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Co- and Post-Translational Modifications of Therapeutic Antibodies and Proteins

1. Aufl.

von: T. Shantha Raju
126,99 €
Verlag:	Wiley
Format:	PDF
Veröffentl.:	15.03.2019
ISBN/EAN:	9781119053347
Sprache:	englisch
Anzahl Seiten:	304

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Beschreibungen

Titelbeschreibung

A Comprehensive Guide to Crucial Attributes of Therapeutic Proteins in Biological Pharmaceuticals With this book, Dr. Raju offers a valuable resource for professionals involved in research and development of biopharmaceutical and biosimilar drugs. This is a highly relevant work, as medical practitioners have increasingly turned to biopharmaceutical medicines in their search for safe and reliable treatments for complex diseases, while pharmaceutical researchers seek to expand the availability of biopharmaceuticals and create more affordable biosimilar alternatives. Readers receive a thorough overview of the major co-translational modifications (CTMs) and post-translational modifications (PTMs) of therapeutic proteins relevant to the development of biotherapeutics. The majority of chapters detail individual CTMs and PTMs that may affect the physicochemical, biochemical, biological, pharmacokinetic, immunological, toxicological etc. properties of proteins. In addition, readers are guided on the methodology necessary to analyze and characterize these modifications. Thus, readers gain not only an understanding of CTMs/PTMs, but also the ability to design and assess their own structure-function studies for experimental molecules. Specific features and topics include: <ul> <li>Discussion of the research behind and expansion of biopharmaceuticals</li> <li>Twenty chapters detailing relevant CTMs and PTMs of proteins, such as glycosylation, oxidation, phosphorylation, methylation, proteolysis, etc.</li> <li>Each chapter offers an introduction and guide to the mechanisms and biological significance of an individual CTM or PTM, including practical guidance for experiment design and analysis</li> <li>An appendix of biologic pharmaceuticals currently on the market, along with an assessment of their PTMs and overall safety and efficacy</li> </ul> This volume will prove a key reference on the shelves of industry and academic researchers involved in the study and development of biochemistry, molecular biology, biopharmaceuticals and proteins in medicine, particularly as biopharmaceuticals and biosimilars become ever more prominent tools in the field of healthcare.

