Even though no new herbicide mode-of-actions have been introduced these past 30 years there has been significant progress in our understanding of the interactions of these herbicides and their targets. During the heyday of discovery and herbicide introduction the MOA was a “nice to have” feature of the commercial development process. Today some very old major herbicides still do not have a definitive MOA. Reviewing our understanding of the specific molecular -enzyme interactions may provide insights into the discovery process. A very good example of competitive inhibition kinetics is provided by phosphinothricin inhibition of glutamine substrate binding to glutamine synthetases. In theory, a competitive inhibitor can be eventually displaced by the accumulating substrate. However, time is critical since the toxic effect of the accumulated ammonium cation does not allow successful competition by glutamate. Phosphinothricin binds tighter than glutamine and has a very slow transition state with bound ATP to form the phosphorylated inhibitor which then slowly releases to provide active enzyme. Overall, phosphinothricin is regenerated, ATP is hydrolyzed in a futile cycle and the enzymatic flux is a small fraction of that required. A great example of non-competitive inhibition is provided by the acetolactate synthase class of inhibitors where the herbicides bind to free enzyme or bind the substrate binary complex before the second substrate. Because, these two enzyme forms are “reversibly connected” the kinetic pattern is non-competitive. However, recent results demonstrate that 2 classes of these herbicides also induce degradation of the thiamine pyrophosphate intermediate to destroy the cofactor. Hence, these are not quite suicide inhibitors since the enzyme can be regenerated eventually and has not itself been modified. The unique and solitary example of un-competitive inhibition is demonstrated by glyphosate inhibition of EPSPS in the shikimate pathway. Glyphosate binds to the Michaelis binary complex a 100x tighter than the second substrate PEP to form a semi-stable ternary dead-end complex. The herbicidal complex is further stabilized by the rapid increase of shikimate 3-phosphate to maintain the Michaelis binary complex while PEP is highly regulated. These nuances and others that have been revealed over the last 3 decades will be discussed and related to the design of new herbicides.

Competitors, non-competitors, and un-competitors in herbicide sites of action

2019 Fall National Meeting

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