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01-12-2014 | Original Paper

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

Authors: Thomas M. Jeitner, Arthur J. L. Cooper

Published in: Metabolic Brain Disease | Issue 4/2014

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.

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 ⁺.

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

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

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Title: Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine—relevance to the treatment of neurological diseases
Authors: Thomas M. Jeitner
Arthur J. L. Cooper
Publication date: 01-12-2014
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 4/2014
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-013-9439-6

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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