Inhaltsverzeichnis

Preface xv About the Author xix Abbreviations xxi 1 Introduction to Co- and Post-translational Modifications of Proteins 1 Brief Introductions to Individual Chapters 8 Chapter 2: Acetylation of Proteins 8 Chapter 3: C-Terminal Lys or Arg Clipping of Proteins 8 Chapter 4: Cysteinylation of Proteins 8 Chapter 5: Deamidation of Proteins 8 Chapter 6: Glycation of Proteins 9 Chapter 7: Glycosylation of Proteins 9 Chapter 8: N-glycosylation of Proteins 9 Chapter 9: O-glycosylation of Proteins 10 Chapter 10: Hydroxylation of Proteins 10 Chapter 11: Methylation of Proteins 10 Chapter 12: Oxidation of Proteins 11 Chapter 13: Phosphorylation of Proteins 11 Chapter 14: Prenylation of Proteins 11 Chapter 15: Proteolysis of Proteins 11 Chapter 16: Selenylation of Proteins 12 Chapter 17: Signal Peptides of Proteins 12 Chapter 18: Sulfation of Proteins and Glycoproteins 12 Chapter 19: SUMOylation 12 Chapter 20: Ubiquitination 13 Chapter 21: Other PTMs 13 References 13 2 Acetylation of Proteins 17 Introduction 17 Mechanism of N-acetylation at the N-termini of Proteins 19 Mechanism of N-acetylation and N-deacetylation of Lysine Residues 21 Mechanism of O-acetylation of Sugar Residues 21 Biological Significance of Protein Acetylation 22 Acetylation in Recombinant Therapeutic Proteins 23 Methods to Analyze Acetylation in Proteins and Carbohydrates 23 References 24 3 C-terminal Lys or Arg Clipping in Proteins 31 Introduction 31 Biological Significance of C-terminal Lys or Arg Clipping in Proteins 31 Analysis of C-terminal Lys or Arg Clipping in Proteins 32 References 32 4 Cysteinylation of Proteins 35 Introduction 35 Biological Significance of Cysteinylation of Proteins 35 Cysteinylation and Trisulfide Bonds in Recombinant Therapeutic Proteins 36 Analysis of Cysteinylation of Proteins 36 References 37 5 Deamidation of Proteins 39 Introduction 39 Mechanism of Deamidation of Proteins 40 Physicochemical Characteristics of Deamidated Proteins 42 Biological Significance of Deamidation of Proteins 43 Deamidation and Immunogenicity 43 Deamidation and Pharmacokinetics Properties of Proteins 44 Deamidation in Recombinant Therapeutic Proteins 44 Methods for the Analysis of Deamidation in Proteins 44 References 45 6 Glycation of Proteins 51 Introduction 51 Mechanism of Protein Glycation 52 Glycation of Proteins in Human 54 Protein Glycation and Human Diseases 55 Glycation in Recombinant Therapeutic Proteins 56 Methods to Analyze Protein Glycation 57 References 58 7 Glycosylation of Proteins 63 Introduction 63 Glycans and Aglycans 64 Glycosidic Bonds 64 Aldoses and Ketoses 66 Anomeric Groups: α- and β-Configurations 69 Natural Diversity of Glycans 70 Glycans and Enzymes 71 N-glycosylation 71 O-glycosylation 72 Phospho-Serine Glycosylation 72 GPI-Anchors (Glypiation) 72 C-mannosylation 73 References 73 8 N-glycosylation of Proteins 77 Introduction 77 Mechanism of N-glycosylation of Proteins 81 Biosynthesis of N-Glycans 81 Biosynthesis of Lipid-linked Precursor Oligosaccharide 81 En Bloc Transfer of the Precursor Oligosaccharide to Nascent Polypeptide Chain 82 Processing of the Glycan 82 Additional Processing of Oligosaccharide Unit for Chain Elongation and/or Modifications 83 Microheterogeneity of N-Glycans 84 Species-Specific N-glycosylation 85 Functions of N-glycans 87 Physicochemical Functions of N-glycans 87 Biological Functions of N-glycans 88 Impact of N-Glycans on Pharmacokinetic Properties of Proteins 88 N-Glycans and Human Diseases 89 N-glycosylation of RTPs 89 Methods to Analyze N-Glycans 90 References 92 9 O-glycosylation of Proteins 101 Introduction 101 Biosynthesis of O-Glycans 103 Biosynthesis of Mucin Type O-Glycans 103 Biosynthesis of O-linked GlcNAc on Proteins 105 Biosynthesis of O-linked Fucose on Proteins 106 Biosynthesis of O-linked Glc Residues 107 Biosynthesis of O-linked Gal Residues 107 Biosynthesis of O-linked Man Residues 107 O-Glycans on Hydroxyproline Residues 108 Physicochemical Properties of O-Glycosylated Proteins 108 Biological Functions of O-Glycans 108 O-glycosylation in RTPs 110 Analysis of O-Glycans 111 References 113 10 Hydroxylation of Proteins 119 Introduction 119 Mechanism of Hydroxylation 120 Mechanism of Hydroxylation in Organic Molecules 120 Mechanism of Hydroxylation in Biomolecules 121 Prolyl 4-Hydroxylase 123 Prolyl 3-Hydroxylase 123 Lysyl 5-Hydroxylase 123 Phenylalanine Hydroxylase 123 Tyrosine Hydroxylase 124 Biological Significance of Hydroxylation 124 Hydroxylation in RTPs 126 Analysis of Hydroxylation 126 References 127 11 Methylation of Proteins 133 Introduction 133 Mechanism of Protein Methylation 135 Chemical Methylation Reactions 135 Biological Methylation Reactions 135 Methylation of Arg Residues 135 Methylation of Lys Residues 137 Methylation of Prenylcysteine Residues 137 Methylation of Protein Phosphatase 2A 137 Methylation of Isoaspartyl Residues 138 O-Methylation of Sugar Residues 138 Physicochemical and Biological Significance of Methylation of Proteins 139 Methylation in RTPs 140 Methods to Analyze Methylation in Proteins and Glycoproteins 140 References 141 12 Oxidation of Proteins 147 Introduction 147 Mechanism of Protein Oxidation 149 Methionine (Met) Oxidation 149 Cysteine (Cys) Oxidation 150 Tryptophan (Trp) Oxidation 151 Tyrosine (Tyr) Oxidation 153 Oxidation of Other Amino Acid Residues and Protein Backbone 155 Oxidation in RTPs 155 Met Oxidation in mAbs 157 Analytical Methods to Measure Protein Oxidation 157 References 158 13 Phosphorylation of Proteins 163 Introduction 163 Mechanism of Protein Phosphorylation in Living Cells 164 Mg2+ Mediated Mechanism of Protein Phosphorylation 165 Protein Kinase-Based Mechanism of Protein Phosphorylation 166 Mechanism of Dephosphorylation of Proteins by Phosphatases 166 Protein Kinases 167 Serine Kinases 167 Tyrosine Kinases 168 Physicochemical and Biological Functions of Protein Phosphorylation 169 Phosphorylation in RTPs 169 Methods to Analyze Protein Phosphorylation 170 Gel Electrophoresis 170 Mass Spectrometry 171 Enrichment of Phosphoproteins 171 Enrichment of Phosphorylated Peptides 171 References 171 14 Prenylation of Proteins 177 Introduction 177 Mechanism of Protein Prenylation 177 Biological Significance of Prenylation of Proteins 179 Analysis of Prenylation of Proteins 179 References 179 15 Proteolysis of Proteins 183 Introduction 183 Chemical Proteolysis 184 Enzymatic Proteolysis 185 Biological Significance of Proteolysis 187 Post-translational Processing of Proteins by Proteolysis 187 Intracellular and Extracelluar Degradation of Proteins by Proteases 189 Proteolysis and Food Digestion 190 Role of Proteases in Apoptosis 190 Role of Proteolysis in Human Diseases 191 Use of Proteases in Laboratories 191 Sources of Proteases 193 Proteolysis in RTPs 193 Chemical Proteolysis in RTPs 193 Enzymatic Proteolysis in RTPs 194 Analytical Methods for the Detection of Proteolysis of Proteins 195 References 196 16 Selenylation 203 Introduction 203 Biological Significance of Selenylation of Proteins 203 References 205 17 Signal Peptides 207 Introduction 207 Biological Significance of Signal Peptides 207 Signal Peptides in RTPs 208 References 208 18 Sulfation of Proteins and Glycoproteins 211 Introduction 211 Biosynthesis of PAPS 212 Sulfation Reactions in the Cytosol 213 Sulfation in the Golgi Compartments 215 Sulfation of Tyrosine Residues 215 Mechanism of Tyrosine Sulfation 216 Biological Functions of Tyr Sulfation 216 Sulfation of Glycosaminoglycans (GAGs) and Proteoglycans 217 Biological Functions of GAGs 219 Sulfation in RTPs 220 Analysis of Sulfation in Biomolecules 221 Analysis of Tyr Sulfation 222 Analysis of Sulfated Glycoconjugates 222 Colorimetric Methods to Analyze Sulfated Glycoconjugates 222 Electrophoretic Methods to Analyze Sulfated Glycoconjugates 223 Chromatographic Methods to Analyze Sulfated Glycoconjugates 223 Analysis of Sulfated Glycoconjugates by Mass Spectrometry 224 References 224 19 SUMOylation 231 Introduction 231 Mechanism of SUMOylation 232 Biological Significance of SUMOylation 232 References 232 20 Ubiquitination 235 Introduction 235 Mechanism of Ubiquitination 235 Biological Significance of Ubiquitination 236 References 236 21 Other CTMs and PTMs of Proteins 239 Adenylylation or AMPylation 239 ADP-Ribosylation 239 Amidation 239 Arginylation 240 Butyrylation 240 Carbamylation 240 Carbonylation 240 γ-Carboxylation 241 Citrullination 241 Diphthamide 241 Formylation 241 Glypiation 242 Hypusine Formation 242 Iodination 242 Lipoylation 243 Malonylation 243 Myristoylation 243 Neddylation 243 Palmitoylation 244 Polyglutamylation 244 Polyglycylation 244 Propionylation 245 Pupylation 245 Pyroglutamate Formation 245 S-Glutathionylation 245 S-Nitrosylation 247 References 247 Appendix A 253 Index 271

