Hydrogen atom transfer (HAT) is a central chemical step of many important chemical and biological processes. Many heme and non-heme enzymes employ HAT to selectively activate C-H bonds, producing an incredibly diverse set of products. Earlier studies have demonstrated that substitutions in the second coordinate sphere (SCS) and long range (LR) regions can significantly affect their catalytic activity. Understanding how such enzymes utilize such regions beyond the immediate vicinity of the active site to control the selectivity and efficiency of natural HAT is essential for metalloenzyme engineering. Furthermore, identifying residues at LR from the active site relevant for catalysis remains a challenge. In this study, we identified three SCS residues aiding the HAT mechanism in the human histone demethylase PHF8 (KDM7B). Additionally, we utilized dynamic cross-correlation analysis (DCCA) analysis to identify LR residues in different regions of PHF8, which are remote to the Fe(IV)-center, but which participate in correlated motions with the Fe(IV)-center and the RC-stabilizing residues in the SCS. We explore the mechanistic pathways of influence of these SCS and LR residues on the HAT reaction in the human histone demethylase PHF8 (KDM7B). The study demonstrates the multifaced mechanistic strategies of influence by the SCS and LR residues on the HAT reaction.

Second coordination sphere and long-range interactions as tools for modulating HAT in a histone demethylase

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ACS Fall 2022

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