Please note these web pages are part of an assignment for a graduate course in Advanced Biochemistry and Molecular Biology BCMB8010 at the University of Georgia. Questions should be directed to Gina Pries (gpries@uga.edu).

History

Study of the shikimate pathway, found in plants, bacteria, and fungi, led to the discovery of EPSP synthase in 1980 by Amrhein and coworkers (13). Ten years prior to the discovery of EPSP synthase, however, glyphosate was found to be an effective herbicide, but its mechanism was as yet unknown. A team of scientists at Monsanto Chemical Company utilized the process of greenhouse screening, synthesizing and testing compounds similar to weak herbicides with the assumption that these compounds would suffer the same metabolic fate and some might therefore display increased toxicity to plants (3). Further study by Monsanto led to the finding that glyphosate's mode of action was interference with aromatic amino acid biosynthesis. Since the discovery of EPSP synthase and the realization of its potential in medicine as a target for antibiotics and in agriculture as a target for herbicides, numerous studies have been launched in an attempt to better understand its mechanism and structure so as to develop inhibitor agents against it. With respect to structure, the first leap forward came with the publication of the three-dimensional backbone of EPSP synthase elucidated through X-ray crystallography in 1991 by W. C. Stallings et al. (14). This provided a basis for more in-depth studies of structure and function, and it was followed by further X-ray chrystallographic analysis by Ernst Schönbrunn and coworkers who resolved in atomic detail the structure and active site of EPSP synthase bound to S3P and EPSP synthase binding S3P and glyphosate (1). Following this stunning work, NMR was used to further detail the interactions of S3P with the N-terminal domain of EPSP synthase and the conformational changes that take place upon substrate binding (15). Presently, the structure and mechanism of EPSP synthase nearing complete understanding, and soon more focus can be placed on designing tailored inhibitors for commercial and medical use.