5-Enolpyruvylshikimate-3-phosphate synthase, glyphosate inhibition

Jaworski (4) reported that growth inhibition of both plant and microbes by glyphosate could be reversed by aromatic amino acids. Further work of Amrhein and his coworkers revealed that glyphosate inhibits the shikimate pathway enzyme, 5-enolpyruvylshikimate 3-phosphate (EPSP) synthase (5). This enzyme catalyzes the reaction shown in Figure 1. Glyphosate-treated plant and bacterial cultures accumulate shikimate and/or shikimate 3-phosphate (S3P), confirming that inhibition of EPSPS is at least a part of the in vivo mechanism of action of this herbicide (6, 7). 

For example, glyphosate inhibits the enzyme, EPSP (5-enolpyruvylshikimate 3-phosphate) synthase, that catalyzes a step in the synthesis of the aromatic amino acids. Similarly, both the imidazolinones and sulfonylureas inhibit acetolactate synthase (ALS), the enzyme that catalyzes the first step in the formation of branched-chain amino acids (11). Triazine herbicides act by binding to a specific protein in the thylakoid membranes of the chloroplasts, preventing the flow of electrons and inhibiting photosynthesis (12). 

Figure 14. Conversion of shikimate-3-phosphate to 5-enolpyruvylshikimate-3-phosphate blocked by glyphosate inhibition of 5-enolpyruvylshikimate-3-phosphate synthase (%1).

Plants synthesize all 20 common amino acids de novo. Glyphosate, a weed killer sold under the trade name Roundup, is an analog of phosphoenolpyruvate that specifically inhibits 3-enolpyruvylshikimate 5-phosphate synthase, a key enzyme of the pathway for chorismate biosynthesis. This compound is a very effective plant herbicide, but has virtually no effect on mammals. Why ... 

Glyphosate inhibition of 5-enolpyruvylshikimate 3-phosphate synthase from suspension-cultured cells of Nicotiana silvestris. Plant Physiol. 75 829-845. 

Steinriicken, H.C. and Amrhein, N. (1984) 5-Enolpyruvylshikimate-3-phosphate Synthase of Klebsiella pneumoniae. 2. Inhibition by Glyphosate [N-(phosphono-methyOglycine], Eur. J. Biochem., 143, 351-357. 

In this chapter, the discussion will concentrate on two inhibitors with a reasonable claim to selective action on enz3ones related to the shikimate pathway glyphosate, which inhibits 5-enolpyruvylshikimate 3-phosphate (EPSP) synthase and L-a-aminooxy-3 phenylpropionic acid (L-AOPP), an inhibitor of phenylalanine ammonia-lyase (PAL) (Fig. 2). In addition to introducing a novel inhibitor of PAL, (R)-(l-amino-2-phenylethyl)phosphonic acid (APEP), previous and current efforts to design inhibitors of other shikimate pathway enzymes will be described. The treatment presented here will show that the deductions and predictions made on the basis of the abstract scheme in Figure 1 can be, and have been, tested on the basis of the real pathway presented in Figure 2. 

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