Mechanism of inactivation of glutamine amidotransferases by the antitumor drug L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125).

Tso, J. Yun; Bower, Stanley; Zalkin, Howard

doi:10.1016/s0021-9258(18)43633-2

Cited by 68 publications

(8 citation statements)

References 19 publications

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“…Similar to isoxazoles, isoxazolines also have pharmacological, industrial, and synthetic applications , are quite rare, and as far as we know, no general method for their preparation has been reported to date.…”

Section: Resultsmentioning

confidence: 99%

A Convenient One-Pot Preparative Method for 4,5-Diarylisoxazoles Involving Amine Exchange Reactions

et al. 1996

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Section: Resultsmentioning

confidence: 99%

A Convenient One-Pot Preparative Method for 4,5-Diarylisoxazoles Involving Amine Exchange Reactions

et al. 1996

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“…The 180 isotope shift on 15N NMR should be useful in studying a variety of kinetic and mechanistic problems such as rearrangement reactions of organic nitrogen compounds and biosynthetic problems such as the formation of the isoxazole ring in the antitumor antibiotic AT-125 produced by Streptomyces sviceus 60 The present study should facilitate many such investigations.…”

Section: Resultsmentioning

confidence: 98%

The oxygen-18 isotope shift in nitrogen-15 NMR spectroscopy. 3. Effects of structure and solvent

Rajendran¹,

Santini²,

Etten³

1987

J. Am. Chem. Soc.

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“…Enzyme Assay Methods. Glutamate synthase glutaminedependent (Mántsálá & Zalkin, 1976a) and NH3-dependent (Tso et al, 1980) activities were assayed as described. Concentrations of glutamate synthase were determined from the absorbance at 278 nm; E^28% = 1.29 (Miller & Stadtman, 1972).…”

Section: Methodsmentioning

confidence: 99%

Chemical modification and ligand binding studies with Escherichia coli glutamate synthase

Bower¹,

Zalkin²

1983

Biochemistry

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The structure and function of Escherichia coli glutamate synthase were studied by ligand binding and chemical modification experiments. Binding of NADP+ was to a single dinucleotide site per alpha beta protomer with a Kd of approximately 5 microM. Phenylglyoxal modified an essential arginyl residue required for binding of NADP+. E. coli glutamate synthase thus employs a single dinucleotide binding site which functions in the NADPH to flavin electron transfer for glutamine-dependent glutamate synthase and for direct reduction of 2-iminoglutarate by NADPH in the NH3-dependent reaction. Binding of 2-oxoglutarate was complex. "Half of the sites" binding of 2-oxoglutarate (Kd less than 0.25 microM) was obtained in the absence of glutamine. Binding to half of the sites was pH independent. In the presence of glutamine, the 2-oxoglutarate binding ratio was approximately 1 equiv per protomer (Kd = 2-3 microM) at pH 7.5. This binding was pH dependent and varied between 0.43 equiv per protomer at pH 6.7 and 2.3 equiv per protomer at pH 9.0. Correlation of half of the sites binding with negative cooperativity for 2-oxoglutarate saturation indicates the utilization of low-Kd 2-oxoglutarate sites for NH3-dependent glutamate synthase. Binding of glutamine promotes a conformational change that exposes additional 2-oxoglutarate sites having a Kd of 2-3 microM which are utilized in the glutamine-dependent reaction. Chemical modification with pyridoxal 5'-phosphate caused inactivation of glutamine-dependent but not NH3-dependent glutamate synthase. Inactivation was ascribed to modification of one to two lysyl residues per protomer by Schiff base formation. The essential lysyl residue has a role in the binding of glutamine.

show abstract

Mechanism of inactivation of glutamine amidotransferases by the antitumor drug L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125).

Cited by 68 publications

References 19 publications

A Convenient One-Pot Preparative Method for 4,5-Diarylisoxazoles Involving Amine Exchange Reactions

A Convenient One-Pot Preparative Method for 4,5-Diarylisoxazoles Involving Amine Exchange Reactions

The oxygen-18 isotope shift in nitrogen-15 NMR spectroscopy. 3. Effects of structure and solvent

Chemical modification and ligand binding studies with Escherichia coli glutamate synthase

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