Herbicides acetolactate synthase target

Matthews, J.M., J.A.M. Holtum, D.R. Liljegren, B. Furness, and S.B. Powles (1990). Cross-resistance to herbicides in annual ryegrass (Lolium rigidum). 1. Properties of the herbicide target enzymes acetyl-coenzyme A carboxylase and acetolactate synthase. Plant... 

Acetolactate synthase (ALS, EC 4.1.3.18) is the first common enzyme in the biosynthetic route to the branched chain amino acids, valine, leucine and isoleucine. It is the primary target site of action for at least three structurally distinct classes of herbicides, the imidazolinones (IM), sulfonylureas (SU), and triazolopyrimidines (TP) (Figure 1). SU and IM were discovered in greenhouse screening programs whereas TP was subsequently targeted as a herbicide. Numerous substitution patterns can be incorporated into the basic structure of all three classes of herbicides to provide crop selectivity as well as broad spectrum weed control. This is amply demonstrated in the seven products based on SU and four based on IM already in the market. A number of others are in various stages of development. The rapid success of ALS inhibitors as herbicidal products has attracted a world-wide research commitment. Not since the photosystem II... 

Inhibits ALS activity by 50%. A good correlation exists between the herbicidal activity of sulfonylureas and their ability to inhibit acetolactate synthase (2). This in vitro assay using the target enzyme along with the three-dimensioFTI structure of the enzyme should aid in the generation of a substantial data base that can be used to design potent inhibitors. 

Interestingly, POX has a genetically closely related cousin acetolactate synthase" (ALS) that still has a bound FAD. Instead of oxidizing the enamine, ALS employs the enamine in nucleophilic addition to a second pyruvate producing acetolactate, an important anabolic intermediate in the biosynthesis of the essential aliphatic amino acids in plants. ALS is a major target for herbicides . ALS may be using the FAD to protect the enamine from being protonated, prior to condensation. 

Acetolactate synthase (ALS) is the target enzyme for three unrelated classes of herbicides, the sulfonylureas, the imidazolinones, and the triazolopyrimidines. We have cloned the genes which specify acetolactate synthase from a variety of wild type plants, as well as from plants which are resistant to these herbicides. The molecular basis of herbicide resistance in these plants has been deduced by comparing the nucleotide sequences of the cloned sensitive and resistant ALS genes. By further comparing these sequences to ALS sequences obtained from herbicide-resistant yeast mutants, two patterns have become clear. First, the ALS sequences that can be mutated to cause resistance are in domains that are conserved between plants, yeast and bacteria. Second, identical molecular substitutions in ALS can confer herbicide resistance in both yeast and plants. 

The sulfonylurea herbicides are a new family of chemical compounds, some of which are selectively toxic to weeds but not to crops. The selectivity of the sulfonylureas results from their metabolism to non-toxic compounds by particular crops, but not by weeds. In addition to efficient weed control, the sulfonylurea herbicides provide environmentally desirable properties such as field use rates as low as two grams/hectare and very low toxicity to mammals. The high specificity of the herbicides for their molecular target contributes to both of these properties. In addition, the low toxicity to mammals results from their lack of the target enzyme for the herbicides. Sulfonylureas inhibit the enzyme acetolactate synthase (ALS), also known as acetohydroxyacid synthase (AHAS), which catalyzes the first common step in the biosynthesis of the branched chain amino acids leucine, isoleucine and valine. In mammals these are three of the essential amino acids which must be obtained through dietary intake because the biosynthetic pathway for the branched chain amino acids is not present. The prototype structure of a sulfonylurea herbicide is shown in Figure 1. 

The discovery of this site of action was quite consistent with the known very low animal toxicity of the sulfonylurea herbicides. Animals do not biosynthesize the branched-chain amino acids and do not possess the target enzyme acetolactate synthase. 

Acetolactate synthase (ALS) is the enzyme target site of the sulfonyl-ureas. In common with the imidazolinone aryl carboxylates, these herbicides inhibit valine and isoleucine biosynthesis. The imidazolinones are exemplified by Assert (8), which consists of a mixture of m- and p-isomers. The selectivity of ALS inhibitors invariably can be accounted for by differential metabolism or uptake or related phenomena rather than by any significant inherent difference in the properties of the ALS enzymes of crop and weed species. Assert is another example of a herbicide activated in plants by deesterification to the phytotoxic acid, and susceptible species such as Avena fatua (wild oat) are unable to metabolize the molecule further. Facile ring-methyl hydroxylation to the m- and p-benzyl alcohols, however, followed by glycosylation confers tolerance to maize and wheat." ... 

New herbicides continue to be introduced. Resolve Q is an herbicide for use on corn, which contains rimsulfuron, 24.10 thifensulfuron, 24.11 and isoxadifen ethyl, 24.12.24.10 and 24.11 are part of a new family of environmentally compatible sulfonyl urea herbicides, which target the acetolactate synthase enzyme. Alachlor, 24.13, is used for grasses and broad-leaved weeds in corn, soya, and peanuts but is banned in the EU because of its toxicity. Mesotrione, 24.14, based on a substance isolated from the Californian bottlebrush plant, is more generally accepted and can be applied both pre- and postemergence it inhibits the plant enzyme 4-hydroxyphenylpyruvate dioxygenase. 

---