Date of Award
John J. Perona
Drugs -- Design, Aminoacyl-tRNA synthetases -- Synthesis
Substrate analogs are small molecules that aid in the understanding of enzyme structure-‐function relationships. By careful design they can be utilized to probe the nature of the transition state in catalysis, and to assist in the process of rational drug design. Aminoacyl-‐sulfamoyl adenylate transition state analogs (aa-‐ AMS) are analogs of the aminoacyl adenylate reaction intermediate in aminoacylation by aminoacyl-‐tRNA synthetases (aaRS). To better understand the chemical mechanism of aaRS, aa-‐AMS are used in crystallography experiments where x-‐ray diffraction helps reveal interactions crucial to catalysis. Here we report the complete synthesis and purification of Ile-‐AMS. The four-‐step process proceeds via a sulfamoyl-‐adenylate precursor, from which a library of aa-‐AMS can then be generated by the addition of particular amino acids. After addition of the amino acid 5 the product is put through an acid work up and purification step, giving an 85% experimental yield. Because commercially produced aa-‐AMS are no longer available, assembly of a library of aa-‐AMS would be beneficial for future research both at PSU and through collaboration with other research teams worldwide.
Nilsson, Emil Mikael, "Synthesis of Sulfamoyl‐Aminoacyl Adenylate Analogs for use in Protein‐RNA Structure Determination" (2013). University Honors Theses. Paper 25.