Cyclohexanedione herbicides are inhibitors of rat heart acetyl-CoA carboxylase

Seng, Thomas; Skillman, Tiffanie R.; Yang, Nengyu; Hammond, Craig

doi:10.1016/s0960-894x(03)00664-4

Cited by 12 publications

(4 citation statements)

References 23 publications

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“…A new DIM compound was found to inhibit the plastid ACC enzyme from rice, but is not harmful to the rice plant [101]. These herbicides are weak inhibitors against mammalian and yeast ACCs [48,102]. These enzymes contain a Leu residue at the first position (1705 of yeast ACC), and a Val residue at the second position (1967 of yeast ACC).…”

Section: Accs As Targets For Drug Action and Drug Discoverymentioning

confidence: 99%

Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery

Tong

2005

CMLS, Cell. Mol. Life Sci.

437

340

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Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in most living organisms. Mice deficient in ACC2 have continuous fatty acid oxidation and reduced body fat and body weight, validating this enzyme as a target for drug development against obesity, diabetes and other symptoms of the metabolic syndrome. ACC is a biotin-dependent enzyme and catalyzes the carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes, whereas it is a large, multi-domain enzyme in most eukaryotes. The activity of the enzyme can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. This review will summarize the structural information that is now available for both the BC and CT enzymes, as well as the molecular mechanism of action of potent ACC inhibitors. The current intense research on these enzymes could lead to the development of novel therapies against metabolic syndrome and other diseases.

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Section: Accs As Targets For Drug Action and Drug Discoverymentioning

confidence: 99%

Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery

Tong

2005

CMLS, Cell. Mol. Life Sci.

437

340

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“…A Leu residue is also found at an equivalent position in herbicide resistant ACCs from other eukaryotes [80] such as fungi [42,80] and mammals [80]. Recent studies, however, have demonstrated that several of the aryloxyphenoxypropionates and cyclohexanediones are capable of inhibiting yeast ACC (IC 50 = 100 -500 uM) [42] and rat ACC1 and ACC2 (IC 50 = 20 -100 uM) [81], although the inhibition is considerably weaker than that noted for plastid ACC of sensitive plants [78]. For plastid ACC, both classes of herbicides demonstrate a noncompetitive pattern of inhibition with respect to the three substrates of the enzyme, although the pattern is essentially competitive for acetyl-CoA [78].…”

Section: Aryloxyphenoxypropionate and Cyclohexanedione Herbicidesmentioning

confidence: 99%

“…For plastid ACC, both classes of herbicides demonstrate a noncompetitive pattern of inhibition with respect to the three substrates of the enzyme, although the pattern is essentially competitive for acetyl-CoA [78]. For rat ACC2, the cyclohexanediones also demonstrated a competitive pattern of inhibition with respect to acetyl-CoA [81] and for yeast ACC, the aryloxyphenoxypropionates demonstrated a competitive pattern of inhibition with respect to malonyl-CoA [37], suggesting a similar mode of interaction of the herbicides within the carboxyltransferase reaction centre of all three ACCs. Furthermore, double inhibition kinetic analyses have demonstrated that the cyclohexanediones and aryloxyphenoxypropionates are mutually exclusive inhibitors of plastid ACC, and interfere with the binding of malonyl-CoA, but not free CoA, to the enzyme, suggesting similar modes of interaction within the enzyme active centre, overlapping with the acyl-thioester region of acetyl-CoA and malonyl-CoA [78].…”

Section: Aryloxyphenoxypropionate and Cyclohexanedione Herbicidesmentioning

confidence: 99%

Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition

Harwood

2005

Expert Opinion on Therapeutic Targets

111

114

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Metabolic syndrome is defined as a clustering of cardiovascular risk factors (abdominal obesity, hyperinsulinaemia, atherogenic dislipidaemia, hypertension, hypercoagulability) that together increase the risk of developing coronary heart disease and Type-2 diabetes. Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favourably affect, in a concerted manner, a multitude of cardiovascular risk factors associated with metabolic syndrome. Studies in ACC2 knockout mice and in experimental animals treated with isozyme-nonselective ACC inhibitors have demonstrated the potential for treating metabolic syndrome through this modality. A variety of structurally diverse, mechanistically distinct classes of ACC inhibitors have been disclosed in the scientific and patent literature. Isozyme-nonselective ACC inhibitors may provide the optimal therapeutic potential for beneficially affecting metabolic syndrome. However, demonstration of the full potential of isozyme-selective inhibitors, once identified, should reveal advantages and liabilities associated with single isozyme inhibition. Whereas demonstrating clinical efficacy of an ACC inhibitor should be straightforward, the heterogeneity of the patient population and absence of established guidelines regarding approval end points for agents simultaneously affecting multiple aspects of metabolic syndrome will pose developmental challenges for initial market entries.

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“…The active ingredients of ACCase inhibitors are classified into the aryloxyphenoxypropionate (FOP), cyclohexanedione (CHD), and phenylpyrazoline (DEN) chemical families (Shergill et al, 2016). CHD derivatives represent a very active research area owing to their extensive structural diversity (Seng et al, 2003; Louie et al, 2010). As shown in Figure 1, there are six frequently used commercial CHD inhibitors: clethodim, sethoxydim, alloxydim, cycloxydim, tepraloxydim, and tralkoxydim.…”

Section: Introductionmentioning

confidence: 99%

Herbicidal Activity and Molecular Docking Study of Novel ACCase Inhibitors

Zhang

et al. 2018

Front. Plant Sci.

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Acetyl-CoA carboxylase (ACCase) is an important target enzyme for the development of new bleaching herbicides. On the basis of structure-activity relationships and active subunit combinations, a series of novel 2-phenyl-3-cyclohexanedione enol ester derivatives was designed and synthesized by coupling and acylation reactions. The preliminary biological tests indicated good post-emergent herbicidal activity at a dosage of 150–300 g ai/ha, superior to that of clethodim against barnyard grass. Compound 3d was safe with respect to maize, even at a dosage of 300 g ai/ha. Compound 3d showed the best ACCase inhibitory activity in vitro, with a value of 0.061 nmol h-1 mg-1 protein, superior to that of clethodim. Molecular docking modeling showed that compound 3d and clethodim had the same interactions with surrounding residues, leading to an excellent combination with the active pocket of ACCase. That may have been the mechanism responsible for the death of the barnyard grass. The present work suggests compound 3d as a potential lead structure for further development of novel ACCase inhibitors.

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Cyclohexanedione herbicides are inhibitors of rat heart acetyl-CoA carboxylase

Cited by 12 publications

References 23 publications

Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery

Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery

Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition

Herbicidal Activity and Molecular Docking Study of Novel ACCase Inhibitors

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