This work focuses on a well-characterized halogenase, SyrB2, which chlorinates/brominates the side chain methyl group of its substrate Thr. Amino acid Thr is delivered to the active site of SyrB2 via partner protein SyrB1's covalently attached phosphopantetheine (Ppt) group. When Thr is substituted with non-native amino acid substrates like alpha-aminobutyric acid or norvaline, SyrB2 primarily hydroxylates them. These studies and others have demonstrated the importance of SyrB2's interaction with Thr and other amino acid substrates to influence halogenation/hydroxylation reaction outcomes. While substrate-protein interactions are wellunderstood, it's unclear how iron's secondary coordination sphere (SCS; amino acid residues that interact with the ligands bound to iron) governs reaction outcome in SyrB2 and other halogenases. From a broader perspective, while the impact of the SCS on the structure and function of heme iron enzymes have been extensively studied, little is known about how nonheme iron enzymes utilize SCS to control their reactivity. In this work, we investigate the importance of iron's SCS in controlling SyrB2 halogenase's reactivity. Specifically, we establish the role of a hydrophobic Phe121 residue that is ~4 Å away from iron's chloride ligand towards configuring halogenase activity in SyrB2. Mutating this residue to Tyr facilitates its intracellular post-translational modification to a dihydroxyphenylalanine (DOPA) residue that renders SyrB2 non-functional. Beyond SyrB2, the F121 residue is highly conserved in halogenases, unlike hydroxylases, signifying the differential nature of the SCS in the two enzyme classes. Overall, our studies emphasize the importance of the SCS in controlling catalytic activities of non-heme iron enzymes, particularly halogenases and hydroxylases.