Proteinases as Drug Targets (Rsc Drug Discovery, 18) - Hardcover

Hardcover

ISBN 10: 1849730490 ISBN 13: 9781849730495

Verlag: Royal Society of Chemistry, 2011

Inhaltsangabe

This unique book describes newly discovered proteolytic enzymes and their biological function. In many cases, these enzymes are targets for new drug discovery in order to provide new therapeutic approaches to control human diseases and/or metabolic conditions. The chapters in this book will help other investigators to pursue drug discovery by detailing methods of production and assay of the enzymes. In addition, the latest structural studies that are described in the book will permit rapid advances in drug design. The most important elements of this book are the state-of-the-art, detailed descriptions of the properties of the proteolytic enzymes. The chapters in the book, written by leading experts in the field, collect the best work on the topics with complete bibliographies for each target enzyme. The illustrations are highly informative to aid and facilitate a new design of inhibitors that can be developed as drug candidates. Key chapters include those by Mark Gorrell and Catherine Abbott, both describing dipeptidyl peptidases, which have been implicated in a number of metabolic conditions including diabetes. The chapters are written from two very different perspectives, thus enriching the literature in this area. In addition, the chapter by Sheena McGowan focuses on aminopeptidases from the malaria parasite, Plasmodium falciparum, and the chapter by Ben Dunn deals with the aspartic peptidases from the same organism.

Über diesen Titel

Über die Autorin bzw. den Autor

Ben M Dunn is a Distinguished Professor of Biochemistry & Molecular Biology at the Department of Biochemistry & Molecular Biology, University of Florida, USA. He is also an NIH-funded Investigator and is currently supported by a MERIT award for the NIAID. He was President of the International Proteolysis Society from 2003-2005 and is currently President of the American Peptide Society.

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Proteinases as Drug Targets

By Ben M. Dunn

The Royal Society of Chemistry

Copyright © 2012 Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-049-5

Contents

Chapter 1 Dipeptidyl Peptidases: Substrates and Therapeutic Targeting in Human Health and Disease Claire H. Wilson and Catherine A. Abbott, 1, 
Chapter 2 The Metalloproteases Meprin α and β: Pathophysiological Roles in Inflammation, Cardiovascular Disease, Cancer, and Fibrosis Christoph Becker-Pauly, 44, 
Chapter 3 Glutamate Carboxypeptidase II as a Therapeutic Target Klára Hlouchová, Cyril Barinka and Jan Konvalinka, 62, 
Chapter 4 The Role of Proteolytically Inactive Serine Proteases from Sarcoptes scabiei in Complement Evasion Simone Reynolds and Katja Fischer, 96, 
Chapter 5 Targeting Dipeptidyl Peptidase-4 (DPP-4) and Fibroblast Activation Protein (FAP) for Diabetes and Cancer Therapy F. M. Keane, S. Chowdhury, T.-W. Yao, N. A. Nadvi, M. G. Gall, Y. Chen, B. Osborne, A. J. V. Ribeiro, W. B. Church, G. W. MCCaughan, M. D. Gorrell and D. M. T. Yu, 118, 
Chapter 6 Discovery of the Cysteine Protease Cathepsin B as a Drug Target for Alzheimer's Disease Vivian Hook, Mark Kindy and Gregory Hook, 145, 
Chapter 7 Plasmodium falciparum Neutral Aminopeptidases: Development of Novel Anti-Malarials by Understanding Enzyme Structure Donald Gardiner, John Dalton and Sheena MCGowan, 169, 
Chapter 8 Blood-Feeding Human Hookworm Proteases A. Loukas, N. Ranjit, D. A. Pickering and M. S. Pearson, 186, 
Chapter 9 Pharmacological Targeting of Human Tissue Kallikrein-Related Peptidases Georgios Pampalakis and Georgia Sotiropoulou, 199, 
Chapter 10 Structural Mechanisms of Inactivation in Proteolytically Inactive Serine Proteases from Sarcoptes scabiei Katja Fischer, James A. Irving, Robert Pike and Ashley M. Buckle, 229, 
Chapter 11 The Aspartic Proteinases from the Malaria Parasite: Structure and Function of the Plasmepsins Ben M. Dunn, 242, 
Subject Index, 270, 

CHAPTER 1

Dipeptidyl Peptidases: Substrates and Therapeutic Targeting in Human Health and Disease

1.1 Introduction

Dipeptidyl peptidase 4 (DP4), fibroblast activation protein (FAP), DP8, and DP9 are the enzymatic members of the serine protease S9b DP4-like gene family. One of the most important features of the DPs is their ability to preferentially cleave the N-terminal post-prolyl bond of regulatory peptides and small protein substrates. DP4 proteolysis results in the inactivation, activation, or alteration of its substrates function via changes in receptor selectivity; thus DP4 plays an important role in regulating biological function. Together, DP4 and FAP have been implicated in a number of diseases including liver disease, obesity, type II diabetes, arthritis, inflammatory bowel disease and cancer. Recently, evidence has emerged to implicate both DP8 and DP9 in innate immunity, and DP8/9 in vitro cleavage of well-known DP4 substrates, including neuropeptide Y (NPY), glucagon-like peptide (GLP)-1, and a number of chemokines, has been demonstrated. Despite this, the true pathophysiological roles of DP8/9 and their involvement within human biology and disease are still to be elucidated. Identification of the in vivo substrate repertoire of each DP will be an important step toward elucidating the biochemical pathways in which each protease is involved. This will allow us to unravel further the roles that the DPs play in human biology and disease, and evaluate further their suitability as therapeutic targets.

