Aminoboronic Acids 167
4.10 Synthesis of Phenethyl Peptide Boronic Acids 170
4.11 Synthesis via Zirconocene Species 172
4.12 Synthesis and Activity of Amine-Carboxyboranes and
their Derivatives 174
4.13 Synthesis of Boron Analogs of Phosphonoacetates 179
4.14 Conclusions 183
References 183
5 Chemistry of Aminophosphonic Acids and Phosphonopeptides 189
Valery P. Kukhar and Vadim D. Romanenko
5.1 Introduction 189
5.2 Physical/Chemical Properties and Analysis 191
5.3 Synthesis of a-Aminophosphonic Acids 193
5.3.1 Amidoalkylation in the ‘‘Carbonyl Compound–Amine–Phosphite’’
Three-Component System 193
5.3.2 Kabachnik–Fields Reaction 195
5.3.3 Direct Hydrophosphonylation of C1⁄4N Bonds 199
5.3.4 Syntheses using C–N and C–C Bond-Forming Reactions 206
5.4 Synthesis of b-Aminophosphonates 212
5.5 Synthesis of g-Aminophosphonates and Higher Homologs 219
5.6 Phosphono- and Phosphinopeptides 227
5.6.1 General Strategies for the Phosphonopeptide Synthesis 229
5.6.2 Peptides Containing P-terminal Aminophosphonate or
Aminophosphinate Moiety 230
5.6.3 Peptides Containing an Aminophosphinic Acid Unit 233
5.6.4 Peptides Containing a Phosphonamide or
Phosphinamide Bond 236
5.6.5 Phosphonodepsipeptides Containing a Phosphonoester Moiety 239
5.6.6 Peptides Containing a Phosphonic or Phosphinic Acid Moiety
in the Side-Chain 240
5.7 Remarks on the Practical Utility of Aminophosphonates 240
5.8 Conclusions 245
5.9 Experimental Procedures 246
5.9.1 Synthesis of N-Protected a-aminophosphinic Acid 10
(R1 1⁄4 EtOCOCH2, R2 1⁄4 Me) 246
5.9.2 Synthesis of Phosphonomethylaminocyclopentane-1-carboxylic
Acid (17) 246
5.9.3 General Procedure for Catalytic Asymmetric Hydrophosphonylation.
Synthesis of a-Aminophosphonate 39 (R1 1⁄4 C5H11, R2 1⁄4 Ph2CH) 247
5.9.4 General Procedure of the Asymmetric Aminohydroxylation
Reaction: Synthesis of b-Amino-a-hydroxyphosphonates 87 247
5.9.5 Dimethyl (S,S)-()3-N,N-bis(a-Methylbenzyl) amino-2-
oxopropylphosphonate (S,S)-100 and Dimethyl 3-[(S,S)-N,
N-bis(a-methylbenzylamino)-(2R)-hydroxypropylphosphonate
(R,S,S)-101 248
5.9.6 General Procedure for the Preparation of Dialkyl Phenyl(4-
pyridylcarbonylamino) methyl-phosphonates 126 249
5.9.7 Synthesis of 1-[(Benzyloxy) carbonyl] prolyl-N1-{[1,10
-biphenyl-4-
yl-methyl)(methoxy) phosphoryl] methyl}leucinamide (159a) 249
References 249
6 Chemistry of Silicon-Containing Amino Acids 261
Yingmei Qi and Scott McN. Sieburth
6.1 Introduction 261
6.1.1 Stability of Organosilanes 261
6.1.2 Sterics and Electronics 262
6.2 Synthesis of Silicon-Containing Amino Acids 263
6.2.1 Synthesis of a-Silyl Amino Acids and Derivatives 263
6.2.2 Synthesis of b-Silylalanine and Derivatives 263
6.2.3 Synthesis of o-Silyl Amino Acids and Derivatives 267
6.2.4 Synthesis of Silyl-Substituted Phenylalanines 269
6.2.5 Synthesis of Amino Acids with Silicon a to Nitrogen 269
6.2.6 Synthesis of Proline Analogs with Silicon in the Ring 269
6.3 Reactions of Silicon-Containing Amino Acids 271
6.3.1 Stability of the Si–C Bond 272
6.3.2 Functional Group Protection 272
6.3.3 Functional Group Deprotection 272
6.4 Bioactive Peptides Incorporating Silicon-Substituted Amino Acids 272
6.4.1 Use of b-Silylalanine 272
