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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 14/06/2019
Pages 304
Version hardback
Readership level Professional and scholarly
ISBN 9781119053316
Categories Biology, life sciences
$165.42 (with VAT)
614.00 PLN / €136.16 / £117.41
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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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