Acetolactate synthase actions

Chaleff, R. S. and Mauvais, C. J. 1984. Acetolactate synthase is the site of action of two sulfonylurea herbicides in higher plants. Science 244, 1443-1445... 

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... 

The mode of their action consists in the acetolactate synthase (ALS) inhibition and, as a result, in the inhibition of the branched-chain amino acid biosynthesis from acetolactate (90MI1, 92MI7, 98MI4). Results of QSAR studies were published (03MI3). Another approach was used to analyze a model of inhibition of photosystem II (96MI1). 

One of the most effective classes of herbicide are the sulfonylureas. They are applied in quantities of no more than a few grams per hectare. The action of sulfonylureas is based on inhibition of acetolactate synthase (ALS) [9]. The fluorine-containing derivative Primsulfuron methyl has selectivity in the cultivation of maize [10]. 

Biological Activity. We have shown that the site of biochemical action for sul fonylureas is the enzyme acetolactate synthase (1,2). This enzyme catalyzes the first common step in the biosynthesis of the essential branched chain amino acids valine and isoleucine. Plants must synthesize these amino acids for protein synthesis and subsequent growth. Therefore, this is a vulnerable or critical... 

A great number of herbicides that work through the inhibition of acetolactate synthase (ALS) have been commercialized. They belong to four chemical groups sulfonylureas (23), triazolopyrimidines (2), imidazolinones (5), and pyrimidinyloxybenzoic analogues (3). (The number of active ingredients in parentheses is taken from The Pesticide Manual.) Also in this case, potent herbicides were developed (e.g., chlorsulfuron) before the site of action was found. 

Application of Global Sequence Similarity to Find an Inhibitor of Acetolactate Synthase. Acetolactate synthase (ALS) Is the site of action of sulfonylurea, Imldazollnone, and trlazolo pyrimidine herbicides (10-14). Their mode of Inhibition and binding sites on ALS were ambiguous, because (1) these herbicides bear no obvious similarity In their chemical structures to those of ALS substrates (pyruvate and acetolactate), cofactors (thiamine pyrophosphate, FAD, and Mg ) and effectors (valine, Isoleuclne, and leucine) and (2) they Inhibit ALS In a mode too complex to be analyzed. 

Both compounds are inhibitors of the acetolactate synthase enzyme, also known as aceto hydroxy acid synthase (AHAS) and are classified in group B by the Herbicide Resistance Action Committee HRAC. Table 2.6.1 gives the physicochemical properties of 1 and 2. 

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. 

Figure 1. Biosynthetic pathway for the branched chain amino acids in plants and microorganisms. Acetolactate synthase is the site of action of the sulfonylurea, imidazolinone and triazolopyiiniidine sulfonanilide herbicides.

The same is true in the case of imazaquin and chlorimuron-ethyl. It is well known that these two herbicides have the same mode of action (, ), namely blocking the biosynthesis of branched chain amino acids by inhibition of acetolactate synthase (ALS) correspondingly, the response patterns are very similar. 

Triazine herbicides and quinoclamine, having the mode of action in inhibition of PS II (Photosynthesis at photosystem II) had low variability on sensitivities in different algal taxa. On tiie other hand. Amide herbicide such as Pretilachlor and Cafenstrole as well as sulfonylurea herbicides of bensulfiironmethyl and imazosulfuron had great variability on sensitivities in different algal taxa. These herbicide have in other the mode of action in inhibition of cell division or in inhibition of acetolactate synthase rather tiian in inhibition of PS II. Carbamate herbicide showed relatively low toxicity on algae. Daimuron and bentazone exhibit low toxicity on all tire tested species (Figure 3). 

Imazaquin, an example of the imidazolinone class of herbicides, is particularly selective to soybeans. These compounds have a similar mode of action to that of the sulfonylurea herbicides, which will be discussed later. They block branched chain amino acid biosynthesis by inhibition of the enzyme acetolactate synthase (ALS). 

Some groups of herbicides depend upon phloem translocation to reach their sites of action. For example, the phenoxyalkanoic acid herbicides, which act on cell growth and development, and glyphosate, which inhibits the biosynthesis of aromatic amino acids, are translocated from leaves to all sites of active growth within the plant. Similarly, the sulfonylureas and imidazolinones, which inhibit acetolactate synthase, are, when applied postemergence, translocated in the phloem to all parts of the plant. 

The first step in valine biosynthesis is a condensation between pyruvate and active acetaldehyde (probably hy-droxyethyl thiamine pyrophosphate) to yield a-acetolactate. The enzyme acetohydroxy acid synthase usually has a requirement for FAD, which, in contrast to most flavopro-teins, is rather loosely bound to the protein. The very same enzyme transfers the acetaldehyde group to a-ketobutyrate to yield a-aceto-a-hydroxybutyrate, an isoleucine precursor. Unlike pyruvate, the a-ketobutyrate is not a key intermediate of the central metabolic routes rather it is produced for a highly specific purpose by the action of a deaminase on L-threonine as shown in figure 21.10. 

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