6.4.2 Use of N-Silylalkyl Amino Acids 274
6.4.3 Use of Silaproline 274
6.5 Conclusions 275
6.6 Experimental Procedures 276
6.6.1 L-b-Trimethylsilylalanine 23 276
6.6.2 ()-b-Trimethylsilylalanine 23 276
6.6.3 L-b-Trimethylsilylalanine 23 277
6.6.4 ()-p-Trimethylsilylphenylalanine 60 277
6.6.5 L-4-Dimethylsilaproline 100 278
References 278

Part Two Amino Acid Organocatalysis 281
7 Catalysis of Reactions by Amino Acids 283
Haibo Xie, Thomas Hayes, and Nicholas Gathergood
7.1 Introduction 283
7.2 Aldol Reaction 285
7.2.1 Intramolecular Aldol Reaction and Mechanisms 285
7.2.1.1 Intramolecular Aldol Reaction 285
7.2.1.2 Mechanisms 287
7.2.2 Intermolecular Aldol Reaction and Mechanisms 289
7.2.2.1 Intermolecular Aldol Reaction 289
7.2.2.2 Mechanisms 292
7.2.3 Carbohydrate Synthesis 294
7.2.3.1 Carbohydrate Synthesis 294
7.2.3.2 Synthesis of Amino Sugars 297
7.3 Mannich Reaction 298
7.3.1 a-Aminomethylation 298
7.3.2 Direct Mannich Reaction 298
7.3.3 Indirect Mannich Reaction using Ketone Donors 303
7.3.4 anti-Mannich Reactions 303
7.4 a-Amination Reaction 306
7.5 Michael Reaction 308
7.5.1 Mechanism for Iminium Ion-Catalyzed Michael Reaction 309
7.5.1.1 Iminium Ion-Catalyzed Intermolecular Michael Reactions 309
7.5.2 Mechanism for the Enamine-Catalyzed Michael Reaction 313
7.5.2.1 Enamine-Catalyzed Intramolecular Michael Reactions 313
7.5.2.2 Enamine-Catalyzed Intermolecular Michael Reactions 313
7.6 Morita–Baylis–Hillman Reaction and Its Aza-Counterpart 319
7.6.1 Morita–Baylis–Hillman Reactions 319
7.6.2 Aza-Morita–Baylis–Hillman Reactions 320
7.7 Miscellaneous Amino Acid-Catalyzed Reactions 321
7.7.1 Diels–Alder Reaction 322
7.7.2 Knoevenagel Condensation 322
7.7.3 Reduction and Oxidation 323
7.7.4 Rosenmund–von Braun Reaction 326
7.7.5 Activation of Epoxides 326
7.7.6 a-Fluorination of Aldehydes and Ketones 327
7.7.7 SN2 Alkylation 328
7.8 Sustainability of Amino Acid Catalysis 328
7.8.1 Toxicity and Ecotoxicity of Amino Acid Catalysis 328
7.8.2 Amino Acid Catalysis and Green Chemistry 329
7.9 Conclusions and Expectations 330
7.10 Typical Procedures for Preferred Catalysis of Reactions
by Amino Acids 330
References 333
Part Three Enzymes 339
8 Proteases as Powerful Catalysts for Organic Synthesis 341
Andrés Illanes, Fanny Guzmán, and Sonia Barberis
8.1 Enzyme Biocatalysis 341
8.2 Proteolytic Enzymes: Mechanisms and Characteristics 345
8.3 Proteases as Process Catalysts 348
8.4 Proteases in Organic Synthesis 350
8.5 Peptide Synthesis 350
8.5.1 Chemical Synthesis of Peptides 351
8.5.2 Enzymatic Synthesis of Peptides 354
8.6 Conclusions 360
References 361
9 Semisynthetic Enzymes 379
Usama M. Hegazy and Bengt Mannervik
9.1 Usefulness of Semisynthetic Enzymes 379
9.2 Natural Protein Biosynthesis 380
9.3 Sense Codon Reassignment 381
9.4 Missense Suppression 385
9.5 Evolving the Orthogonal aaRS/tRNA Pair 387
9.6 Nonsense Suppression 390
9.7 Mischarging of tRNA by Ribozyme 395
9.8 Evolving the Orthogonal Ribosome/mRNA Pair 396
9.9 Frame-Shift Suppression 397
9.10 Noncanonical Base Pairs 399
9.11 Chemical Ligation 401
9.12 Inteins 404
9.13 EPL 410
9.14 Post-Translational Chemical Modification 411
9.15 Examples of Semisynthetic Enzymes 415
9.16 Conclusions 419
