Native metalloenzymes are unparalleled in their ability to perform efficient small molecule activation reactions, converting simple substrates into complex products. Most of these natural systems possess multiple metallocofactors to facilitate electron transfer or cascade catalysis. While the field of artificial metalloenzymes is growing at a rapid rate, examples of artificial enzymes that leverage two distinct cofactors remain scarce. In this work, we describe a new class of artificial enzymes containing two different metallocofactors, incorporated through bioorthogonal strategies. Nickel-substituted rubredoxin (Ni