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

Metabolic Brain Disease volume 29, pages 983–989 (2014)Cite this article

Abstract

At high concentrations, the glutamine synthetase inhibitor L-methionine-S,R-sulfoximine (MSO) is a convulsant, especially in dogs. Nevertheless, sub-convulsive doses of MSO are neuroprotective in rodent models of hyperammonemia, acute liver disease, and amyotrophic lateral sclerosis and suggest MSO may be clinically useful. Previous work has also shown that much lower doses of MSO are required to produce convulsions in dogs than in primates. Evidence from the mid-20th century suggests that humans are also less sensitive. In the present work, the inhibition of recombinant human glutamine synthetase by MSO is shown to be biphasic—an initial reversible competitive inhibition (K i 1.19 mM) is followed by rapid irreversible inactivation. This K i value for the human enzyme accounts, in part, for relative insensitivity of primates to MSO and suggests that this inhibitor could be used to safely inhibit glutamine synthetase activity in humans.

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Fig. 1
Fig. 2

Notes

  1. Ammonia free base (NH3) has a pK a of ~9.2. Thus, under normal intracellular physiological conditions (pH 7.2–7.4) ammonia exists predominantly (~99 %) as the conjugate acid, ammonium (NH4 +). For convenience, unless otherwise stated, the term ammonia is used throughout the text to indicate the sum of NH3 plus NH4 +.

  2. Glutamine synthetase inactivated by MSO can be reactivated by certain non-physiological manipulations (Maurizi and Ginsburg 1982).

  3. Flour bleached with NCl3, which converts some protein methionine residues to MSO.

Abbreviations

ALS:

Amyotrophic lateral sclerosis

MSO:

L-methionine-S,R-sulfoximine

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Acknowledgments

Mark Horswill and Michael Haywood (Department of Pediatrics, Medical College of Wisconsin) provided technical assistance and Dr. Chad D. Listrom (University of Maryland) supplied the glutamine synthetase expression system. Drs. Owen Griffith and William Antholine of the Departments of Biochemistry and Biophysics at the Medical College of Wisconsin are thanked for their insights into these studies and their review of the manuscript. Funding was generously supplied by National Institutes of Health grants RO3-NS074286 (TMJ) and RO1 ES 008421 (AJLC) and the Theresa Pantnode Santmann Foundation Award (TMJ).

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  1. Neurosciences, Biomedical Research Core, Winthrop University Hospital, 222 Station Plaza North, Mineola, NY, 11501, USA

    Thomas M. Jeitner

  2. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, USA

    Arthur J. L. Cooper

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Jeitner, T.M., Cooper, A.J.L. Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine—relevance to the treatment of neurological diseases. Metab Brain Dis 29, 983–989 (2014). https://doi.org/10.1007/s11011-013-9439-6

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Keywords

  • Amyotrophic lateral sclerosis
  • Glutamine synthetase
  • Hyperammonemia
  • L-methionine-S,R-sulfoximine