References 419
10 Catalysis by Peptide-Based Enzyme Models 433
Giovanna Ghirlanda, Leonard J. Prins, and Paolo Scrimin
10.1 Introduction 433
10.2 Peptide Models of Hydrolytic Enzymes 434
10.2.1 Ester Hydrolysis and Acylation 434
10.2.1.1 Catalytically Active Peptide Foldamers 435
10.2.1.2 Self-Organizing Catalytic Peptide Units 438
10.2.1.3 Multivalent Catalysts 440
10.2.2 Cleavage of the Phosphate Bond 444
10.2.2.1 DNA and DNA Models as Substrates 446
10.2.2.2 RNA and RNA Models as Substrates 450
10.3 Peptide Models of Heme Proteins 456
10.3.1 Heme Proteins 457
10.3.1.1 Early Heme-Peptide Models: Porphyrin as Template 457
10.3.1.2 Bishistidine-Coordinated Models 458
10.3.1.2.1 Water-Soluble Models: Heme Sandwich 458
10.3.1.2.2 Water-Soluble Models: Four-Helix Bundles 460
10.3.1.2.3 Membrane-Soluble Heme-Binding Systems 462
10.3.2 Diiron Model Proteins: the Due-Ferri Family 464
10.4 Conclusions 467
References 467
11 Substrate Recognition 473
Keith Brocklehurst, Sheraz Gul, and Richard W. Pickersgill
11.1 Recognition, Specificity, Catalysis, Inhibition, and Linguistics 473
11.2 Serine Proteinases 476
11.3 Cysteine Proteinases 480
11.4 Glycoside Hydrolases 485
11.5 Protein Kinases 488
11.6 aaRSs 490
11.7 Lipases 492
11.8 Conclusions 493
References 494
12 Protein Recognition 505
Robyn E. Mansfield, Arwen J. Cross, Jacqueline M. Matthews,
and Joel P. Mackay
12.1 General Introduction 505
12.2 Nature of Protein Interfaces 506
12.2.1 General Characteristics of Binding Sites 506
12.2.2 Modularity and Promiscuity in Protein Interactions 507
12.2.3 Hotspots at Interfaces 508
12.3 Affinity of Protein Interactions 509
12.3.1 Introduction 509
12.3.2 ‘‘Irreversible’’ Interactions 510
12.3.3 Regulatory Interactions 510
12.3.4 Ultra-Weak Interactions 511
12.4 Measuring Protein Interactions 512
12.4.1 Introduction 512
12.4.2 Discovering/Establishing Protein Interactions 512
12.4.3 Determining Interaction Stoichiometry 513
12.4.4 Measuring Affinities 514
12.4.5 Modulation of Binding Affinity 515
12.5 Coupled Folding and Binding 515
12.5.1 Introduction 515
12.5.2 Characteristics of Intrinsically Unstructured Proteins 516
12.5.3 Advantages of Disorder for Protein Recognition 516
12.5.4 Diversity in Coupled Folding and Binding 518
12.6 Regulation of Interactions by PTMs 519
12.6.1 Introduction 519
12.6.2 Types of PTMs 519
12.6.3 A Case Study – Histone Modifications 520
12.7 Engineering and Inhibiting Protein–Protein Interactions 521
12.7.1 Introduction 521
12.7.2 Engineering Proteins with a Specific Binding Functionality 521
12.7.3 Optimizing Protein Interactions 523
12.7.4 Engineering DNA-Binding Proteins 523
12.7.5 Searching for Small-Molecule Inhibitors of Protein Interactions 524
12.7.6 Flexibility and Allosteric Inhibitors 526
12.8 Conclusions 527
References 527
13 Mammalian Peptide Hormones: Biosynthesis and Inhibition 533
Karen Brand and Annette G. Beck-Sickinger
13.1 Introduction 533
13.2 Mammalian Peptide Hormones 534
13.3 Biosynthesis of Peptide Hormones 535
13.3.1 Production and Maturation of Prohormones before Entering the
Secretory Pathway 535
13.3.2 Secretory Pathways 540
13.3.3 Prohormone Cleavage 542
13.3.3.1 Basic Amino Acid-Specific Members of the Proprotein
