Inhibition by sulfonylurea

Acetolactate synthase inhibition by herbicides, 36,38 inhibition by sulfonylurea herbicides, 33,36,37/... 

Some are inhibited by ATP 173 l7 lb and others by eicosanoids475 or inositol hexaphosphate.476 Some of the ATP-sensitive channels contain an ABC transporter subunit and are binding sites for sulfonylureas and other drugs. See discussion on p. 421. A number of human disorders in Kir channels have been identified.468 Tire human Kir channels participate in regulation of resting membrane potentials in K+ homeostasis, control of heart rate, and hormone secretion.468 A third group of K+ channels are dimeric, but each subunit contains two tandem P regions and 4-8 transmembrane helices.455... 

Tamargo et al gave a very recent review.139 They point out that KATP channels are inhibited by ATP and activated by Mg ADP, so that the channel activity is influenced by the ATP/ADP ratio. They also draw attention to the fact that mitochondrial KATp channel is responsible for ischemic preconditioning. They suggest that these channels are not blocked only by sulfonylureas, but also by many antiarrhythmic drugs, such as bretylium, disopyramide, flecainide and propafenone, and also by diltiazem and verapamil, but not by amiodarone or dronedarone, which will be addressed later. 

ALS is also inhibited by a number of compounds which are structurally unrelated to the sulfonylureas. These include two other classes of herbicides the imidazolinones (5) and the triazolopyrimidines (Hawkes, T.R. Howard, J.L. Pontin, S.E. In Herbicides and Plant Metabolism, in press). LaRossa et al. have speculated on why ALS is such an effective target for so many inhibitors (6). Blocking ALS leads to the buildup of the toxic substrate a-ketobutyrate. The elevated levels of this metabolite combined with the reduced levels of the branched chain amino acids appear to make the inhibition of ALS a particularly lethal event. 

ALS has also been shown to be inhibited by two other structurally unrelated classes of herbicides, the imidazolinones (8,9) and the triazolopyrimidines (10,11). It has been shown that the toxicity of the sulfonylurea herbicides to bacteria is due, in part, to the accumulation of an ALS substrate a-ketobutyrate, which is itself toxic. It has been suggested that the dual effects of the accumulation of a toxic substrate and the inability to synthesize isoleucine, leucine and valine make ALS a particularly good target for herbicides (12). 

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

Inhibitors of Acetolactate Synthase (ALS/AHAS) The enzyme acetolactate synthase (ALS) plays in plants an essential role in branched-chain amino acid biosynthesis. In the pathway leading to valine and leucine, ALS catalyzes the formation of 2-acetolactate from two pyruvate molecules, and in the pathway to isoleucine the formation of 2-acetohydroxybutyrate from 2-ketobutyrate and pyruvate. Due to this double function the enzyme is also called with a more general term aceto-hydroxyacid synthase. ALS is inhibited by several groups of herbicides, mainly the sulfonylureas (SUs), imidazolinones (IMIs), triazolopyrimidines (TPs), pyrimidinylthiobenzoates(PTBs) and sulfonylaminocarbonyltriazolinone (SCTs) (see Chapter 2.1, M. E. Thompson). 

The drug works by inhibiting the sulfonylurea receptor 1 (SURl), the regulatory subunit of the ATP-sensitive potassium channels (K p) pancreatic beta cells. This inhibition causes cell membrane depolarization opening voltage-dependent calcium channel. This results in an increase in intracellular calcium in the beta cell and subsequent stimulation of insulin release. 

All four herbicides belong to completely different chemical classes sethoxydim is a cyclohexanone, fluazif op-butyl a phenoxyphenoxy-type con und, imazaquin an imidazolinone, and chlorimuron-ett l a sulfonylurea. The mode of action of fluazifop-butyl and imazaquin is inhibition of acetyl-CoA carboxylase (ACC) (, 7 ) Obviously, this is reflected by the similarity of the response patterns. The way it corresponds is not a direct one we can say nothing ed>out fatty acid biosynthesis inhibition by looking at the response pattern. What we see is the influence on other meted>olites, which are in most cases only indirectly connected with fatty acid biosynthesis. But the patterns are strikingly similar. 

The inhibition by the sulfonylurea herbicide sulfometuron-methyl (SMM, Oust Figure 2.4) has been well characterized. The inhibition is complex and shows rapid and slow phases. Reaction progress curves are biphasic in the presence of the inhibitor both stages are inhibited reversibly and competitively with respect to pyruvate. With ALS II from... 

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... 

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