The type of DUOX-dependent ROS production is dictated by defined sequences in DUOXA

► The DUOXA1 COOH-terminal end is critical for DUOX1 H2O2 production. ► The NH2-terminal end of native DUOXA2 constrains DUOX2 to produce H2O2. ► Alterations of DUOXA2 NH2-terminus modify DUOX2 activity triggering O2.− leaking.