Acetolactate synthase herbicides

Herbicides also inhibit 5- (9/-pymvylshikiniate synthase, a susceptible en2yme in the pathway to the aromatic amino acids, phenylalanine, tyrosine and tryptophan, and to the phenylpropanes. Acetolactate synthase, or acetohydroxy acid synthase, a key en2yme in the synthesis of the branched-chain amino acids isoleucine and valine, is also sensitive to some herbicides. Glyphosate (26), the sulfonylureas (136), and the imida2oles (137) all inhibit specific en2ymes in amino acid synthesis pathways. 

Fig. 3. Generation of propionyl-CoA from the isoleucine biosynthetic pathway. The intermediate 2-ketobutyrate can be decarboxylated by either the 2-oxoacid dehydrogenase complex or at low efficiency by the pyruvate dehydrogenase complex. Inhibition of the threonine deaminase by isoleucine and of the acetolactate synthase by herbicides are indicated with dashed arrows...

A. Seki, F. Ortega, and J.L. Marty, Enzyme sensor for the detection of herbicides inhibiting acetolactate synthase. Anal. Lett. 29,1259—1271 (1996). 

There are several commercially available sulfonylurea herbicides that contain a 2-pyrimidine group <2006H(68)561>. These compounds, which function by inhibition of acetolactate synthase (ALS), an enzyme involved in the early stage of branched-chain amino acid synthesis, include sulfometuron-methyl 1095, primisulfuron-methyl 1096, chlorimuron-ethyl 1097, bensulfuron-methyl 1098, ethoxysulfuron 1099, nicosulfuron 1100, and pyrazosulfuron-ethyl 1101. Related nonsulfonylureas include the sulfide pyrftalid 1102 and the ether pyriminobac-methyl 1103. 

Haughn, G., Smith, J., Mazur, B. Sommerville, C. (1988). Transformation with a mutant Arabidopsis acetolactate synthase gene renders tobacco resistant to sulfonylurea herbicides. Molecular and General Genetics 211, 266-71. 

What are the criteria for regarding a compound as a TS analog The observation that the binding affinity of an inhibitor is greater than that of a substrate, i.e., X, < XM, is insufficient as many potent inhibitors bind differently to an enzyme than the substrate examples are methotraxate, inhibiting dihydrofolate reductase (DHFR) X] = 0.15 pM (Werkheiser, 1961), and sulfonyl urea herbicides, inhibiting acetolactate synthase (ALS) at picomolar levels. 

Maertens, K.D., C.L. Sprague, P.J. Tranel, and R.A. Hines (2004). Amaranthus hyridus populations resistant to triazine and acetolactate synthase-inhibiting herbicides. Weed Res., 44 21-26. 

Christopher, J.T., S.B. Powles, and J.A.M. Holtum (1992). Resistance to acetolactate synthase-inhibiting herbicides in annual ryegrass (Lolium rigidum) involves at least two mechanisms. Plant Physiol., 100 1909-1913. 

Saari, L.L., J.C. Cotterman, and D.C. Thill (1994). Resistance to acetolactate synthase-inhibitor herbicides. In Powles, S.B. and Holtum, J.A.M., eds., Herbicide Resistance in Plants Biology and Biochemistry. Boca Raton, FL Lewis Publishers, pp. 83-139. 

Sibony, M., A. Michel, H.U. Haas, B. Rubin, and K. Hurle (2001). Sulfometuron-resistant Amaranthus retroflexus Cross-resistance and molecular basis for resistance to acetolactate synthase-inhibiting herbicides. Weed Res., 41 509-522. 

Sprague, C.L., E.W. Stoller, and L.M. Wax (1997c). Response of an acetolactate synthase (ALS)-resistant biotype of Amaranthus rudis to selected ALS-inhibiting and alternative herbicides. Weed Res., 37 93-101. 

White, A.D., M.D.K. Owen, R.G. Hartzler, and J. Cardina (2001). Common sunflower (Helianthus annuus) resistance to acetolactate synthase inhibiting herbicides. Resistant Pest Management. East Lansing, MI Michigan State University, 11 3-5. 

Zelaya, I.A. and M.D.A. Owen (2004). Evolved resistance to acetolactate synthase-inhibiting herbicides in common sunflower (Helianthus annuus), giant ragweed (Ambrosia trifida), and shattercane (Sorghum bicolor) in Iowa. Weed Sci., 52 538-548. 

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... 

Figure 1. Three chemical families known to exhibit herbicidal activity through the inhibition of acetolactate synthase. A. sulfonylurea (sulfometuron) B. imidazolinone (imazapyr) and C. A representative triazolopyrimidine.

In the 1950s and 1960s, Geigy and other firms developed a series of herbicides based on alkyl and dialkyl triazines, such as the root-herbicide atrazine (83)64. They are made by stepwise introduction of suitable nucleophiles into precursors. Other members are ametryn, the non-selective simazine (84) and the cyanuric chloride-derived methylthio triazine desmetryne (85) (Scheme 19). Chlorotoluron is 3-(3-chloro-p-toly 1 )-1,1-dimethylurea (86), a phenylurea herbicide. These products act on the photosynthetic pathway. Both 83 and 84 are used for weed control in maize65. Sulfonylureas such as the triazine chlorosulfone (87) inhibit the enzyme acetolactate synthase. They offer the major advantage of requiring no more than 10 to 20 g per hectare. 

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]. 

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. 

The sulfonylureas, an extremely potent class of herbicides, act by inhibiting acetolactate synthase (ALS), which is the first common enzyme in the biosynthetic pathways leading to the branched chain amino acids. Two other unrelated classes of herbicides also act by interfering with this enzyme. We have cloned and characterized the genes encoding ALS from several higher plants. The ALS genes isolated from herbicide sensitive and herbicide resistant plants have been compared, and several mutations which confer the herbicide resistant phenotype have been identified. 

This has changed dramatically in recent years, as is apparent throughout the herbicide chapters of this book. Of particular note are the surprising speed of resistance development to acetolactate synthase inhibitors (Mazur al., Gressel, this volume), and the emergence of multiply resistant ryegrass and blackgrass biotypes noted earlier. 

Lolium biotypes exist which have resistance to the sulfonylurea herbicides chlorsulfuron and metsulfuron methyl (4). The biotype used in the studies presented here is resistant to both these sulfonylurea herbicides. Sulfonylurea herbicides inhibit the chloroplastic enzyme acetolactate synthase (ALS), also known as acetohydroxyacid synthase (AHAS) (16). Inhibition of this enzyme results in disruption of the synthesis of the branched-chain amino acids valine and isoleucine (161. The imidazolinone herbicides also inhibit ALS Q2). In some species auxins can protect against chlorsulfuron inhibition (S. Frear, USDA North Dakota, personal communication) the mechanistic basis for this protection is not known. We have measured the ALS activity in the resistant and susceptible Lolium and have also checked for any induction of ALS activity following treatment with the sulfonylurea herbicide chlorsulfuron. 

It is not yet clear whether such factors will delay the rate of appearance of other types of resistance e.g. the multiple resistances to grass-killing herbicides in wheat, or to inhibitors of acetolactate synthase, where the fitness of resistant biotypes may be higher. 

Herbicide-Resistant Plants Carrying Mutated Acetolactate Synthase Genes... 

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. 

Acetolactate synthase inhibition by imidazolinones and triazolopyrimidines, 460 sensitivity to sulfonylurea herbicides, 460 Acetolactate synthase gene activity and inheritance of resistance in tobacco, 461... 

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