A uniform treatment of the four protease groups and a discussion of the differences and similarities in their action is presented in this important new publication. Serine, cysteine, aspartate, and zinc proteases are systematically discussed by nomenclature, evolution, specificity and their regulatory role. The chemistry of the peptide bond, including the catalysis of ester and peptide hydrolyses, is explained. For each protease group the emphasis is placed on the structure and function. Kinetics, enzyme modifications, isotope effects, subzero temperature investigations, nuclear magnetic resonance measurements, X-ray diffraction data, binding of transition-state analogs, zymogen activation, and site-specific mutagenesis are combined to rationalize the action of proteases. Both natural and synthetic inhibitors are considered because of their importance in mechanistic studies and drug design.

Proteolysis is an irreversible posttranslational modification affecting each and every protein from its biosynthesis to its degradation. Limited proteolysis regulates targeting and activity throughout the lifetime of proteins. Balancing proteolysis is therefore crucial for physiological homeostasis. Control mechanisms include proteolytic maturation of zymogens resulting in active proteases and the shut down of proteolysis by counteracting endogenous protease inhibitors. Beyond the protein level, proteolytic enzymes are involved in key decisions during development that determine life and death – from single cells to adult individuals. In particular, we are becoming aware of the subtle role that proteases play in signaling events within proteolysis networks, in which the enzymes act synergistically and form alliances in a web-like fashion. Proteases come in different flavors. At least five families of mechanistically distinct enzymes and even more inhibitor families are known to date, many family members are still to be studied in detail. We have learned a lot about the diversity of the about 600 proteases in the human genome and begin to understand their physiological roles in the degradome. However, there are still many open questions regarding their actions in pathophysiology. It is in this area where the development of small molecule inhibitors as therapeutic agents is extremely promising. Approaching proteolysis as the most important, irreversible post-translational protein modification essentially requires an integrated effort of complementary research disciplines. In fact, proteolytic enzymes seem as diverse as the scientists working with these intriguing proteins. This book reflects the efforts of many in this exciting field of research where team and network formations are essential to move ahead.

This book provides a comprehensive overview of the multifaceted field of protease in the cellular environment and focuses on the recently elucidated functions of complex proteolytic systems in physiology and pathophysiology. Given the breadth and depth of information covered in the respective contributions, the book will be immensely useful for researchers working to identify targets for drug development. Multidisciplinary in scope, the book bridges the gap between fundamental and translational research, with applications in the biomedical and pharmaceutical industry, making it a thought-provoking read for basic and applied scientists engaged in biomedical research. Proteases represent one of the largest and most diverse families of enzymes known, and we now know that they are involved in every aspect of a given organism’s life functions. Under physiological conditions, proteases are regulated by their endogenous inhibitors. However, when the activity of proteases is not correctly regulated, disease processes such as tumour progression, vascular remodelling, atherosclerotic plaque progression, ulcer, rheumatoid arthritis, Alzheimer’s disease and inflammation can result. Many infective microorganisms require proteases for replication or use them as virulence factors, which has facilitated the development of protease-targeted therapies for a variety of parasitic diseases.

Researchers seeking problems that offer more hope of success often avoid subjects that seem to be difficult to approach experimentally, or subjects for which experimental results are difficult to interpret. The breakdown part of protein turnover in vivo, particularly in nervous tissue, was such a subject in the past – it was difficult to measure and difficult to explore the mechanisms involved. For factors that influence protein metabolism, it was thought that protein content, function, and distribution are controlled only by the synthetic mechanisms that can supply the needed specificity and response to stimuli. The role of breakdown was thought to be only a general metabolic digestion, elimination of excess polypeptides. We now know that the role of breakdown is much more complex: it has multiple functions, it is coupled to turnover, and it can affect protein composition, function, and synthesis. In addition to eliminating abnormal proteins, breakdown has many modulatory functions: it serves to activate and inactivate enzymes, modulate membrane function, alter receptor channel properties, affect transcription and cell cycle, form active peptides, and much more. The hydrolysis of peptide bonds often involves multiple steps, many enzymes, and cycles (such as ubiquination), and often requires the activity of enzyme complexes. Their activation, modification, and inactivation can thus play an important role in biological functions, with numerous families of proteases participating. The specific role of each remains to be elucidated.

