Inhibition of acetyl coenzyme

Aryloxyphenoxypropanoates and cyclohexanediones are two classes of herbicides that control many monocotyledoneous species. Although these herbicides are structurally very different (Fig. 1), there has been some conjecture that they have a similar mode of action because of their similarity in selectivity and symptomology. This paper describes the experiments that led to the discovery that aryloxyphenoxypropanoate and cyclohexanedione herbicides inhibit acetyl coenzyme A carboxylase (acetyl-coenzyme A bicarbonate ligase [ATP], EC 6.4.1.2) activity in susceptible species (1). In addition, evidence is presented indicating that the inhibition of acetyl coenzyme A carboxylase (ACCase) is well correlated to observed herbicidal activity. Similar, independent findings have recently been reported by two other research groups (2.3). 

SECOR ET AL. Herbicidal Inhibition of Acetyl Coenzyme A Carboxylase 267... 

Shirra, M.K., Patton-Vogt, J., Ulrich, A., Liuta-Tehlivets, O., Kohlwein, S.D., Henry, S.A., and Arndt, K.M., 2001, Inhibition of acetyl coenzyme A carboxylase activity restores expression of the INOl gene in a snfl mutant strain of Saccharomyces cerevisiae. Mol. Cell. Biol. 21 5710-5722. 

Petrasovits, L. A., McQualter, R. B., Gebbie, L. K., Blackman, D. M., Nielsen, L. K., Brum-bley, S. M. Chemical inhibition of acetyl coenzyme A carboxylase as a strategy to increase polyhydroxybutyrate yields in transgenic sugarcane. Plant BiotechnolJ 2013, 11,1146-1151. 

Gamble, J. Lopaschuk, G.D. Insulin inhibition of 5 -adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation. Metabolism, 46, 1270-1274 (1997)... 

Phosphoenol pyruvate pyruvate. The third big step in the free-energy diagram is the pyruvate-kinase reaction, where ATP is formed from phosphoenol pyruvate. ATP inhibits pyruvate kinase, similar to the inhibition of PFK. Pyruvate kinase is also inhibited by acetyl-Coenzyme A, the product of pyruvate metabolism that enters the TCA cycle. Fatty acids also allosterically inhibit pyruvate kinase, serving as an indicator that alternative energy sources are available for the cell. 

Intracellular degradation occurs via hydrolytic cleavage [7] and 3-ketothiolase is the enzyme that plays a key role in the production and degradation of PHA. The presence of a limited carbon source in the medium stimulates the process of degradation. In these conditions, the level of acetyl-coenzyme A (CoA) increases and prevents the inhibition of 3-ketothiolase by acetoacetyl-CoA. This allows the release of acetyl-CoA from P(3HB) and inhibits the condensation of acetyl-CoA to acetoacetyl-CoA [8]. PhaZ enzymes are secreted in order to break down the polymer into hydroxyacids which are then ntilised by the microorganism as a carbon source for growth [9]. Once... 

Wilkinson E.E. and Oswald T.H., 1987. S-ethyl-dipropylthiocarbamate (EPIC) and 2,2-dichloro-N,N-di-2-propenylacetamide (dichlortnid) inhibitions of synthesis of acetyl-coenzyme A derivates. Pestic. Biochem. Physiol. 28, 38-43. ... 

In plants, the step of conversion from pyruvate to acetyl coenzyme A, which is catalyzed by the El component, is the only irreversible step in the overall PDHc catalytic reaction. Once the El activity is inhibited, the overall enzymatic reaction and production of acetyl coenzyme A will be blocked [2]. In the absence of acetyl coenzyme A which is necessary for the tricarboxylic acid cycle, the production of ATP will be reduced, which can lead to the difficulty in energy-metabolism and the injury of the cellular tissue, ultimately it can cause death of the plant. In view of its important role in metabolism, plant PDHc El should be an interesting site of action for herbicide R D. 

Histone Acetylation. Figure 1 Histone acetylation is a posttranslational modification of lysine residues of histones. This modification is catalyzed by histone actyl transferases (HATs), which transfer an acetyl group (yellow) from acetyl-Coenzyme A onto the E-amino group of the lysine residue. Histone deacetylation is catalyzed by histone deacetylases (HDACs), which hydrolyze the lysine bound acetyl group. HDAC inhibitors like Trichostatin A (TSA) are known to inhibit the deacetylation reaction in vivo and in vitro. 

Figure 13.3. An overview of the chemical events at a cholinergic synapse and agents commonly used to alter cholinergic transmission acetyl CoA, acetyl coenzyme A Ch, choline. Nicotine and scopolamine bind to nicotinic and muscarinic receptors, respectively (nicotine is an agonist while scopolamine is an antagonist). Most anti-Alzheimer drugs inhibit the action of the enzyme cholinesterase.

ATP and magnesium were required for the activation of acetate. Acetylations were inhibited by mercuric chloride suggesting an SH group was involved in the reaction either on the enzyme or, like lipoic acid, as a cofactor. Experiments from Lipmann s laboratory then demonstrated that a relatively heat-stable coenzyme was needed—a coenzyme for acetylation—coenzyme A (1945). The thiol-dependence appeared to be associated with the coenzyme. There was also a strong correlation between active coenzyme preparations and the presence in them of pantothenic acid—a widely distributed molecule which was a growth factor for some microorganisms and which, by 1942-1943, had been shown to be required for the oxidation of pyruvate. 

When cucurbit cells are fed O-acetylserine or its metabolic precursors the rate of hydrogen sulfide emission in response to sulfate declines, and the incorporation of labeled sulfur from 35S-sulfate into cysteine increases (18). Inhibition of the synthesis of the O-acetylserine precursor acetyl coenzyme A by 3-fluoropyruvate (22) enhances hydrogen sulfide emission, but inhibits cysteine synthesis (1 ). These observations indicate that the availability of O-acetylserine is the rate limiting factor in cysteine synthesis. Hydrogen sulfide may be emitted to the extent the amount of sulfate reduced exceeds the synthesis of O-acetylserine. Therefore, direct release of sulfide from carrier-bound sulfide appears to be responsible for the emission of hydrogen sulfide in response to sulfate (Figure 1, pathway 1). 

In the first control point, citrate synthase catalyzes the condensation of acetyl-CoA with oxaloacetate to produce citrate (AG° = -32.2 kJ mol ). Although the reaction is reversible, the equilibrium lies very much in favor of citrate formation because of the hydrolysis of a bond in the intermediate compound, citroyl-CoA (Fig. 12-4). Citroyl-CoA is bound to citrate synthase, and the hydrolysis of the thioester bond, to produce citrate and coenzyme A, is an exergonic process. Citrate synthase is inhibited by its substrates (acetyl-CoA and oxaloacetate), and its activity is affected by... 

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