Inhibition of gamma-glutamylcysteine synthetase by cystamine: an approach to a therapy of 5-oxoprolinuria (pyroglutamic aciduria).

γ-Glutamylcysteine synthetase is strongly inhibited by cystamine; thus, 20 μM cystamine inhibited the activity by 50%. Inhibition is rapid and the inhibited enzyme is reactivated by dithiothreitol suggesting that cystamine reacts with an enzyme sulfhydryl group. Inhibition by cystamine is not prevented by MgATP, L-α-aminobutyrate, or L-glutamate suggesting that cystamine may not interact at the active site. Little or no inhibition was observed with N,N′-diacetyl cystamine, L-cystine, glutathione disulfide, 2-hydroxyethyl disulfide, and thioglycolate disulfide, whereas thiocholine disulfide produced moderate inhibition. Cystamine or an inhibitory analog of cystamine might be useful in the therapy of the disease 5-oxoprolinuria in which there is an overproduction of γ-glutamylcysteine.