Mechanism of Inhibition of Glutamine Synthetase by Methionine Sulphoximine

Abstract

Glutamine synthetase catalyses the coupled energy-requiring synthesis of glutamine from glutamate and ammonia and the energy-providing cleavage of adenosine 5′-triphosphate (ATP) to adenosine 5′-diphosphate (ADP) and inorganic phosphate (Pi) in accordance with the reaction shown in Fig. 1 (for reviews, Meister, 1962, 1968). During the past few years a number of studies have been carried out in this laboratory on the properties of the glutamine synthetase of sheep brain and on the mechanism of the reaction catalysed by this enzyme. To provide a background for the subject of the present report, we may briefly summarize some of the significant earlier findings and conclusions. Glutamine synthetase of sheep brain has a molecular weight of about 500,000; hydrodynamic studies and electron microscopy indicate that the enzyme is composed of eight apparently identical subunits which are arranged in a manner analogous to the corners of a cube (Ronzio et al., 1969b; Haschemeyer, 1968). The native octameric enzyme can be reversibly dissociated to a tetrameric form and irreversibly dissociated to the monomer (Wilk et al., 1969, 1970). The available evidence indicates that each of the eight subunits has an active site capable of combining with the substrates.