Proteases are everywhere from prokaryotes to eukaryotes, from virus to bacteria and in all human tissues, playing a role in many biological functions. Among these functions, the inflammatory reaction is of particular interest. In inflamed tissues, proteases can have a microbial and/or host origin and are involved not only in tissue remodeling, but also in specific signaling to resident or inflammatory cells, thereby contributing to the innate immune response. This volume presents all advances in our knowledge of the role proteases and their inhibitors play in various diseases associated with inflammatory response. Mechanisms involved in protease signaling to cells are presented, and the different types of proteases that are present at inflammatory sites and their effects on the course of inflammation are discussed. Finally, the evidence for considering proteases and their receptors as potential molecular targets for therapeutic interventions in the treatment of inflammatory diseases is discussed in the context of specific organ inflammatory pathologies (the lung, gastrointestinal tract, skin, joints, etc.).

Using a multidisciplinary approach, this book describes the biochemical mechanisms associated with dysregulation of proteases and the resulting pathophysiological consequences. It highlights the role and regulation of different types of proteases as well as their synthetic and endogenous inhibitors. The role of proteases was initially thought to be limited to general metabolic digestion. However, we now know that the role of protein breakdown is much more complex, and proteases have multiple functions: they are coupled to turnover and can affect protein composition, function and synthesis. In addition to eliminating abnormal proteins, breakdown has many modulatory functions, including activating and inactivating enzymes, modulating membrane function, altering receptor channel properties, affecting transcription and cell cycles and forming active peptides. The ubiquity of proteases in nature makes them an important target for drug development. This in-depth, comprehensive is a valuable resource for researchers involved in identifying new targets for drug development. With its multidisciplinary scope, it bridges the gap between fundamental and translational research in the biomedical and pharmaceutical industries, making it thought-provoking reading for scientists in the field.

Advances in knowledge and technology have revolutionized the process of drug development, making it possible to design drugs for a given target or disease. Building on the foundation laid by the previous three editions, Smith and Williams Introduction to the Principles of Drug Design and Action, Fourth Edition includes the latest informatio

Presenting a comprehensive overview of the multifaceted field of proteases in the extracellular matrix environment, this reference focuses on the recently elucidated functions of complex proteolytic systems in physiological and pathological tissue remodeling. The proteases treated include both serine proteases such as plasminogen activators and TTSPs, metalloproteases such as MMPs and ADAMS and cysteine protease cathepsins. The text specifically addresses the role of extracellular proteases in cancer cell invasion, stroke and infectious diseases, describing the basic biochemistry behind these disease states, as well as therapeutic strategies based on protease inhibition. With its trans-disciplinary scope, this reference bridges the gap between fundamental research and biomedical and pharmaceutical application, making this required reading for basic and applied scientists in the molecular life sciences.

Of the many special roles played by proteolytic enzymes in immune reactions, this book addresses different aspects of membrane peptidases, signal transduction via ligation of membrane peptidases (especially of dipeptidyl peptidase IV/CD26 and aminopeptidase N/CD13), and regulation of membrane peptidases in vivo and in vitro. A number of newly discovered peptidases (including cathepsin F, W and X, carboxypeptidase X, attractin) are described, with special emphasis given to the role of peptidases in immune and defense reactions and in the pathogenesis of inflammatory and other diseases, including rheumatoid arthritis, pancreatitis, multiple sclerosis, Alzheimer's disease and tumours of various origins. The focus on the involvement of a selection of proteolytic enzymes in immune reactions and diseases is a unique feature of this multifaceted work , which combines biochemical, immunological and clinical research reports with literary reviews of the field.