This review describes the multiple advantages of using of EcNikA, a nickel transport protein, in the design of artificial metalloenzymes as alternative catalysts for synthetic biology. The rationale behind the strategy of artificial enzyme design is discussed, with particular emphasis on de novo active site reconstitution. The impact of the protein scaffold on the artificial active site and thus the final catalytic properties is detailed, highlighting the considerable aptitude of hybrid systems to catalyze selective reactions, from alkene to thioether transformations (epoxidation, hydroxychlorination, sulfoxidation). The different catalytic approaches – from in vitro to in cristallo – are compared, revealing the considerable advantages of protein crystals in terms of stabilization and acceleration of reaction kinetics. The versatility of proteins, based on metal and ligand diversity and medium/physical conditions, are thus illustrated for oxidation catalysis.