Proteolytic Cleavage, Reaction Mechanisms

Résumé fourni par la source

Abstract Proteolytic cleavage, the hydrolysis of peptide bonds in a protein, is a ubiquitous reaction in nature catalyzed by enzymes calledpeptidases(also referred to asproteases,proteinases, andproteolytic enzymes). Whether the purpose served is digestive scavenging of nutrients or regulation of a critical physiological process such as blood coagulation, peptidases play an essential role in the growth and survival of all living organisms. Because of their abundance and importance, the reaction mechanisms of peptidases have been studied more extensively than any other class of enzyme. Many of the first high resolution x‐ray crystal structures of proteins were obtained for peptidases. Our understanding of the mechanism of rate acceleration used by peptidases and the structural basis for their specificity has improved dramatically through the use of a recombinant DNA technique calledsite‐specific mutagenesis. Developed in the early 1980s, site‐specific mutagenesis is a method whereby one or more specific residues in the amino acid sequence of a protein can be removed or, more commonly, replaced with another amino acid via mutagenesis of its corresponding cloned gene. The contribution to catalysis of an amino acid functional group in the active site of an enzyme can then be determined directly. Because of the valuable insight into the reaction mechanism of peptidases afforded by site‐specific mutagenesis studies and high resolution x‐ray crystallography, there has been significant progress made in the design of new peptidase inhibitor drugs as well as the development of peptidases with improved properties for medicinal and industrial applications.

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