What is it about?
The article describes biochemical studies on an oxygen-dependent formaldehyde-producing demethylase, KDM4A, which contains a key lysine residue in its active site. Combined MS and NMR analyses suggest this lysine residue (lysine-241) is essential for ensuring efficient demethylation activity, but does not affect KDM4A’s reaction with oxygen. The work implies that small molecule binders to lysine-241 in KDM4A may induce catalytic inactivation.
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Why is it important?
Lysine demethylases (KDMs) catalyse removal of lysyl N-methyl groups by coupling methyl group hydroxylation with oxygen-dependent 2OG decarboxylation. One such KDM, KDM4A, contains a key active site lysine residue, K241, which is essential for efficient demethylation activity; K241 is proposed to bind oxygen, thus regulating catalysis. The MS-based studies confirm K241 is required for efficient demethylation; however, NMR analyses indicate 2OG decarboxylation is insensitive to K241 substitution to alanine. Further, K241 does not affect histone binding to KDM4A.
Perspectives
Overall, our studies suggest K241 regulates coupling of 2OG turnover and histone demethylation, and implies small molecules interacting with K241 may be catalytic inactivators.
Martine I Abboud
University of Oxford
Read the Original
This page is a summary of: Lysine-241 has a role in coupling 2OG turnover with substrate oxidation during KDM4-catalysed histone demethylation, ChemBioChem, February 2018, Wiley,
DOI: 10.1002/cbic.201800002.
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