In this chapter, we will provide an introduction to the significance of post-proline cleavage, the DP4-like gene family enzymatic members, and the related enzymes prolyl endopeptidase (PEP) and DP2. This will be followed by an in-depth examination of the biochemical characteristics of DP4, FAP, DP8, and DP9, their natural substrates, and biological relevance following DP cleavage. Lastly, the suitability of targeting the DP family for the development of therapeutics for the treatment of human health and disease will be discussed.

1.2 Post-Proline-Cleaving Enzymes

A number of biologically active proteins and regulatory peptides such as cytokines, chemokines, growth hormones, and neuropeptides are protected from general proteolysis due to an evolutionary conserved N-terminal proline residue. Such protection results from the unique cyclic and imino structure of proline imposing conformational restrictions on the polypeptide backbone. Even proteases exhibiting a very broad substrate specificity are unable to attack peptide bonds where the prolyl residue is situated, and hence degradation of such peptides requires the use of proline specific peptidases.

Although a number of proline-cleaving enzymes have been identified, only a limited number of these proteases are capable of cleaving the N-terminal post-prolyl, X-Pro-, bond (Figure 1.1). The most notable of these enzymes are the N-terminal-specific, dipeptidyl peptidases of the serine protease SC clan, S9b sub-family such as DP4 (EC 3.4.15.5), the endopeptidase of the parent S9 family prolyl-endopeptidase (PEP; EC 3.4.21.26), and the S28 family member DP2 (EC 3.4.14.2). Lysosomal prolylcarboxypeptidase (PCP) (EC 3.4.16.2) also belongs to the S28 family, but in contrast to DP2, it functions as a C-terminal-specific protease cleaving the Pro-Xaa bond at the C-termini of proteins to release a single C-terminal amino acid. Carboxypeptidase P (EC 3.4.17.16) is a membrane-localized protease with similar cleavage specificity to lysosomal PCP; however, it is a metallo-, as opposed to serine, protease. Aminopeptidase P (EC 3.4.17.16), prolidase (EC 3.4.13.19) and prolinase are additional proline-cleaving metalloproteases. Aminopeptidase P is an N-terminal-specific protease, cleaving the pre-prolyl bond to release single amino acids at the N-termini of proteins. Importantly, aminopeptidase P is involved in cooperative activities with DP4 and related enzymes. Prolidase and prolinase cleave dipeptides with pre- and post-proline respectively to release two amino acids. The metalloprotease angiotensin-converting enzyme (ACE; EC 3.4.15.1) is also capable of cleaving prolyl bonds, although it is not renowned for its ability to do this. DP4, first discovered in 1966 by Hopsu-Havu and Glenner as the dipeptidyl cleaving glyclproline napthylamidase, was the first N-terminal post-proline-cleaving enzyme identified and hence the most readily investigated. Since its discovery, related enzymes have been identified including fibroblast activation FAP, then DP8 and DP9.

1.3 DP4-Like Gene Family and Related Enzymes

Members of the DP4-like gene family, S9b, make up a sub-family of the prolyl-oligopeptidase (POP) S9 family within the serine protease clan SC. In total the S9b family consists of six homologous members; the four pro- teases, DP4, FAP, DP8 and DP9 and two inactive protease homologs, DP6 and DP10 (Figure 1.2). Sharing similar features, PEP from the parent S9 family is also capable of cleaving the N-terminal post-prolyl bond but with endopeptidase specificity. In contrast to DP4, PEP is limited in its ability to cleave unblocked, free N-terminal dipeptides from substrates; however, inhibitors designed specifically for DPs can still bind to, and block, the enzymatic function of PEP. FAP, in addition to its DP activity, also functions as an endopeptidase. Structurally, the three crystallized S9b family members DP4, FAP and DP6 contain an α/β hydrolase domain and eight-bladed b-propeller domain (Figure 1.2) distinguishing it from that of...

Details zur Ausgabe

• Verlag: Royal Society of Chemistry
• Erscheinungsdatum: 2011
• Sprache: Englisch
• ISBN 10: 1849730490
• ISBN 13: 9781849730495
• Einband: Gebundene Ausgabe
• Anzahl der Seiten: 292
• Herausgeber: Dunn Ben
• Kontakt zum Hersteller: Nicht verfügbar
• Verantwortliche Person: GPSR Kontakt; gpsr@libri.de; ; Friedensallee 273; Hamburg; 22763; Deutschland