Magdolen / Sommerhoff / Fritz Kallikrein-related peptidases

Vol. 1: Characterization, regulation, and interactions within the protease web
1. Auflage 2012
ISBN: 978-3-11-026037-3
Verlag: De Gruyter
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band Volume 1, 426 Seiten

Reihe: Kallikrein-related peptidases

This handbook is the first comprehensive book of its kind reviewing the clinically relevant current status of tissue kallikrein and kallikrein-related peptidases research. Since several members of the KLK family are key players in (patho-)physiological processes, structural, functional, and regulatory studies are under way to develop new strategies to prevent and treat disorders to which individual members of the KLK protease family contribute significantly. The goal of this book is to inform clinicians, physician scientists and researchers about the prominent role of the multifaceted and interactive KLK system in normal physiology and pathological organ function.

Zielgruppe

Researchers in Biochemistry, Molecular Biology, Molecular Medicine; Clinicians, Physician Scientists

Autoren/Hrsg.

Magdolen, Viktor

Sommerhoff, Christian P.

Fritz, Hans

Schmitt, Manfred

Fachgebiete

• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Vorklinische Medizin: Grundlagenfächer Molekulare Medizin, Zellbiologie
• Naturwissenschaften Biowissenschaften Molekularbiologie
• Naturwissenschaften Biowissenschaften Proteinforschung
• Naturwissenschaften Biowissenschaften Biochemie (nichtmedizinisch)

