Fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases

Abstract Histone lysine methyltransferases (KMTs) play an important role in epigenetic gene regulation and have emerged as promising targets for drug discovery. However, the scope and limitation of KMT catalysis on substrates possessing substituted lysine side chains remain insufficiently explored....

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Autores principales:	Abbas H. K. Al Temimi, Jona Merx, Christian J. van Noortwijk, Giordano Proietti, Romano Buijs, Paul B. White, Floris P. J. T. Rutjes, Thomas J. Boltje, Jasmin Mecinović
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d597a3d415a940e1a621ac071eda0bb4
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spelling	oai:doaj.org-article:d597a3d415a940e1a621ac071eda0bb42021-12-02T15:11:51ZFine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases10.1038/s41598-020-78331-02045-2322https://doaj.org/article/d597a3d415a940e1a621ac071eda0bb42020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78331-0https://doaj.org/toc/2045-2322Abstract Histone lysine methyltransferases (KMTs) play an important role in epigenetic gene regulation and have emerged as promising targets for drug discovery. However, the scope and limitation of KMT catalysis on substrates possessing substituted lysine side chains remain insufficiently explored. Here, we identify new unnatural lysine analogues as substrates for human methyltransferases SETD7, SETD8, G9a and GLP. Two synthetic amino acids that possess a subtle modification on the lysine side chain, namely oxygen at the γ position (KO, oxalysine) and nitrogen at the γ position (KN, azalysine) were incorporated into histone peptides and tested as KMTs substrates. Our results demonstrate that these lysine analogues are mono-, di-, and trimethylated to a different extent by trimethyltransferases G9a and GLP. In contrast to monomethyltransferase SETD7, SETD8 exhibits high specificity for both lysine analogues. These findings are important to understand the substrate scope of KMTs and to develop new chemical probes for biomedical applications.Abbas H. K. Al TemimiJona MerxChristian J. van NoortwijkGiordano ProiettiRomano BuijsPaul B. WhiteFloris P. J. T. RutjesThomas J. BoltjeJasmin MecinovićNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Abbas H. K. Al Temimi Jona Merx Christian J. van Noortwijk Giordano Proietti Romano Buijs Paul B. White Floris P. J. T. Rutjes Thomas J. Boltje Jasmin Mecinović Fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases
description	Abstract Histone lysine methyltransferases (KMTs) play an important role in epigenetic gene regulation and have emerged as promising targets for drug discovery. However, the scope and limitation of KMT catalysis on substrates possessing substituted lysine side chains remain insufficiently explored. Here, we identify new unnatural lysine analogues as substrates for human methyltransferases SETD7, SETD8, G9a and GLP. Two synthetic amino acids that possess a subtle modification on the lysine side chain, namely oxygen at the γ position (KO, oxalysine) and nitrogen at the γ position (KN, azalysine) were incorporated into histone peptides and tested as KMTs substrates. Our results demonstrate that these lysine analogues are mono-, di-, and trimethylated to a different extent by trimethyltransferases G9a and GLP. In contrast to monomethyltransferase SETD7, SETD8 exhibits high specificity for both lysine analogues. These findings are important to understand the substrate scope of KMTs and to develop new chemical probes for biomedical applications.
format	article
author	Abbas H. K. Al Temimi Jona Merx Christian J. van Noortwijk Giordano Proietti Romano Buijs Paul B. White Floris P. J. T. Rutjes Thomas J. Boltje Jasmin Mecinović
author_facet	Abbas H. K. Al Temimi Jona Merx Christian J. van Noortwijk Giordano Proietti Romano Buijs Paul B. White Floris P. J. T. Rutjes Thomas J. Boltje Jasmin Mecinović
author_sort	Abbas H. K. Al Temimi
title	Fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases
title_short	Fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases
title_full	Fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases
title_fullStr	Fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases
title_full_unstemmed	Fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases
title_sort	fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/d597a3d415a940e1a621ac071eda0bb4
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Fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases

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