Human histone demethylase KDM6B can catalyse sequential oxidations

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• Jumonji domain-containing demethylases (JmjC-KDMs) are crucial enzymes involved in epigenetic regulation.
• These enzymes catalyze the removal of methyl groups from Nε-methylated lysines on histone proteins, thereby influencing gene expression.
• KDM6B (JMJD3) is a specific JmjC-KDM implicated in various cellular processes and disease states.

Purpose of the Study:

• To investigate the substrate selectivity of KDM6B (JMJD3) using synthetic lysine analogues.
• To understand the enzymatic activity and product formation of KDM6B (JMJD3) beyond its known demethylation function.

Main Methods:

• Synthesis of various Nε-alkylated lysine analogues.
• Enzymatic assays using KDM6B (JMJD3) and the synthetic analogues.
• Analysis of reaction products using biochemical and analytical techniques.

Main Results:

• KDM6B (JMJD3) demonstrated an unexpected ability to accept and process multiple Nε-alkylated lysine analogues.
• The enzyme catalyzed the formation of alcohol, aldehyde, and carboxylic acid products from these analogues, indicating broader substrate acceptance than previously known.
• This suggests a more versatile catalytic mechanism for KDM6B (JMJD3).

Conclusions:

• KDM6B (JMJD3) exhibits broader substrate specificity than anticipated, processing various Nε-alkylated lysines.
• The enzyme can generate diverse products, including alcohols, aldehydes, and carboxylic acids, expanding our understanding of its enzymatic repertoire.
• These findings have implications for understanding KDM6B's role in gene regulation and disease, and for the development of targeted therapeutics.