Structure and Function of the Aspartic Proteinases

In September, 1990, a group of 160 scientists from 19 countries and 21 of the United States met at the Red Lion Inn in Rohnert Park, Sonoma County, California. The purpose of this meeting was to share new information from recent research on the Aspartic Proteinases. This book is a compilation of the information transferred in that forum. The Aspartic Proteinases include all those enzymes from the "fourth" class of proteolytic enzymes, the first three being the Serine, Cysteine and Metalloproteinases. Of course, all the scientists in attendance at the Sonoma Aspartic Proteinase Conference would agree that our current level of understanding of the structure and function of the Aspartic Proteinase class of enzymes is clearly first class. The reasons for this require a bit of historical perspective. The group of scientists who are engaged in study of this family of enzymes first met as a separate entity in 1976, in Norman, Oklahoma, at a meeting organized by Jordan Tang of the Oklahoma Medical Research Foundation. This was an exciting time, as the first crystal structures of some of these enzymes were described by Blundell, James and Davies. During that conference, the relationship between the two halves of the mammalian and fungal enzymes was recognized and this has provided a structural foundation for analysis of the retroviral enzymes, which came later. A book was published by Plenum Press documenting l this conference, and the current book is an update to that important work.

Mammalian Gastric Proteinases: Plenary Lectures.- Studies on Pepsin Mutagenesis and Recombinant Rhizopuspepsin.- Inhibitor Binding Induces Structural Changes in Porcine Pepsin.- Functional Implications of the Three-Dimensional Structure of Bovine Chymosin.- Why Does Pepsin Have a Negative Charge at Very Low pH? An Analysis of Conserved Charged Residues in Aspartic Proteinases.- X-Ray Structural Studies of Mammalian Aspartic Proteinases.- Aspartic Protease Inhibitors from the Parasitic Nematode Ascaris.- Nonspecific Electrostatic Binding of Substrates and Inhibitors to Porcine Pepsin.- Mammalian Gastric Proteinases: Poster Reports.- Analysis of the Promoter of a Human Pepsinogen A Gene.- Separation and Characterization of Human Pepsinogens and Pepsins by High-Resolution Discontinuous Electrophoresis.- A Highly Informative Polymorphism of the Pepsinogen C Gene Detected by Polymerase Chain Reaction.- Consequences of Intramolecular Ionic Interactions for the Activation Rate of Human Pepsinogens A and C as Revealed by Molecular Modelling.- Characteristics and Composition of Pepsins from Atlantic Cod.- Reduction of Non-Steroidal Anti-Inflammatory Drug Induced Gastric Damage in the Rat by Soluble Pepstatin Derivatives.- Production of Prochymosin in Lactococci.- Structure and Chromosomal Localization of the Human Prochymosin Pseudogene.- Amino Acid Sequence of Lamb Preprochymosin and Its Comparison to Other Chymosins.- Quantum-Chemical Study of the Catalytic Mechanism of Aspartic Proteinases.- Effects of Viscosity and Solvent Deuterium Identify Multiple Partially Rate-Limiting Steps in the Kinetics of Porcine Pepsin.- Structure-Function Database for Active Site Binding to the Aspartic Proteinases.- Microbial Aspartic Proteinases: Plenary Lectures.- to Fungal Proteinases and Expression in Fungal Systems.- Characterization of the Bar Proteinase, an Extracellular Enzyme from the Yeast Saccharomyces cerevisiae.- Candidia albicans Acid Proteinase: Characterization and Role in Candidiasis.- Pepstatin-Insensitive Carboxyl Proteinases.- Structure and Function of a Pepstatin-Insentitive Acid Proteinase from Aspergillus niger var. macrosporus.- Infection and Pathogenesis of Cash Crops by Botrytis cinerea: Primary Role of an Aspartic Proteinase.- Crystal Structures of Rhizopuspepsin/Inhibitor Complexes.- A Yeast Expression System and Site-Directed Mutagenesis of a Fungal Aspartic Proteinase, Mucor Rennin.- Studies on the Mechanism of Action of Penicillopepsin.- Microbial Aspartic Proteinases: Poster Reports.- Thermopsin, a Thermostable Acid Protease from Sulfolobusacidocaldarius.- Purification of an Aspartic Proteinase from Aspergillus aculeatus.- Effect of Growth Conditions on the Extracellular Production of the Aspartic Proteinase by Candida Albicans.