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

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

Authors
Publisher John Wiley and Sons Ltd
Year 2019
Pages 304
Version hardback
Readership level Professional and scholarly
Language English
ISBN 9781119053316
Categories Biology, life sciences
$164.15 (with VAT)
729.75 PLN / €156.46 / £135.82
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Book description

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:





Discussion of the research behind and expansion of biopharmaceuticals

Twenty chapters detailing relevant CTMs and PTMs of proteins, such as glycosylation, oxidation, phosphorylation, methylation, proteolysis, etc.

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

An appendix of biologic pharmaceuticals currently on the market, along with an assessment of their PTMs and overall safety and efficacy



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.

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

Table of contents

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: - and -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





-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

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