Human histone demethylase KDM6B can catalyse sequential oxidations

Hopkinson, Richard J.; Langley, Gareth W.; Belle, Roman; Walport, Louise J.; Dunne, Kate; Münzel, MMartin; Salah, E.; Kawamura, Akane; Claridge, Timothy D. W.; Schofield, Christopher J.

doi:10.1039/c8cc04057e

Cited by 4 publications

(4 citation statements)

References 16 publications

(20 reference statements)

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“…However, JHDMs were shown to be unable to de-alkylate substrates containing N ɛ -formyl-, N ɛ -acetyl-, or N ɛ -crotonyl [ 115 ]. In a separate study, the histone demethylase KDM6B was evaluated with a set of histone peptides bearing several unnatural analogues [ 116 ]. It was shown that KDM6B can efficiently demethylate N ɛ -diethyllysine, N ɛ -monomethylmonoethyllysine, and N ɛ -isopropyllysine.…”

Section: Erasing Kme3mentioning

confidence: 99%

Trimethyllysine: From Carnitine Biosynthesis to Epigenetics

Maas

Hintzen

Porzberg

et al. 2020

IJMS

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Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics. Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition. Dysregulation of protein methylation is linked to various diseases, including cancer, inflammation, and genetic disorders. In this review, we cover biomolecular studies on the role of trimethyllysine in carnitine biosynthesis, different enzymatic reactions involved in the synthesis and removal of trimethyllysine, trimethyllysine recognition by reader proteins, and the role of trimethyllysine on the nucleosome assembly.

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Section: Erasing Kme3mentioning

confidence: 99%

Trimethyllysine: From Carnitine Biosynthesis to Epigenetics

Maas

Hintzen

Porzberg

et al. 2020

IJMS

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“…Analogous probes may also be useful for other Fe(II)/α-KG-dependent enzymes such as histone demethylases, which have been recently shown to accept N ε -alkylated-Lys analogs. 22 Transfecting probe-containing oligonucleotides or feeding nucleoside analogs for genomic incorporation 23 could offer a powerful means to localize TET enzymes or otherwise track epigenome dynamics in future work.…”

mentioning

confidence: 99%

“…Also, eyC, due to its cross-linking reactivity, can be applied to understand when and where TET isozymes are active in given cellular niches or to identify TET-like enzymes in other species, such as the TET-like enzyme from the amoeba Naegleria gruberi, which readily reacts with the probe (Figure S12). Analogous probes may also be useful for other Fe(II)/α-KG-dependent enzymes such as histone demethylases, which have been recently shown to accept N ε -alkylated-Lys analogs . Transfecting probe-containing oligonucleotides or feeding nucleoside analogs for genomic incorporation could offer a powerful means to localize TET enzymes or otherwise track epigenome dynamics in future work.…”

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confidence: 99%

Exploiting Substrate Promiscuity To Develop Activity-Based Probes for Ten-Eleven Translocation Family Enzymes

et al. 2018

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TET enzymes catalyze repeated oxidations of 5-methylcytosine in genomic DNA. Due to the challenges of track-ing reactivity within a complex DNA substrate, chemical tools to probe TET activity are limited, despite these enzyme’s crucial role in epigenetic regulation. Here, building on precedents from related Fe(II)/α-ketoglutarate-dependent dioxygenases, we show that TET enzymes can promiscuously act upon cytosine bases with unnatural 5-position modifications. Oxidation of 5-vinylcytosine (vC) in DNA results in the predominant formation of a 5-formylmethylcytosine product that can be efficiently labeled to provide an end-point read-out for TET activity. The reaction with 5-ethynylcytosine (eyC), moreover, results in the formation of a high-energy ketene intermediate that can selectively trap any active TET isoform as a covalent enzyme-DNA complex, even in the complex milieu of a total cell lysate. Exploiting substrate promiscuity therefore offers a new and needed means to directly track TET activity in vitro or in vivo.

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“…In a follow-up study Schofield and co-workers surprisingly found that KDM6B accepted alkylated lysine, resulting in the formation of de-alkylated, hydroxylated or carboxylated products. 100 However, KDM catalysis required the presence of the charged N e -alkylamino group to take place. Moreover, H3K P 9me3, and not H3K P 9me2, was found to be a substrate for KDM4A/D/E JmjC demethylases, indicating that selectivity could be achieved.…”

Section: Lysine Demethylasesmentioning

confidence: 99%