Closing down on glyphosate inhibition—with a new structure for drug discovery

Among enzyme inhibitors used in agriculture, glyphosate (N-phosphomethyl glycine) is remarkable. A nonselective herbicide discovered in 1970 by a group of scientists at Monsanto led by Dr. John Franz (1), glyphosate, since first commercialization under the trade name Roundup, has been used globally as a safe and effective means of weed control. The discovery of glyphosate's herbicidal activity was not quite serendipity, but instead resulted from a synthetic strategy based on the hypothesis that the weak herbicidal activities of related compounds derived from the possibility of their similar metabolic fate (2). Nevertheless, the initial discovery by greenhouse screening has been followed by intensive biochemical studies that have now led to nearly complete understanding of glyphosate's mode of action. In 1972, scientists at Monsanto led by Dr. E. Jaworski observed (3) that application of glyphosate resulted in the inhibition of aromatic amino acid biosynthesis in plants. In 1980, Professor N. Amrhein and coworkers (4) identified its target enzyme from the shikimate pathway (4): 5-enolpyruvoylshikimate-3-phosphate synthase (EPSPS; EC 2.5.1.19). EPSPS is a key enzyme involved in aromatic amino acid biosynthesis (5). The enzyme catalyzes an unusual reaction, wherein the enolpyruvoyl group from phosphoenol pyruvate (PEP) is transferred to the 5-hydroxyl of shikimate-3-phosphate (S3P) to form the products 5-enolpyruvylshikimate-3-phosphate (EPSP) and inorganic phosphate (Pi). The only other enzyme known to catalyze carboxyvinyl transfer by using PEP is UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), which catalyzes the first committed step in the biosynthesis of the peptidoglycan layer of the bacterial cell. In the case of EPSPS, the reaction proceeds through a tetrahedral intermediate (Scheme S1) formed from S3P and PEP (6). Inhibition of EPSPS by glyphosate has been shown to proceed through the formation of an EPSPS-S3P-glyphosate ternary complex and the binding is ordered with glyphosate binding to the enzyme only …