Catalysis by KDM6 Histone Demethylases – A Synergy between the Non‐Heme Iron(II) Center, Second Coordination Sphere, and Long‐Range Interactions

Abstract

AbstractKDM6A (UTX) and KDM6B (JMJD3) are human non‐heme Fe(II) and 2‐oxoglutarate (2OG) dependent JmjC oxygenases that catalyze the demethylation of trimethylated lysine 27 in the N‐terminal tail of histone H3, a post‐translational modification that regulates transcription. A Combined Quantum Mechanics/ Molecular Mechanics (QM/MM) and Molecular Dynamics (MD) study on the catalytic mechanism of KDM6A/B reveals that the transition state for the rate‐limiting hydrogen atom transfer (HAT) reaction in KDM6A catalysis is stabilized by polar (Asn217) and aromatic (Trp369)/non‐polar (Pro274) residues in contrast to KDM4, KDM6B and KDM7 demethylases where charged residues (Glu, Arg, Asp) are involved. KDM6A employs both σ‐ and π‐electron transfer pathways for HAT, whereas KDM6B employs the σ‐electron pathway. Differences in hydrogen bonding of the Fe‐chelating Glu252(KDM6B) contribute to the lower energy barriers in KDM6B vs. KDM6A. The study reveals a dependence of the activation barrier of the rebound hydroxylation on the Fe−O−C angle in the transition state of KDM6A. Anti‐correlation of the Zn‐binding domain with the active site residues is a key factor distinguishing KDM6A/B from KDM7/4s. The results reveal the importance of communication between the Fe center, second coordination sphere, and long‐range interactions in catalysis by KDMs and, by implication, other 2OG oxygenases.