- X-Ray Analysis of a Difluorostatone Renin Inhibitor Bound as the Tetrahedral Hydrate to the Aspartic Protease Endothiapepsin.- Substrate Specificity Study of Recombinant Rhizopus chinensis Aspartic Proteinase.- Non-Gastric Mammalian Proteinases: Plenary Lectures.- Localization of Cathepsin D in Endosomes: Characterization and Biological Importance.- Proteolytic Activation of Human Procathepsin D.- Biological Significance and Activity Control of Cathepsin E Compared with Cathepsin D.- Exploiting the Molecular Template of Angiotensinogen in the Discovery and Design of Peptidyl, Pseudopeptidyl and Peptidemimetic Inhibitors of Human Renin: A Structure-Activity Perspective.- Design of Renin Inhibitors Containing Conformationally Restricted Mimetics of the P1-P1? and P1 Through P2? Sites.- Non-Gastric Mammalian Proteinases: Poster Reports.- Efficient Mutagenesis, Expression and Purification of Procathepsin D.- Mapping of Lysosomal Targeting Determinants of Cathepsin D.- Comparison of Kinetic Properties of Native and Recombinant Human Cathepsin D.- Cathepsin D Inhibitor from Potato Tubers (Solanum tuberosum L.).- Aspartic Proteinase from Barley Seeds Is Related to Animal Cathepsin D.- Immunohistochemical and Immunocytochemical Localization of Cathepsin E Compared with Cathepsin D.- Origins of the Multiple Cathepsin E Transcripts Observed in Human Gastric Mucosa and Gastric Adenocarcinoma.- Human Stomach Cathepsin E Action on Human Immunoglobins.- The Engineering of Recombinant Active Human Prerenin and Its Expression in Mammalian and Insect Cells.- Simple Procedure for Recovery of Crystallizable Human Recombinant Renin from Mammalian Cell-Conditioned Medium.- Substrate Specificity of Human Renin: The Effect of Substitutions at the Amino Terminus and P3 Position of the Substrate.- Substrate Analogue Renin Inhibitors Containing Replacements of Histidine in P2 or Isosteres of the Amide Bond between P3 and P2 Sites.- Molecular Modeling of Renin Inhibitor P2 Substituents.- Retroviral Aspartic Proteinases: Plenary Lectures.- Human Immunodeficiency Virus Proteinase: Now, Then, What’s Next?.- Substrate Specificity of the Human (Type 1) and Simian Immunodeficiency Virus Proteases.- Expression and Characterization of Genetically Linked Homo- and Hetero-Dimers of HIV Proteinase.- Expression of the HIV Aspartic Protease Fused to a Bacterial Phenotypic Marker.- Comparison of Three Inhibitor Complexes of Human Immunodeficiency Virus Protease.- Comparisons of the Sequences, 3-D Structures and Mechanisms of Pepsin-Like and Retroviral Aspartic Proteinases.- The Three-Dimensional X-Ray Crystal Structure of HIV-1 Protease Complexed with a Hydroxyethylene Inhibitor.- Substrate Cleavage by HIV-1 Proteinase.- The Evaluation of Non-Viral Substrates of the HIV Protease as Leads in the Design of Inhibitors for AIDS Therapy.- Interaction of Mutant Forms of the HIV-1 Protease with Substrate and Inhibitors.- Structure-Based Inhibition of HIV-1 Protease Activity and Viral Infectivity.- Retroviral Aspartic Proteinases: Poster Reports.- Analysis of Temperature-Sensitive Mutants of the HIV-1 Protease.- Studies of the Autoprocessing of the HIV-1 Protease Using Cleavage Site Mutants.- Mutational Analysis of a Native Substrate of the HIV-1 Proteinase.- Monoclonal and Polyclonal Antibodies: Reagents for Studying HIV-1 Proteinase Variants.- Cloning, Expression and Kinetic Characterization of the Feline Immunodeficiency Virus Proteinase.- Protein-Engineered Proteinase of Myeloblastosis Associated Virus, An Enzyme of High Activity and HIV-1 Proteinase-Like Specificity.- p 15gag Proteinase of Myeloblastosis Associated Virus: Specificity Studies with Substrate Based Inhibitors.- Scintillation Proximity Enzyme Assay. A Rapid and Novel Assay Technique Applied to HIV Proteinase.- Improved Chromatographic Method for the Assay of Retroviral Proteases.- Cleavage of the Intermediate Filament Subunit Protein Vimentin by HIV-1 Protease: Utilization of a Novel Cleavage Site and Identification of Higher Order Polymers of Pepstatin A.- A New Type of Aspartic Proteinase Inhibitors with a Symmetric Structure.- Time Dependent Heterodimer Formation Leads to Inhibition of HIV Protease Activity.- Molecular Modeling of the HIV-2 Protease.- Theoretical Models of Aspartic Proteases: Active Site Properties, Dimer Stability and Interactions with Model Inhibitors.- A Consensus Template for the Aspartic Proteinase Fold.- Author Index.