Kinetic Analysis of Iron-Dependent
Histone Demethylases:
α‑Ketoglutarate Substrate Inhibition and Potential Relevance
to the Regulation of Histone Demethylation in Cancer Cells
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Abstract
The Jumonji C domain-containing histone demethylases
(JmjC-HDMs)
are α-ketoglutarate (αKG)-dependent, O<sub>2</sub>-activating,
non-heme iron enzymes that play an important role in epigenetics.
Reported herein is a detailed kinetic analysis of three JmjC-HDMs,
including the cancer-relevant JMJD2C, that was achieved by employing
three enzyme activity assays. A continuous O<sub>2</sub> consumption
assay reveals that HDMs have low affinities for O<sub>2</sub>, suggesting
that these enzymes can act as oxygen sensors in vivo. An interesting
case of αKG substrate inhibition was found, and the kinetic
data suggest that αKG inhibits JMJD2C competitively with respect
to O<sub>2</sub>. JMJD2C displays an optimal activity in vitro at
αKG concentrations similar to those found in cancer cells, with
implications for the regulation of histone demethylation activity
in cancer versus normal cells