Interaction of phosphonates related to glutathione with the rat kidney gamma-glutamylcysteine synthetase.

Various phosphonic and sulfonic glutamate analogues as well as phosphonopeptides related to glutathione were studied for their interaction with rat kidney gamma-glutamylcysteine synthetase activity. We found, in all cases, that the presence of a phosphonic group increases the affinity for the enzyme. Among the tripeptides tested, the phosphonic analogue of ophthalmic acid (gamma Glu-Abu-Gly-P) is the most potent inhibitor. The glutamate and cysteine sites of the enzyme seem to be involved in the binding of this compound, since either substrate protects against inhibition. The types of inhibition with respect to the different substrates show dissimilar behaviors of the tripeptides, in spite of their structural analogy. Investigations relative to the role of the divalent ion Mg2+ provided evidence that the actual inhibitors are Mg2+-tripeptide complexes for the phosphonic compounds, whereas chelation with a metal ion is not required for inhibition by glutathione.