Autorenportrait

T. Shantha Raju has more than 20 years of experience in the research and development of biotherapeutics, including monoclonal antibodies and glycoproteins. Dr. Raju has published over 40 research articles, several reviews and book chapters and serves on the editorial boards of several leading journals.

Back cover copy

A Comprehensive Guide to Critical Attributes of Therapeutic Antibodies and Proteins With this book, Dr. Raju offers a valuable resource for professionals involved in research and development of biopharmaceutical and biosimilar drugs. This is a highly relevant work, as medical practitioners have increasingly turned to biopharmaceutical medicines in their search for safe and reliable treatments for complex diseases, while pharmaceutical researchers seek to expand the availability of biopharmaceuticals and create more affordable biosimilar alternatives. Readers receive a thorough overview of the major co-translational modifications (CTMs) and post-translational modifications (PTMs) of therapeutic proteins relevant to the development of biotherapeutics. The majority of chapters detail individual CTMs and PTMs that may affect the physicochemical, biochemical, biological, pharmacokinetic, immunological, toxicological etc. properties of proteins. In addition, readers are guided on the methodology necessary to analyze and characterize these modifications. Thus, readers gain not only an understanding of CTMs/PTMs, but also the ability to design and assess their own structure-function studies for experimental molecules. Specific features and topics include: <ul> <li>Discussion of the research behind and expansion of biopharmaceuticals.</li> <li>Twenty chapters detailing relevant CTMs and PTMs of proteins, such as glycosylation, oxidation, phosphorylation, methylation, proteolysis, etc.</li> <li>Each chapter offers an introduction and guide to the mechanisms and biological significance of an individual CTM or PTM, including practical guidance for experiment design and analysis.</li> <li>An appendix of biologic pharmaceuticals currently on the market, along with an assessment of their PTMs and overall safety and efficacy.</li> </ul> This volume will prove to be a key reference on the shelves of industry and academic researchers involved in the study and development of biochemistry and molecular biology of proteins in medicine, particularly as biopharmaceuticals and biosimilars become ever more prominent tools in the field of healthcare.