Inhaltsverzeichnis

1;Preface;5
2;List of contributing authors;7
3;Table of Contents;11
4;Introduction to Volume 1: Kallikrein-related Peptidases. Characterization, Regulation, and Interactions Within the Protease Web;19
4.1;Bibliography;21
5;1 Genomic Structure of the KLK Locus;23
5.1;1.1 Introduction;23
5.2;1.2 Kallikreins in rodents;24
5.2.1;1.2.1 The mouse kallikrein gene family;25
5.2.2;1.2.2 The rat kallikrein gene family;26
5.3;1.3 Characterization and sequence analysis of the human KLK gene locus;27
5.3.1;1.3.1 Locus overview;27
5.3.2;1.3.2 Repeat elements and pleomorphism;29
5.4;1.4 Structural features of the human KLK genes and proteins;30
5.4.1;1.4.1 Common structural features;30
5.5;1.5 Sequence variations of human KLK genes;31
5.6;1.6 Regulation of KLK activity;32
5.6.1;1.6.1 At the mRNA level;32
5.6.2;1.6.2 Locus control of KLK expression;33
5.6.3;1.6.3 Epigenetic regulation of KLK gene expression;35
5.7;1.7 Isoforms and splice variants of human KLKs;36
5.8;1.8 Evolution of KLKs;39
5.9;Bibliography;40
6;2 Single Nucleotide Polymorphisms in the Human KLK Locus and Their Implication in Various Diseases;49
6.1;2.1 Introduction;49
6.2;2.2 KLKSNPs - data-mining from SNPdb and 1000 Genomes;50
6.3;2.3 Functional annotations using web-based prediction tools;52
6.4;2.4 Experimentally validated functional KLK SNPs;53
6.5;2.5 KLKSNP haplotypes and tagging;54
6.6;2.6 Malignant and non-malignant diseases and association with KLK SNPs;56
6.6.1;2.6.1 Association studies on high-risk variants in KLK genes;57
6.6.2;2.6.2 Association studies on low-risk variants in KLK genes;57
6.7;2.7 Conclusions;89
6.8;Bibliography;89
7;3 Evolution of Kallikrein-related Peptidases;97
7.1;3.1 Introduction;97
7.2;3.2 Basic elements of phylogenetic analysis;98
7.3;3.3 Evolutionary trends at the KLK locus;98
7.4;3.4 Evolution of the KLK1-KLK4 sublocus;100
7.4.1;3.4.1 KLK2 and KLK3 originate from a duplicated segment containing both KLK1 and KLK15;100
7.4.2;3.4.2 A large number of KLK1 tandem repeats in the house mouse;103
7.4.3;3.4.3 The rat KLK1 sublocus consists of 10 large repeats;105
7.4.4;3.4.4 Four duplications of KLK1 and KLK15 in the dog;106
7.4.5;3.4.5 A large repeat containing KLK4 in the horse;108
7.5;3.5 KLK genes in non-mammalian species;110
7.6;3.6 General conclusions and remarks on the evolution of KLK genes;111
7.7;Bibliography;112
8;4 Structural Aspects of Kallikrein-related Peptidases;115
8.1;4.1 Introduction;115
8.2;4.2 Individual KLK structures;116
8.2.1;4.2.1 Tissue kallikrein (KLK1);116
8.2.2;4.2.2 Prostate specific antigen (PSA/KLK3);118
8.2.3;4.2.3 Prostase (KLK4);119
8.2.4;4.2.4 Stratum corneum tryptic enzyme (SCTE/KLK5);122
8.2.5;4.2.5 Myelencephalon-specific protease or neurosin (MSP/KLK6);124
8.2.6;4.2.6 Stratum corneum chymotryptic enzyme (SCCE/KLK7);126
8.2.7;4.2.7 Neuropsin (KLK8);128
8.2.8;4.2.8 Other mammalian KLK structures;129
8.3;Bibliography;130
9;5 Molecular Recognition Properties of Kallikrein-related Peptidases on Synthetic and Endogenous Substrates;135
9.1;5.1 Introduction;135
9.2;5.2 Substrate specificities of individual kallikrein-related peptidases;139
9.2.1;5.2.1 The classical kallikreins (KLK1, KLK2, KLK3);139
9.2.2;5.2.2 KLK4/KLK5/KLK7;143
9.2.3;5.2.3 KLK6/KLK13/KLK14;145
9.2.4;5.2.4 KLK8/KLK10/KLK12;147
9.2.5;5.2.5 KLK9/KLK11/KLK15;148
9.3;Bibliography;150
10;6 Natural, Engineered and Synthetic Inhibitors of Kallikrein-related Peptidases;159
10.1;6.1 Introduction;159
10.2;6.2 KLK diversity;159
10.3;6.3 The KLK superfamily: Structure and catalytic mechanism;159
10.4;6.4 KLK inhibition: Rationale and mechanisms;161
10.5;6.5 Proteinaceous inhibitors;162
10.5.1;6.5.1 Kunitz domain inhibitors;162
10.5.2;6.5.2 Kazal domain inhibitors;164
10.5.3;6.5.3 Other canonical inhibitors;165
10.5.4;6.5.4 Serpins;165
