Sulfonylureas enzyme inhibition

Most sulfonylureas are at least partly metabolized in the liver (SEDA-9, 709) (57), and hence liver insufficiency, liver disease, and liver enzyme inhibition (alcohol) or induction (drugs) can alter the half-life of the drug and its duration of action. 

F. Matsumura An important contribution of this more basic research is identifying areas on which we can focus our synthesis effort. We know that the sulfonylurea herbicides inhibit an enzyme that is important in the synthesis of amino acids in plants but not mammals. Now it is turning out that several new classes of herbicides attack plants at the same site. Another example are the new sterol... 

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. 

This strategy was used to engineer resistance against glyphosate, and imidazoli-nones and sulfonylureas that inhibit acetolactate synthase (ALS), a key enzyme in the biosynthesis of branched chain amino acids. ALS resistant crops have primarily been generated through selection for an herbicide insensitive ALS allele from natural or mutagenized cell or plant populations [3]. 

In AChE-based biosensors acetylthiocholine is commonly used as a substrate. The thiocholine produced during the catalytic reaction can be monitored using spectromet-ric, amperometric [44] (Fig. 2.2) or potentiometric methods. The enzyme activity is indirectly proportional to the pesticide concentration. La Rosa et al. [45] used 4-ami-nophenyl acetate as the enzyme substrate for a cholinesterase sensor for pesticide determination. This system allowed the determination of esterase activities via oxidation of the enzymatic product 4-aminophenol rather than the typical thiocholine. Sulfonylureas are reversible inhibitors of acetolactate synthase (ALS). By taking advantage of this inhibition mechanism ALS has been entrapped in photo cured polymer of polyvinyl alcohol bearing styrylpyridinium groups (PVA-SbQ) to prepare an amperometric biosensor for... 

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. 

Flucetosulfuron [188,189] is a sulfonylurea experimental postemergence herbicide for controlling grasses such as barnyard grass in rice and broadleaf weeds such as Galium aparine in cereals. It shares with previously introduced sulfonylurea herbicides a common mode of action, inhibition of the ALS enzyme, a key enzyme in the biosynthesis of branched amino acids, such as leucine, isoleucine, and valine [76],... 

The selective toxicity of sulfonylureas to certain weeds without damage to the cereal crop arises from their rapid metabolism in the crop plant to inactive compounds, whereas in sensitive weeds the metabolism is much slower. The very high herbicidal activity suggests a specific biochemical mode of action, which is concluded to be the inhibition of plant cell division. Sulfonylureas block the enzyme acetolacetate synthase (ALS), which catalyses the biosynthesis of the essential branched chain amino acids valine, leucine and isoleucine. 

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. 

Drug interactions metabolized by CYP450 3A4, may interact with drugs that inhibit or induce this enzyme May cause hypoglycemia in patients receiving insulin, sulfonylureas, or metformin contraindicated in pregnant women Limit vitamin A supplements... 

An in vitro assay for intrinsic sulfonylurea activity has been developed using isolated plant enzyme (5). The Icn for ALS inhibition is defined as the concentration of sulfonylurea that... 

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. 

Second, a key enzyme or receptor in the pathway should be identified as the target. It is best to select enzymes whose products are important for several functions in the species. Cellular response to such a metabolic blockade should also be considered (e.g., cascading effects). Often end-product limitation results in more metabolites entering the pathway. After sufficient substrate accumulation, catalysis may occur even in the presence of an inhibitor (10). However, accumulation of toxic intermediates would prevent tTTTs cellular response and lead to death. Again using sulfonylureas as an example, acetolactate synthase is a common enzyme in the pathway for two essential amino acids rather than just one. Also, inhibition of acetolactate synthase leads to high levels of a-ketobutyrate which is thought to have deleterious effects (11). 

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. 

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. 

Miglitol is an alpha-glucosidase inhibitor that inhibits intestinal enzymes that digest carbohydrates, thereby reducing carbohydrate digestion after meals, which lowers postprandial glucose elevation in diabetics. It is used in patients with non-insulin-dependent diabetes mellitus (NIDDM) who have failed dietary therapy. It may be used alone or in combination with sulfonylureas. 

Sulfonylureas are systemic herbicides absorbed by the foliage and roots. They act by inhibiting acetolactate synthase, a key enzyme in the biosynthesis of branched chain aminoacids." This results in stopping cell division and plant growth. The most important degradation pathways of sulfonylureas are chemical hydrolysis and microbial degradation. 

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). 

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