Interaction of a new γ-glutamyl-phosphate analog, 4-(phosphonoacetyl)-l-α-aminobutyrate, with glutamine synthetase enzymes from Escherichia coli, plant, and mammalian sources

Wedler, Frederick C.; Horn, Bradley R.; Roby, W G

doi:10.1016/0003-9861(80)90453-1

Cited by 14 publications

(6 citation statements)

References 18 publications

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“…L-Glutamate gave values of 2.6 and 2.7 mM with these methods, in agreement with published values determined under comparable conditions (2.5 mM; Rowe et al, 1970). Competitive inhibition experiments using the phosphate release and coupled assay methods yielded K{ values for L-methionine (/?,5)-sulfoximine of 0.21 and 0.23 mM, respectively, also in agreement with published values (0.21 mM; Wedler et al, 1980).…”

Section: Resultssupporting

confidence: 87%

Substrate variability as a factor in enzyme inhibitor design: inhibition of ovine brain glutamine synthetase by .alpha.- and .gamma.-substituted phosphinothricins

Logusch¹,

Walker²,

McDonald³

et al. 1989

Biochemistry

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Ovine brain glutamine synthetase (GS) utilizes various substituted glutamic acids as substrates. We have used this information to design alpha- and gamma-substituted analogues of phosphinothricin [L-2-amino-4-(hydroxymethylphosphinyl)butanoic acid], a naturally occurring inhibitor of GS. These compounds display competitive inhibition of GS, and a correlation between the inhibitor Ki values and the Km/Vmax values of the analogously substituted glutamates supports the hypothesis that the phosphinothricins participate in transition-state analogue inhibition of GS. At concentrations greater than Ki these inhibitors caused biphasic time-dependent loss of enzyme activity, with initial pseudo-first-order behavior; k'inact parameters were determined for several compounds and were similar to the 2.1 X 10(-2)s-1 value measured for PPT. Dilution after GS inactivation caused a non-first-order recovery of activity. Reactivation kinetics were insensitive to inhibitor and ADP concentrations over wide ranges, although very high postdilution concentrations of inhibitor suppressed reactivation. The burst activity level, beta, as well as the concentration of inhibitor required to suppress reactivation to this level, mu, expressed as a multiple of the Ki value, was characteristic for each compound in the phosphinothricin series. Increasing substitution of the phosphinothricin parent structure caused an increase in Ki values as well as in the inactivation/reactivation parameters. The kinetic behavior of these inhibitors is consistent with a mechanistic scheme involving initial phosphorylation and rapid partial inhibitor dissociation, followed by slow release of remaining bound inhibitor.

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Section: Resultssupporting

confidence: 87%

Substrate variability as a factor in enzyme inhibitor design: inhibition of ovine brain glutamine synthetase by .alpha.- and .gamma.-substituted phosphinothricins

Logusch¹,

Walker²,

McDonald³

et al. 1989

Biochemistry

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“…Numerous compounds derived from the structure of PPT were synthesized and used to investigate the steric and electronic requirements needed for effective interaction with the glutamate binding site. Despite these efforts, in no case was the activity of the lead compound improved. ,,− PPT and the natural tripeptide from which it originates ( l -phosphinothricil- l -alanyl- l -alanine) have been successfully introduced to agricultural practice as nonselective herbicides because inactivation of plant GS causes a dramatic and rapid increase of toxic ammonia concentration inside the cell and subsequent death of the organism …”

Section: Introductionmentioning

confidence: 99%

“…Despite these efforts, in no case was the activity of the lead compound improved. 7,8,[16][17][18][19][20][21][22] PPT and the natural tripeptide from which it originates (Lphosphinothricil-L-alanyl-L-alanine) have been successfully introduced to agricultural practice as nonselective herbicides because inactivation of plant GS causes a dramatic and rapid increase of toxic ammonia concentration inside the cell and subsequent death of the organism. 23 A new promising perspective for GS inhibition studies is the design and synthesis of novel pharmaceuticals against Mycobacterium tuberculosis.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Activity of Analogues of Phosphinothricin as Inhibitors of Glutamine Synthetase

et al. 2005

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A new group of potent inhibitors of glutamine synthetase was designed and synthesized. The X-ray structure of bacterial glutamine synthetase complexed with phosphinothricin was used for computer-aided structure-based design of the inhibitors, in which the methyl group of phosphinothricin was chosen as the modification site. Amino and hydroxyl moieties were introduced into the phosphinic acid portion of the lead molecule to interact with ammonium binding site in the active cleft of the enzyme. Designed compounds were synthesized in enantiomerically pure form analogous to l-glutamic acid. In vitro kinetic studies with Escherichia coli glutamine synthetase confirmed the biological activity of the designed inhibitors, which with K(i) values in the micromolar range (K(i) = 0.59 microM for the most potent compound 2) appear to be slightly weaker inhibitors or equipotent to phosphinothricin.

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“…Glufosinate (1) acts by inhibiting this enzyme; it is itself phosphorylated and closely mimics the transition state. 6 A beta-keto phosphonate (2) was reported 7 to also inhibit GS, and we started a program to identify herbicides with improved activity.…”

Section: Transition-state Analogsmentioning

confidence: 99%

The Role of Phosphorus in Crop Protection: Commercial and Experimental Weed Control Agents

Hall

2008

Phosphorus, Sulfur, and Silicon and the Related Elements

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Interaction of a new γ-glutamyl-phosphate analog, 4-(phosphonoacetyl)-l-α-aminobutyrate, with glutamine synthetase enzymes from Escherichia coli, plant, and mammalian sources

Cited by 14 publications

References 18 publications

Substrate variability as a factor in enzyme inhibitor design: inhibition of ovine brain glutamine synthetase by .alpha.- and .gamma.-substituted phosphinothricins

Substrate variability as a factor in enzyme inhibitor design: inhibition of ovine brain glutamine synthetase by .alpha.- and .gamma.-substituted phosphinothricins

Design, Synthesis, and Activity of Analogues of Phosphinothricin as Inhibitors of Glutamine Synthetase

The Role of Phosphorus in Crop Protection: Commercial and Experimental Weed Control Agents

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