Convertase Family 548
13.3.3.2 Different Biologically Active Peptides from one Precursor 551
13.3.3.3 Nomenclature at the Cleavage Site 551
13.3.3.4 Prediction of Cleavage Sites – Discovery of New Bioactive Peptides 552
13.3.4 Further PTMs 552
13.3.4.1 Removal of Basic Amino Acids 552
13.3.4.2 C-Terminal Amidation 553
13.3.4.3 Acylation 554
13.3.4.4 Pyroglutamylation 554
13.3.4.5 N-Terminal Truncation 554
13.4 Inhibition of Biosynthesis 555
13.4.1 Readout Systems to Investigate Cleavage by Proteases 555
13.4.2 Rational Design of Inhibitors of the Angiotensin-Converting
Enzyme 557
13.4.3 Proprotein Convertase Inhibitors 561
13.4.3.1 Endogenous Protein Inhibitors and Derived Inhibitors 562
13.4.3.2 Peptide Inhibitors 563
13.4.3.3 Peptide-Derived Inhibitors 563
13.4.3.4 Are there Conformational Requirements for Substrates? 564
13.5 Conclusions 565
References 565
14 Insect Peptide Hormones 575
R. Elwyn Isaac and Neil Audsley
14.1 Introduction 575
14.2 Structure and Biosynthesis of Insect Peptide Hormones 576
14.3 Proctolin 578
14.4 Sex Peptide 580
14.5 A-Type Allatostatins 582
14.6 CRF-Related Diuretic Hormones (DH) 584
14.7 Insect Peptide Hormones and Insect Control 586
14.8 Conclusions 589
References 590
15 Plant Peptide Signals 597
Javier Narváez-Vásquez, Martha L. Orozco-Cárdenas, and Gregory Pearce
15.1 Introduction 597
15.2 Defense-Related Peptides 599
15.2.1 Systemin 599
15.2.2 Hydroxyproline-Rich Systemin Glycopeptides 603
15.2.3 Arabidopsis AtPep1-Related Peptides 604
15.3 Peptides Involved in Growth and Development 605
15.3.1 CLAVATA3 and the CLE Peptide Family 605
15.3.1.1 CLAVATA3 (CLV3) 605
15.3.1.2 CLV3-Related Peptides 607
15.3.2 Rapid Alkalinization Factor Peptides 609
15.3.3 Rotundifolia4 and Devil1 610
15.3.4 C-Terminally Encoded Peptide 1 611
15.3.5 Tyrosine-Sulfated Peptides 611
15.3.5.1 Phytosulfokine 611
15.3.5.2 Plant Peptides Containing Sulfated Tyrosine 1 613
15.3.6 Polaris 613
15.3.7 Inflorescence Deficient in Abscission 614
15.3.7.1 4-kDa Peptide 615
15.4 Peptides Involved in Self-Recognition 615
15.4.1 S-Locus Cysteine Rich Peptides 615
15.5 Methods in Plant Regulatory Peptide Research 616
15.5.1 Discovery of Systemin 617
15.5.2 Identification of Novel Peptide Signals using the Cell
Alkalinization Assay 618
15.5.3 Isolation of Tyrosine-Sulfated Peptides 621
15.5.4 Use of Peptidomics 622
15.5.5 Fishing Ligands with Bait Receptors 622
15.6 Conclusions 623
References 624
16 Nonribosomal Peptide Synthesis 631
Sean Doyle
16.1 Introduction 631
16.2 NRPs 632
16.3 NRP Synthetase Domains 635
16.3.1 Adenylation Domains 635
16.3.2 Thiolation Domains 638
16.3.3 Condensation Domains 638
16.4 PPTases 639
16.4.1 40
PPTase Activity Determination 640
16.5 Experimental Strategies for NRPS Investigations 642
16.5.1 Degenerate PCR 645
16.5.2 Determination of Adenylation Domain Specificity 647
16.5.2.1 Protein MS 647
16.5.2.2 Identification of NRP Synthetase Adenylation
Domain Specificity (Strategy I) 648
16.5.2.3 Identification of NRP Synthetase Adenylation
Domain Specificity (Strategy II) 649
16.6 Non-NRPS 649
16.7 Conclusions 650
References 650
Index 657

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