Evolution of Catalysis in the Serine Proteases

The hydrolytic cleavage of peptide bonds by proteases is an ancient biochemical reaction prevalent in all forms of living organisms. Hydrolysis of a peptide substrate by a protease requires specificity in binding and catalytic efficiency. Certain constellations of amino acid residues comprise the substrate binding pocket, which in turn confers the unique substrate specificity of each enzyme. Productive binding of the substrate in this pocket positions the scissile bond next to a characteristic set of functional amino acid residues arranged in a particular conformation to form the active site. The active-site residues polarize the peptide bond by nucleophilic attack on the carbon-oxygen bond assisted by the donation of a proton to the peptide amide nitrogen. The evolution of this highly sophisticated protein "machine" has been the topic of previous studies involving protein sequencing, crystallography, and enzyme kinetics (Neurath 1984). A prototypic hydrolytic enzyme that has been the subject of many...