TY - JOUR
T1 - Reaction Mechanism of Histone Demethylation in αKG-Dependent Non-Heme Iron Enzymes
AU - Singh, Warispreet
AU - Quinn, Derek
AU - Moody, Thomas
AU - Huang, Meilan
N1 - This is a computational study funded by the Invest NI project, in collaboration with Almac.
PY - 2019/9/19
Y1 - 2019/9/19
N2 - Histone demethylases (KDMs) catalyze histone lysine demethylation, an important epigenetic process that controls gene expression in eukaryotes, and represent important cancer drug targets for cancer treatment. Demethylation of histone is comprised of sequential reaction steps including oxygen activation, decarboxylation, and demethylation. The initial oxygen binding and activation steps have been studied. However, the information on the complete catalytic reaction cycle is limited, which has impeded the structure-based design of inhibitors targeting KDMs. Here we report the mechanism of the complete reaction steps catalyzed by a representative nonheme iron αKG-dependent KDM, PHF8 using QM/MM approaches. The atomic-level understanding on the complete reaction mechanism of PHF8 would shed light on the structure-based design of selective inhibitors targeting KDMs to intervene in cancer epigenetics.
AB - Histone demethylases (KDMs) catalyze histone lysine demethylation, an important epigenetic process that controls gene expression in eukaryotes, and represent important cancer drug targets for cancer treatment. Demethylation of histone is comprised of sequential reaction steps including oxygen activation, decarboxylation, and demethylation. The initial oxygen binding and activation steps have been studied. However, the information on the complete catalytic reaction cycle is limited, which has impeded the structure-based design of inhibitors targeting KDMs. Here we report the mechanism of the complete reaction steps catalyzed by a representative nonheme iron αKG-dependent KDM, PHF8 using QM/MM approaches. The atomic-level understanding on the complete reaction mechanism of PHF8 would shed light on the structure-based design of selective inhibitors targeting KDMs to intervene in cancer epigenetics.
U2 - 10.1021/acs.jpcb.9b06064
DO - 10.1021/acs.jpcb.9b06064
M3 - Article
SN - 1520-6106
VL - 123
SP - 7801
EP - 7811
JO - The Journal of Physical Chemistry B
JF - The Journal of Physical Chemistry B
IS - 37
ER -