Inhibition of glutamine synthetase by methionine sulfoximine. Studies On Methionine sulfoximine phosphate

Rowe, William Bruce; Ronzio, Robert A.; Meister, Alton

doi:10.1021/bi00834a065

Cited by 154 publications

(68 citation statements)

References 17 publications

(19 reference statements)

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“…phate intermediate formed during catalysis (Manning et al, 1969;Rowe et al, 1969;Eads et al, 1988). It is also established that MSOX interacts with at least one of the active-site metals, presumably the metal at the n1 site (Eads et al, 1988).…”

Section: Msox Bindingmentioning

confidence: 96%

Time‐resolved fluorescence studies of tryptophan mutants of Escherichia coli glutamine synthetase: Conformational analysis of intermediates and transition‐state complexes

Atkins

Villafranca

1992

Protein Science

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Single tryptophan-containing mutants of low adenylylation state Escherichia coli glutamine synthetase have been studied by frequency-domain fluorescence spectroscopy in the presence of various substrates and inhibitors. At pH 6.5, the Mn-bound wild-type enzyme (wild type has two tryptophans/subunit) and the mutant enzymes exhibit heterogeneous fluorescence decay kinetics; the individual tryptophans are adequately described by a triple exponential decay scheme. The recovered lifetime values are 5.9 ns, 2.6 ns, and 0.4 ns for Trp-57 and 5.8 ns, 2.3 ns, and 0.4 ns for Trp-158. These values are nearly identical to the previously reported results at pH 7.5 (Atkins, W.M., Stayton, P.S., & Villafranca, J.J., 1991, Biochemistry30,3406-3416). In addition, Trp-57 and Trp-158 both exhibit an ATP-induced increase in the relative fraction of the long lifetime component, whereas only Trp-57 is affected by this ligand at pH 7.5. The transition-state analogue L-methionine-(R,S)-sulfoximine (MSOX) causes a dramatic increase in the fractional intensity of the long lifetime component of Trp-158. This ligand has no effect on the W158S mutant protein and causes a small increase in the fractional intensity of the long lifetime component of the W158F mutant protein. Addition of glutamate to the ATP complex, which affords the yglutamylphosphate-ADP complex, results in the presence of new lifetime components at 7, 3.2, and 0.5 ns for Trp-158, but has no effect on Trp-57. Similar results were obtained when ATP was added to the MSOX complex; Trp-57 exhibits heterogeneous fluorescence decay with lifetimes of 7, 3.5, and 0.8 ns. Decay kinetics of Trp-158 are best fit to a nearly homogeneous decay with a lifetime of 5.5 ns in the MSOX-ATP inactivated complex. These results provide a model for the sequence of structural and dynamic changes that take place at the Trp-57 loop and the central loop (Trp-158) during several intermediate stages of catalysis.Keywords: Escherichia coli; fluorescence studies; glutamine synthetase; transition-state complexes; tryptophan mutants Glutamine synthetase (GS) plays a central role in the nitrogen metabolism of both prokaryotes and eukaryotes, catalyzing the ATP-dependent condensation of glutamate with ammonia to form glutamine (Ginsburg, 1972;Stadtman & Ginsburg, 1974). The bacterial enzymes consist of a highly symmetrical dodecamer formed by two face-toReprint requests to: Joseph J. Villafranca, Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802.Abbreviations: W57L, the site-directed mutant that has Trp-57 replaced by leucine; W158S or WlSSF, the site-directed mutants that have Trp-158 replaced by serine or phenylalanine; glutamylphosphate-ADP-GS, the ternary complex formed after the addition of ATP and glutamate to glutamine synthetase.

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Section: Msox Bindingmentioning

confidence: 96%

Time‐resolved fluorescence studies of tryptophan mutants of Escherichia coli glutamine synthetase: Conformational analysis of intermediates and transition‐state complexes

Atkins

Villafranca

1992

Protein Science

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“…Furthermore, the diastereomer of 4 (compound 11) was synthesized. Another compound (5) described in the literature, which inhibits both sheep brain GS and soybean GS with similar potency to that of MSO, 35 was also synthesized, as well as the analogue having a methyl group in the same position as MSO and PPT (12). Finally, three close analogues (9, 10 and 13) to these were purchased.…”

Section: Literature Surveymentioning

confidence: 99%

“…The analogue having a terminal methyl group corresponding to the methyl group in the sulfoximine and phosphinyl moiety of MSO and PPT, respectively, was also synthesized (12). However, this compound lacked inhibitory activity.…”

Section: Literature Surveymentioning

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%

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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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“…13 ) We then tried to find the optimum growth stage for the application and dosage of three GS inhibitors, bialaphos, L-PTC 7 ) and L-MSO, [14][15][16][17][18] for the induction of sterility in rice, and to examine the effects of those inhibitors on GS and the accumulation of ammonia in vivo.…”

mentioning

confidence: 99%

Effects of Glutamine Synthetase Inhibitors on Rice Sterility

Kimura

Shimada

Nagai

1994

Bioscience, Biotechnology, and Biochemistry

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Inhibition of glutamine synthetase by methionine sulfoximine. Studies On Methionine sulfoximine phosphate

Cited by 154 publications

References 17 publications

Time‐resolved fluorescence studies of tryptophan mutants of Escherichia coli glutamine synthetase: Conformational analysis of intermediates and transition‐state complexes

Time‐resolved fluorescence studies of tryptophan mutants of Escherichia coli glutamine synthetase: Conformational analysis of intermediates and transition‐state complexes

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

Effects of Glutamine Synthetase Inhibitors on Rice Sterility

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