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;16