Inhibition of Plant Glutamine Synthetases by Substituted Phosphinothricins

Logusch, Eugene W.; Walker, Daniel M.; McDonald, John F.; Franz, John E.

doi:10.1104/pp.95.4.1057

Cited by 52 publications

(40 citation statements)

References 15 publications

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“…[23][24][25][26][27] However, none of the 2-amino-phosphono-carboxylic acids (16)(17)(18) identified in the virtual screening showed any inhibitory activity, despite the fact that the 9 phosphono group of docked 2-amino-6-phosphonohexanoic acid (17) overlaps well with the phosphono group of MSO-P. This is in accordance with results for DL-homophosphinothricin, which did not show any inhibition of sheep brain GS.…”

Section: Virtual Screeningsupporting

confidence: 77%

“…In fact a number of inhibitors, including MSO, 8 or its diastereomeric mixture L-(SR), 8,11,13,23 PPT, 8,19,20,[22][23][24][25]28 3, 19,20 and 4 29,35 have shown inhibitory activity when tested on both bacterial and eukaryotic GSs. Therefore a literature search was performed to identify known GS inhibitors for both eukaryotic and prokaryotic enzymes.…”

Section: Literature Surveymentioning

confidence: 99%

“…Several functional groups, including a carboxylic acid, a thioether, a sulfoxide, a sulfonamide and a phosphonate ester, were investigated as R 2 substituents. The compounds were synthesized from glycine (24)(25)(26)(27)(28) or from L- (29)(30)(31)(32)(33) or D-serine (34)(35)(36)(37)(38), as described in the experimental section. The desired products were prepared via a CuI catalyzed N-arylation of glycine, D-and L-serine, using K 2 CO 3 as a base, with an appropriately substituted arylbromide (Scheme 2).…”

Section: Synthesis Of a Small Librarymentioning

confidence: 99%

“…[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Much effort has been invested in developing GS inhibitors not only for antibacterial research, but also for weed control, 20,25,[30][31][32] since GS is a key enzyme in ammonia assimilation in plants. However, no inhibitor has shown improved activity compared to MSO or PPT.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery

Nordqvist

Nilsson

Röttger

et al. 2008

Bioorganic & Medicinal Chemistry

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Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery. Bioorganic & Medicinal AbstractA combination of a literature survey, structure-based virtual screening and synthesis of a small library was performed to identify hits to the potential antimycobacterial drug target, glutamine synthetase. The best inhibitor identified from the literature survey was (2S,5R)-2,6-diamino-5-hydroxyhexanoic acid (4, IC 50 of 610  15 µM). In the virtual screening 46,400 compounds were docked and subjected to a pharmacophore search. Of these compounds, 29were purchased and tested in a biological assay, allowing three novel inhibitors containing an aromatic scaffold to be identified. Based on one of the hits from the virtual screening a small library of 15 analogues was synthesized producing four compounds that inhibited glutamine synthetase.

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Section: Virtual Screeningsupporting

confidence: 77%

Section: Literature Surveymentioning

confidence: 99%

Section: Synthesis Of a Small Librarymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery

Nordqvist

Nilsson

Röttger

et al. 2008

Bioorganic & Medicinal Chemistry

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“…This is an unusual feature, since all GS inhibitors described to date share the property of being glutamate analogues that compete for the same binding site as the natural substrate (Farrington et al 1987;Köcher 1989;Logusch et al 1991). Methionine sulfoximine, tabtoxinine-β-lactam (2-amino-4-[3-hydroxy-2-oxo-azacyclobutan-3-yl]butanoic acid) and phosphinothricin inactivate the enzyme irreversibly through the formation of phosphorylated intermediates that strictly bind to the active site (Köcher 1989).…”

Section: Discussionmentioning

confidence: 99%

The herbicidally active compound N-2-(5-chloro-pyridyl) aminomethylene bisphosphonic acid acts by inhibiting both glutamine and aromatic amino acid biosynthesis

Forlani¹,

Lejczak²,

Kafarski³

2000

Functional Plant Biol.

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Abstract. The effect of the herbicidally active compound N-2-(5-chloro-pyridyl)aminomethylene bisphosphonic acid (Cl-pyr-AMBPA), previously found in vitro to inhibit the activity of the first enzyme in the shikimate pathway 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase, was investigated in vivo on suspension cultured cells of Nicotiana plumbaginifolia Viviani. Amino acid pool measurement showed an actual reduction of tyrosine, tryptophan and phenylalanine level following the addition of the compound to the growth medium. However, an even stronger effect was noticed for other amino acids, mainly glutamine. When the activity of the enzymes involved in the glutamate cycle was measured in the presence of Cl-pyr-AMBPA, glutamate synthase was unaffected, while glutamine synthetase was significantly inhibited. Contrary to the herbicide phosphinothricin, the inhibitor bound reversibly to the enzyme. Kinetic analysis accounted for an inhibition of uncompetitive type with respect to ammonium, glutamate and ATP, with K i values of 113, 97 and 39 µM, respectively. Only the exogenous supply of a mixture of glutamine and aromatic amino acids relieved cell growth inhibition, suggesting that the phytotoxic properties of Cl-pyr-AMBPA are due to inhibition of key enzymes in both the corresponding pathways.

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The design and synthesis of inhibitors of dethiobiotin synthetase as potential herbicides

et al. 1999

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Dethiobiotin synthetase (DTBS ; E.C. 6.6.6.6), the penultimate enzyme in the biosynthesis of the essential vitamin biotin, is a new potential target for novel herbicides. Inhibitors were designed based on mechanistic and structural information. The in-vitro activities of these potential inhibitors versus the bacterial enzyme are reported here. Mimics of 7,8-diaminopelargonic acid (DAPA) or the DAPA carbamate reaction intermediate were substrates or partial substrates for the enzyme. Synergistic binding with ATP was noted with compounds which contained an amino functionality. NMR studies and X-ray structures conürmed that the inhibitors could be phosphorylated by the enzyme. Several series of potential inhibitors were designed to take advantage of this partial substrate activity by generating potentially more tightly bound phosphorylated inhibitors in situ. Structure-activity relationships for these series based on both substrate and inhibitory activity are described herein. An X-ray structure for one of these inhibitors is also discussed. Although considerable potential for inhibitors of this type was demonstrated, none of the compounds reported showed sufficient herbicidal activity to be a commercial proposition.

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Inhibition of Plant Glutamine Synthetases by Substituted Phosphinothricins

Cited by 52 publications

References 15 publications

Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery

Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery

The herbicidally active compound N-2-(5-chloro-pyridyl) aminomethylene bisphosphonic acid acts by inhibiting both glutamine and aromatic amino acid biosynthesis

The design and synthesis of inhibitors of dethiobiotin synthetase as potential herbicides

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