Investigating the inhibitor and substrate diversity of the JmjC histone demethylases

Shamo Schiller, R

Abstract:: Epigenetic control of gene expression by histone post-translational modifications (PTMs) is a complex process regulated by proteins that can 'read', 'write' or 'erase' these PTMs. The histone lysine demethylase (KDM) family of epigenetic enzymes remove methyl modifications from lysines on histone tails. The Jumonji C domain (JmjC) family is the largest family of KDMs. Investigating the scope and mechanisms of the JmjC KDMs is of interest for understanding the diverse functions of the ...
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APA Style

Shamo Schiller, R. (2016). Investigating the inhibitor and substrate diversity of the JmjC histone demethylases [PhD thesis]. University of Oxford.

MLA Style

Shamo Schiller, R. Investigating the Inhibitor and Substrate Diversity of the JmjC Histone Demethylases. University of Oxford, 2016.

Chicago Style

Shamo Schiller, R. 2016. “Investigating the Inhibitor and Substrate Diversity of the JmjC Histone Demethylases.” PhD thesis, University of Oxford.
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Authors

+ Shamo Schiller, R More by this author

Division:: MPLS
Department:: Chemistry
Sub department:: Organic Chemistry
Role:: Author

Contributors

+ Kawamura, A

Role:: Supervisor

+ Schofield, C

Role:: Supervisor

+ Clarendon Fund More from this funder

Funding agency for:: Shamo Schiller, R

+ Eli Lilly and Company More from this funder

DOI:: 10.5287/ora-xvz7jjy8x
Type of award:: DPhil
Level of award:: Doctoral
Awarding institution:: University of Oxford

Language:: English
Keywords:: methyllysine

histone lysine demethylases (KDM)

tricarboxylic acid (TCA) cycle

methylarginine

2-oxoglutarate dependent oxygenases

deacetylation

demethylation

deformylation

histone post translational modification (PTM)

intraflagellar transport (IFT)

acetyllysine

epigenetics

citric acid cycle (CAC)

epigenetic inhibitor

Krebs cycle

IOX1

JmjC

JMJD1C

formyllysine

KDM3A
Subjects:: Epigenetics

JmjC KDMs
UUID:: uuid:1e7fd2a1-a9c3-48f7-8fa7-a041299d42f9
Deposit date:: 2017-04-04

Related item:: A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1
Description:: The 2-oxoglutarate (2OG)-dependent Jumonji C domain (JmjC) family is the largest family of histone lysine demethylases. There is interest in developing small-molecule probes that modulate JmjC activity to investigate their biological roles. 5-Carboxy-8-hydroxyquinoline (IOX1) is the most potent broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases, reported to date; however, it suffers from low cell permeability. Here, we describe structure–activity relationship studies leading to the discovery of an n-octyl ester form of IOX1 with improved cellular potency (EC50 value of 100 to 4 μM). These findings are supported by in vitro inhibition and selectivity studies, docking studies, activity versus toxicity analysis in cell cultures, and intracellular uptake measurements. The n-octyl ester was found to have improved cell permeability; it was found to inhibit some JmjC demethylases in its intact ester form and to be more selective than IOX1. The n-octyl ester of IOX1 should find utility as a starting point for the development of JmjC inhibitors and as a use as a cell-permeable tool compound for studies investigating the roles of 2OG oxygenases in epigenetic regulation.
Related item:: Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases
Description:: While the oxygen-dependent reversal of lysine N(ɛ)-methylation is well established, the existence of bona fide N(ω)-methylarginine demethylases (RDMs) is controversial. Lysine demethylation, as catalysed by two families of lysine demethylases (the flavin-dependent KDM1 enzymes and the 2-oxoglutarate- and oxygen-dependent JmjC KDMs, respectively), proceeds via oxidation of the N-methyl group, resulting in the release of formaldehyde. Here we report detailed biochemical studies clearly demonstrating that, in purified form, a subset of JmjC KDMs can also act as RDMs, both on histone and non-histone fragments, resulting in formaldehyde release. RDM catalysis is studied using peptides of wild-type sequences known to be arginine-methylated and sequences in which the KDM's methylated target lysine is substituted for a methylated arginine. Notably, the preferred sequence requirements for KDM and RDM activity vary even with the same JmjC enzymes. The demonstration of RDM activity by isolated JmjC enzymes will stimulate efforts to detect biologically relevant RDM activity.

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Licence:: Terms and Conditions of Use for Oxford University Research Archive

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Investigating the inhibitor and substrate diversity of the JmjC histone demethylases

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Investigating the inhibitor and substrate diversity of the JmjC histone demethylases

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