10.6;6.6 Naturally occurring small molecule kallikrein inhibitors;166
10.7;6.7 Engineered KLK Inhibitors;167
10.7.1;6.7.1 Approaches to inhibitor design;168
10.7.2;6.7.2 Pharmacological challenges for therapeutic inhibitors;168
10.7.3;6.7.3 Serpins;168
10.7.4;6.7.4 Ecotin;169
10.7.5;6.7.5 Sunflower Trypsin Inhibitor (SFTI);170
10.7.6;6.7.6 Warhead inhibitors;171
10.8;6.8 Conclusions and outlook;172
10.9;Acknowledgements;172
10.10;Bibliography;172
11;7 Kallikrein-related Peptidases as Pharmaceutical Targets;179
11.1;7.1 Introduction;179
11.2;7.2 KLK disease markers as potential therapeutic targets;180
11.3;7.3 KLKs in oncology;183
11.3.1;7.3.1 Prostate cancer;183
11.3.2;7.3.2 Ovarian and pancreatic cancer;185
11.4;7.4 KLKs in inflammatory skin diseases;187
11.4.1;7.4.1 Kallikrein expressions and activities in skin;187
11.4.2;7.4.2 Netherton Syndrome as most relevant clinical model;188
11.4.3;7.4.3 Atopic dermatitis, the potential major indication for kallikrein targeting;189
11.4.4;7.4.4 Psoriasis and relevance of kallikreins;190
11.4.5;7.4.5 Other potential skin disorders with kallikrein involvement;190
11.5;7.5 KLKs in neurological disorders;191
11.5.1;7.5.1 Alzheimer’s disease and dementia;191
11.5.2;7.5.2 Multiple sclerosis (MS);191
11.6;7.6 Kallikrein inhibitors to treat human diseases;192
11.6.1;7.6.1 Design of KLK inhibitors and clinical development;192
11.6.2;7.6.2 KLK inhibitors in oncology;194
11.6.3;7.6.3 KLK inhibitors in dermatology;197
11.7;7.7 Conclusions and Outlook;198
11.8;Bibliography;199
12;8 Expression of Kallikrein-related Peptidases under (Patho-)Physiological Conditions;205
12.1;8.1 Introduction;205
12.2;8.2 KLK expression in tissues and biological fluids under physiological conditions;206
12.2.1;8.2.1 KLKs in the central and peripheral nervous system;206
12.2.2;8.2.2 KLKs in the female reproductive system;210
12.2.3;8.2.3 KLKs in the male reproductive system;214
12.2.4;8.2.4 Cellular distribution of KLKs in the gastrointestinal system;216
12.2.5;8.2.5 KLKs in the skin and skin appendages;221
12.2.6;8.2.6 KLKs in the respiratory system;225
12.2.7;8.2.7 KLKs in the urinary system;225
12.2.8;8.2.8 KLKs in lymphatic and endocrine organs (adrenal glands, thyroid gland, parathyroid glands, pituitary gland);225
12.2.9;8.2.9 KLKs in the cardiovascular system;229
12.2.10;8.2.10 KLKs in the skeletomuscular system;229
12.3;8.3 Expression of KLKs in non-malignant diseases;230
12.3.1;8.3.1 Non-malignant diseases of the CNS;230
12.3.2;8.3.2 Inflammatory-related conditions;233
12.4;8.4 Expression of KLKs in cancer tissues;235
12.4.1;8.4.1 Cancers of the brain;240
12.4.2;8.4.2 Cancers of the female reproductive system;240
12.4.3;8.4.3 Cancers of the male reproductive system;241
12.4.4;8.4.4 Cancers of the gastrointestinal system;242
12.4.5;8.4.5 Cancers of the skin;243
12.4.6;8.4.6 Lung cancer;244
12.4.7;8.4.7 Cancers of the urinary system;244
12.5;8.5 Conclusion;245
12.6;Abbreviations;245
12.7;Bibliography;246
13;9 Kallikrein-related Peptidases within the Proteolytic Web;269
13.1;9.1 Introduction;269
13.2;9.2 KLKs as actors and targets during the initiation and amplification of extracellular proteolytic activity;270
13.2.1;9.2.1 The KLK-dependent KLK activome;270
13.2.2;9.2.2 Cross- and reciprocal activation of KLK and non-KLK proteases;274
13.2.3;9.2.3 Inactivation of protease inhibitors;278
13.3;9.3 KLKs in the termination of proteolytic activity;278
13.3.1;9.3.1 Proteolytic inactivation of (non-)KLK proteases;278
13.3.2;9.3.2 Processing of the uPA receptor;279
13.3.3;9.3.3 Disarming of the proteinase-activated receptors;280
13.4;9.4 Conclusion;281
13.5;Bibliography;282
14;10 Kallikrein-Kinin Cascade: Bioregulation by Human Tissue Kallikrein 1 (hK1, KLK1);289
14.1;10.1 Discovery of classical (true) tissue kallikrein and kinins;289
