Catalyzes the formation of an amide bond between glutathione (GSH) and spermidine coupled with hydrolysis of ATP; also catalyzes the opposing reaction, i.e. the hydrolysis of glutathionylspermidine (Gsp) back to glutathione and spermidine. May act synergistically with glutaredoxin to regulate the redox environment and defend against oxidative damage. ATP + glutathione + spermidine = ADP + glutathionylspermidine + H(+) + phosphate glutathionylspermidine + H2O = glutathione + spermidine When exposed to oxidative stress, Gsp amidase activity is transiently inhibited in vivo by oxidation of the catalytic Cys-59 thiol to sulfenic acid; this modification does not affect Gsp synthetase activity. Sulfur metabolism; glutathione metabolism. Amine and polyamine metabolism; spermidine metabolism. Homodimer. The two activities reside in distinct domains (N-terminal amidase and C-terminal synthetase). The two domains expressed independently are folded and functional (By similarity). Oxidation of Cys-59 to sulfenic acid during oxidative stress selectively inhibits the amidase activity. In the C-terminal section; belongs to the glutathionylspermidine synthase preATP-grasp family.