Aspartic Proteinases Physiology and Pathology

Abstract

INTRODUCTION ASPARTIC PROTEINASES-AN OVERVIEW Aspartic Proteinases Family of Aspartic Proteinases-Characteristic Properties Evolution of Aspartic Proteinases-Their Primary, Secondary, and Tertiary Structures Catalytic Mechanism of Aspartic Proteinases Specificity of the Proteinase Action Inhibition of Aspartic Proteinases Propeptides of Aspartic Proteinases and Activation of Zymogens Concluding Remarks PEPSIN A AND GASTRICSIN AND THEIR ZYMOGENS Introduction Nomenclature Localization of Pepsin A and Gastricsin and Their Physiological Role Localization of Pepsinogen A and Progastricsin in the Human Body Intracellular Synthesis of Pepsinogen A and Progastricsin Secretion of Pepsinogen A and Progastricsin Activation of Zymogens Age Dependent Changes in Gastric Enzyme Seminal Progastricsin Sequence and Expression Sequences-Pepsinogen A and Progastricsin Polymorphism of Pepsinogen A and Progastricsin Three-Dimensional Structure Overall Shape-Pepsinogen A Phosphoserine 68 Active Site Comparison of Pepsin and Pepsinogen Structures Proteolytic Activity Pepsin A and Gastricsin and Patho-Physiological Conditions Determination of Serum Pepsinogen and Gastricsin Normal Levels Serum Pepsinogen A and Progastricsin and Patho-Physiological States Concluding Remarks RENIN Introduction Localization, Secretion, and Physiological Function of Renin Localization of Renin and Prorenin Mammalian Secretory Pathways and Regulation of Renin Secretion The Proteolytic Cleavage of Angiotensinogen-Basic Physiological Function of Renin Sequence and Posttranslational Modifications Gene Structure Primary Structure The Posttranslational Modifications Three-Dimensional Structure Overall Shape Active Site Specificity of Renin Catalysis The Clinical Potential of Renin Inhibition Introduction Renin Specific Antibodies Synthetic Renin Inhibitors Pharmacology of Renin Inhibition Concluding Remarks CATHEPSIN D Introduction Physiological Functions Intracellular Catabolism Processing of Antigens and Peptide Hormones Tissue Remodeling Sequence and Regulation of Expression Sequence of Cathepsin D Regulation of the Expression Cellular Targeting, Processing and Localization of Cathepsin D Targeting of Cathepsin D to the Lysosomes Posttranslational Modifications of Cathepsin D Localization of Cathepsin D Three-Dimensional Structure Overall Shape, Processed Loop Targeting, Recognition Signal The Active Site Catalytic Properties Characterization of Subsite Preferences Patho-Physiological Involvement of Cathepsin D Involvement of Cathepsin D in Neurodegenerative Diseases Involvement of Cathepsin D in Neoplastic Diseases Conclusions CATHEPSIN E Introduction Localization of Cathepsin E Subcellular Localization of Cathepsin E Physiologic Function Primary Structure of Cathepsin E and its Molecular Forms Catalytic Properties of Cathepsin E Cathepsin E and Gastric Cancers Concluding Remarks ASPARTIC PROTEINASES OF CANDIDA YEASTS Introduction Candida Yeasts: An Opportunistic Pathogen The Aspartic Proteinase: Virulence Factor of Candidal Infections The Biochemistry of Candida Aspartic Proteinases Conditions for Proteinase Secretion-Induction by Substrate and pH Complex Genetic of Candida Aspartic Proteinases and Their Primary Structures Three-Dimensional Structures of Candida Aspartic Proteinases Specificity of Proteinases and Inhibitor Design Concluding Remarks ASPARTIC PROTEINASE OF PLASMODIUM FALCIPARUM Introduction The Life-Cycle of Plasmodium falciparum Parasite The Production of Aspartic Proteinase Sequence of Plasmodium Aspartic Proteinases Specificity of the Proteinases and Inhibitors HIV AND RETROVIRAL PROTEINASES Principles of HIV Infection Introduction HIV Genome Immunopathogenesis HIV Interaction with Myeloid Cells Role of B Lymphocytes Activation of Latent Infection Immune Response Retroviral Aspartic Proteinases-Members of the Family of Aspartic Proteinases Similarity of Retroviral Proteinases with Eucaryotic Enzymes Biochemical and Molecular Biology Studies on Similarity of the Two Types of Proteinases Three-Dimensional Structures of the Two Types of Aspartic Proteinases Three-Dimensional Structures of Retroviral Aspartic Proteinases Methods of Preparation of Retroviral Proteinases Structural Features of Retroviral Proteinases Catalytic Properties of Retroviral Proteinases Inhibitors of Retroviral Proteinases and Design of Drugs for AIDS Treatment Overview of HIV Proteinase Inhibitors Mode of Binding of Inhibitors High Rate of Resistant Mutants Appearance-Problem of HIV Drug Design Concluding Remarks Appendix Index