Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine—relevance to the treatment of neurological diseases

Jeitner, Thomas M.; Cooper, Arthur J. L.

doi:10.1007/s11011-013-9439-6

Cited by 29 publications

(35 citation statements)

References 68 publications

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“…2) are reminiscent of those shown previously for inhibition of this enzyme by L-methionine- S , R -sulfoximine (MSO) [37]. The inhibition of human GS by MSO was shown to be biphasic – an initial reversible competitive inhibition ( K i = 1.19 mM) is followed by rapid irreversible inactivation [37].…”

Section: Discussionmentioning

confidence: 54%

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Fluorination at the 4 position alters the substrate behavior of l-glutamine and l-glutamate: Implications for positron emission tomography of neoplasias

Jeitner

Kristoferson

Azcona

et al. 2016

Journal of Fluorine Chemistry

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Two 4-fluoro-L-glutamine diastereoisomers [(2S,4R)-4-FGln, (2S,4S)-4-FGln] were previously developed for positron emission tomography. Label uptake into two tumor cell types was greater with [18F](2S,4R)-4-FGln than with [18F](2S,4S)-4-FGln. In the present work we investigated the enzymology of two diastereoisomers of 4-FGln, two diastereoisomers of 4-fluoroglutamate (4-FGlu) (potential metabolites of the 4-FGln diastereoisomers) and another fluoro-derivative of L-glutamine [(2S,4S)-4-(3-fluoropropyl)glutamine (FP-Gln)]. The two 4-FGlu diastereoisomers were found to be moderate-to-good substrates relative to L-glutamate of glutamate dehydrogenase, aspartate aminotransferase and alanine aminotransferase. Additionally, alanine aminotransferase was shown to catalyze an unusual γ-elimination reaction with both 4-FGlu diastereoisomers. Both 4-FGlu diastereoisomers were shown to be poor substrates, but strong inhibitors of glutamine synthetase. Both 4-FGln diastereoisomers were shown to be poor substrates compared to L-glutamine of glutamine transaminase L and α-aminoadipate aminotransferase. However, (2S,4R)-4-FGln was found to be a poor substrate of glutamine transaminase K, whereas (2S,4S)-4-FGln was shown to be an excellent substrate. By contrast, FP-Gln was found to be a poor substrate of all enzymes examined. Evidently, substitution of H in position 4 by F in L-glutamine/L-glutamate has moderate-to-profound effects on enzyme-catalyzed reactions. The present results: 1) show that 4-FGln and 4-FGlu diastereoisomers may be useful for studying active site topology of glutamate- and glutamine-utilizing enzymes; 2) provide a framework for understanding possible metabolic transformations in tumors of 18F-labeled (2S,4R)-4-FGln, (2S,4S)-4-FGln, (2S,4R)-4-FGlu or (2S,4S)-4-FGlu; and 3) show that [18F]FP-Gln is likely to be much less metabolically active in vivo than are the [18F]4-FGln diastereoisomers.

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Section: Discussionmentioning

confidence: 54%

“…It is assumed that the hydroxamate of the fluorinated glutamates exhibits an identical extinction coefficient to that of L-glutamate hydroxamate in the presence of acidic ferric chloride. The specific activity of purified recombinant human GS (ammonia in place of hydroxylamine as substrate) was 17.9 U/mg [37]. …”

Section: Methodsmentioning

confidence: 99%

Fluorination at the 4 position alters the substrate behavior of l-glutamine and l-glutamate: Implications for positron emission tomography of neoplasias

Jeitner

Kristoferson

Azcona

et al. 2016

Journal of Fluorine Chemistry

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“…The administration of MSO decreased both the contents of glutamate and glutamine in the G93A superoxide dismutase 1 mice [102]. As we have discussed in early work, MSO may be safe to use in humans [15,103,104]. These observations suggest that the inhibition of glutamine synthetase by compounds such as MSO may provide avenues for the treatment of cerebral strokes.…”

Section: Glutamine Synthetase and Strokementioning

confidence: 74%

“…2) [8]. Figures 1 and 2 were obtained with glutamine synthetase complexed to phosphorylated L-methionine-S,R-sulfoximine (MSO) [15], which facilitated the crystallization of the enzyme [8].…”

Section: Structure and Enzymology Of The Mammalian Glutamine Synthetasementioning

confidence: 99%

“…MSO is an inhibitor of glutamine synthetase that competes with glutamate for binding at the active site and upon phosphorylation irreversibly inactivates the enzyme [15]. ATP binds by alignment of the adenosine moiety with the side chains of Trp130 and Arg262 to form an aromaticarginine planar stacking configuration.…”

Section: Structure and Enzymology Of The Mammalian Glutamine Synthetasementioning

confidence: 99%

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Critical Evaluation of the Changes in Glutamine Synthetase Activity in Models of Cerebral Stroke

2015

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The following article addresses some seemingly paradoxical observations concerning cerebral glutamine synthetase in ischemia-reperfusion injury. In the brain, this enzyme is predominantly found in astrocytes and catalyzes part of the glutamine-glutamate cycle. Glutamine synthetase is also thought to be especially sensitive to inactivation by the oxygen- and nitrogen-centered radicals generated during strokes. Despite this apparent sensitivity, glutamine synthetase specific activity is elevated in the affected tissues during reperfusion. Given the central role of the glutamine-glutamate cycle in the brain, we sought to resolve these conflicting observations with the view of providing an alternative perspective for therapeutic intervention in stroke.

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Glutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model

Mao

Chen

Lin

et al. 2022

J of Inher Metab Disea

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Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otcspf‐ash) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8‐mediated delivery of a short hairpin RNA in Otcspf‐ash mice diminished hyperammonemia and reduced lethality. Knockdown of Gls2 but not Glud1 in Otcspf‐ash mice exhibited reduced body weight loss and increased plasma glutamine concentration. These data suggest that Gls2 hepatic knockdown could potentially help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.

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Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine—relevance to the treatment of neurological diseases

Cited by 29 publications

References 68 publications

Fluorination at the 4 position alters the substrate behavior of l-glutamine and l-glutamate: Implications for positron emission tomography of neoplasias

Fluorination at the 4 position alters the substrate behavior of l-glutamine and l-glutamate: Implications for positron emission tomography of neoplasias

Critical Evaluation of the Changes in Glutamine Synthetase Activity in Models of Cerebral Stroke

Glutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model

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