Reaction Mechanism of Histone Demethylation in αKG-Dependent Non-Heme Iron Enzymes

Warispreet Singh, Derek Quinn, Thomas Moody, Meilan Huang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
262 Downloads (Pure)


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.
Original languageEnglish
Pages (from-to)7801-7811
Number of pages11
JournalThe Journal of Physical Chemistry B
Issue number37
Early online date30 Aug 2019
Publication statusPublished - 19 Sept 2019

Bibliographical note

This is a computational study funded by the Invest NI project, in collaboration with Almac.


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