Human leukocyte and porcine pancreatic elastase: x-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors

• Published in: Biochemistry (Easton) 1989-03, Vol.28 (5), p.1951-1963
• Main Authors: Bode, Wolfram, Meyer, Edgar, Powers, James C
• Format: Article
• Language: English
• Subjects: 550602 - Medicine- External Radiation in Diagnostics- (1980-); Amino Acid Sequence; ANIMALS; BIOLOGICAL FUNCTIONS; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BODY; BODY FLUIDS; Catalysis; COHERENT SCATTERING; CRYSTALLOGRAPHY; DIFFRACTION; DIGESTIVE SYSTEM; ENDOCRINE GLANDS; ENZYME ACTIVITY; ENZYME INHIBITORS; ENZYMES; FUNCTIONS; GLANDS; Humans; HYDROLASES; LEUKOCYTES; Leukocytes - enzymology; MAMMALS; MAN; MATERIALS; Models, Biological; Molecular Sequence Data; ORGANS; PANCREAS; Pancreas - enzymology; Pancreatic Elastase - antagonists & inhibitors; Pancreatic Elastase - metabolism; PEPTIDE HYDROLASES; PRIMATES; Protease Inhibitors - pharmacology; Protein Conformation; RADIOLOGY AND NUCLEAR MEDICINE; SCATTERING; SERINE PROTEINASES; Structure-Activity Relationship; Substrate Specificity; Swine; VERTEBRATES; X-RAY DIFFRACTION
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi00431a001

The serine protease family of enzymes is one of the most widely studied group of enzymes, as evidenced by the fact that more crystal structures are available for individuals of this superfamily than for any other homologous group of enzymes. These enzymes contain a conserved triad of catalytic residues including Ser-195, His-57, and Asp-102. The active-site serine is very nucleophilic, and serine proteases are inhibited by specific serine protease reagents such as diisopropyl phosphorofluoridate (DFP), phenylmethanesulfonyl fluoride, and 3,4-dichloroisocoumarin. Elastases are a group of proteases that possess the ability to cleave the important connective tissue protein elastin. Elastin has the unique property of elastic recoil, is widely distributed in vertebrate tissue, and is particularly abundant in the lungs, arteries, skin, and ligaments. Human neutrophil elastase and pancreatic elastase are two major serine proteases that cleave elastin. Neutrophil elastase is found in the dense granules of polymorphonuclear leukycytes and is essential for phagocytosis and defense against infection by invading microorganisms. Pancreatic elastase is stored as an inactive zymogen in the pancreas and is secreted into the intestines where it becomes activated by trypsin and then participates in digestion. Both elastases cleave substrates at peptide bonds where the P{sub 1} residue is an amino acid residue with a small alkyl side chain.