14.2;10.2 Cellular localization;290
14.3;10.3 Genomics and molecular structure;291
14.4;10.4 Inhibitors of hK1;294
14.5;10.5 Modulation of membrane receptors;295
14.6;10.6 Epigenetic regulation;295
14.7;10.7 Kinin receptors and signaling;296
14.7.1;10.7.1 Receptor subtypes;296
14.7.2;10.7.2 Kinin receptor signaling;297
14.7.3;10.7.3 Regulation of kinin receptor signaling;298
14.8;10.8 Human disease;299
14.8.1;10.8.1 Hypertension and renal damage;299
14.8.2;10.8.2 Cardiac protection;301
14.8.3;10.8.3 Inflammation and neutrophil function;301
14.8.4;10.8.4 Cancer;304
14.8.5;10.8.5 Angiogenesis;304
14.9;10.9 Conclusion;305
14.10;Abbreviations;306
14.11;Bibliography;307
15;11 Role of KLK4 in Dental Enamel Formation;313
15.1;11.1 Introduction;313
15.2;11.2 Early studies implicated proteases in dental enamel formation;313
15.3;11.3 Investigations of enamel proteases discovered KLK4;314
15.4;11.4 KLK4 and amelogenesis imperfecta;315
15.5;11.5 Klk4 lacZ/lacZ mice;315
15.6;11.6 Other enamel specific genes;320
15.7;11.7 Role of KLK4 in enamel formation;322
15.8;11.8 Conclusion;325
15.9;Bibliography;325
16;12 Kallikrein-related Peptidases and Semen;329
16.1;12.1 Introduction;329
16.2;12.2 Expression pattern and origin of seminal KLKs;330
16.3;12.3 Physiological function of seminal KLKs;330
16.3.1;12.3.1 Seminal coagulation and fibrinolytic balance;330
16.3.2;12.3.2 Sperm motility;332
16.3.3;12.3.3 Reproductive immune interactions;334
16.4;12.4 Proteolytic pathways of seminal KLKs;336
16.4.1;12.4.1 Role of seminal zinc;337
16.4.2;12.4.2 Role of seminal KLK inhibitors;337
16.4.3;12.4.3 Other inhibitory mechanisms of seminal KLKs;338
16.4.4;12.4.4 Seminal proteolytic activation cascade;339
16.5;12.5 Conclusions and outlook;340
16.6;Abbreviations;341
16.7;Bibliography;341
17;13 Kallikrein-related Peptidases and Inhibitors of the Skin;347
17.1;13.1 Introduction;347
17.2;13.2 KLKs in the epidermis;349
17.3;13.3 Desquamation;350
17.4;13.4 Regulation of protease activity;351
17.4.1;13.4.1 KLK activation;351
17.4.2;13.4.2 KLK inhibitors;352
17.5;13.5 Skin disorders;355
17.6;13.6 Conclusions and outlook;358
17.7;Bibliography;359
18;14 Physiological and Pathophysiological Roles of Kallikrein-related Peptidases in the Central Nervous System;367
18.1;14.1 Introduction;367
18.2;14.2 KLK expression and roles in CNS physiology;367
18.2.1;14.2.1 KLK expression in the CNS;367
18.2.2;14.2.2 Physiological roles of KLKs in the CNS;371
18.2.3;14.2.3 Pathophysiological roles of KLKs in the CNS;377
18.3;14.3 Conclusions and outlook;381
18.4;Acknowledgements;382
18.5;Abbreviation;382
18.6;Bibliography;382
19;15 Kallikrein-related Peptidases (KLKs), Proteinase-mediated Signaling and Proteinase-activated receptors (PARs);391
19.1;15.1 Proteinases: shocktroops ofthe innate immune response;391
19.2;15.2 Multiple mechanisms for proteinase-mediated signaling;392
19.3;15.3 Proteinases and PAR-mediated signaling;394
19.4;15.4 Linking PARs to the KLKs: the prostate connection;396
19.5;15.5 Proteolytic cascades, KLKs and the innate immune response;397
19.6;15.6 KLKs, other serine proteinases, PARs and inflammation;397
19.7;15.7 KLKs, PARs and inflammation of the central nervous system and the skin;398
19.8;15.8 KLKs, PARs and cancer;400
19.9;15.9 KLKs and PARs: Therapeutic targets for inflammatory diseases, cancer and other disorders;401
19.10;15.10 Blocking proteinase-mediated PAR activation: PAR-targeted blocking antibodies versus proteinase inhibitors;405
19.11;15.11 Summary and outlook for the future;407
19.12;Acknowledgements;407
19.13;Bibliography;408
20;Index;417

Über Autor(innen)

Viktor Magdolen, Technical University Munich; Christian Sommerhoff and Hans Fritz, Ludwig Maximilian University, Munich; Manfred Schmitt,Technical University Munich, Germany.