Lysine Propionylation and Butyrylation Are Novel Post-translational Modifications in Histones

Chen, Yue; Sprung, Robert W.; Tang, Yi; Ball, Haydn L.; Sangras, Bhavani; Kim, Sung Chan; Falck, John R.; Peng, Junmin; Gu, Wei; Zhao, Yingming

doi:10.1074/mcp.m700021-mcp200

Cited by 619 publications

(638 citation statements)

References 31 publications

(28 reference statements)

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“…The propionyl-CoA synthetase of Salmonella enterica was also found to be propionylated at lysine 592, which inactivates the enzyme activity in vivo (8). In vitro experiments showed that histone acetyltransferase p300 and CREBbinding protein (CBP) can propionylate histone H4, suggesting that propionylation and acetylation may share the common enzymes that recognize both propionyl-CoA and acetyl-CoA (9). The in vivo propionylation of propionyl-CoA synthetase is catalyzed by a protein related to GCN5 histone acetyltransferase (HAT), and the propionyl group can be removed by NAD ϩ -dependent human Sir2 histone deacetylase (sirtuins) in vitro (8).…”

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confidence: 99%

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Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells

Liu

Lin

Darwanto

et al. 2009

Journal of Biological Chemistry

114

131

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Propionylation has been identified recently as a new type of protein post-translational modification. Bacterial propionylCoA synthetase and human histone H4 are propionylated at specific lysine residues that have been known previously to be acetylated. However, other proteins subject to this modification remain to be identified, and the modifying enzymes involved need to be characterized. In this work, we report the discovery of histone H3 propionylation in mammalian cells. Propionylation at H3 lysine Lys 23 was detected in the leukemia cell line U937 by mass spectrometry and Western analysis using a specific antibody. In this cell line, the propionylated form of Lys 23 accounted for 7%, a level at least 6-fold higher than in other leukemia cell lines (HL-60 and THP-1) or non-leukemia cell lines (HeLa and IMR-90). The propionylation level in U937 cells decreased remarkably during monocytic differentiation, indicating that this modification is dynamically regulated. Moreover, in vitro assays demonstrated that histone acetyltransferase p300 can catalyze H3 Lys 23 propionylation, whereas histone deacetylase Sir2 can remove this modification in the presence of NAD ؉ .These results suggest that histone propionylation might be generated by the same set of enzymes as for histone acetylation and that selection of donor molecules (propionyl-CoA versus acetylCoA) may determine the difference of modifications. Because like acetyl-CoA, propionyl-CoA is an important intermediate in biosynthesis and energy production, histone H3 Lys 23 propionylation may provide a novel epigenetic regulatory mark for cell metabolism.Eukaryotic histones are rich in multiple post-translational modifications, the combinatory array of which is the basis for epigenetic regulation of gene expression (1). Appropriate histone modifications are required for normal cell growth and differentiation, whereas aberrant histone modifications contribute to tumor formation such as malignant hematopoiesis (2). For example, genome-wide alterations of histone modification patterns are found in prostate cancer and are predictive of clinical outcomes (3); histone H3 Lys 79 (H3K79) hypermethylation and the activation of oncogenic HOX genes are prominent causes for leukemia with chromosome translocation involving the AF10 gene (4, 5), whereas global hypomethylation at H3K79 sites has been proposed to cause genome instability in AF10-related leukemia cancers (6). Alteration in histone modification patterns serves as a hallmark of cancer that provides clues for cancer diagnosis and treatment (7).Lysine propionylation has recently been identified as a new type of post-translational modification. It was first discovered in human histone H4 enriched for acetylation using anti-acetyl H4 antibodies (9). The propionyl-CoA synthetase of Salmonella enterica was also found to be propionylated at lysine 592, which inactivates the enzyme activity in vivo (8). In vitro experiments showed that histone acetyltransferase p300 and CREBbinding protein (CBP) can propionylate histone H4,...

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“…It was first discovered in human histone H4 enriched for acetylation using anti-acetyl H4 antibodies (9). The propionyl-CoA synthetase of Salmonella enterica was also found to be propionylated at lysine 592, which inactivates the enzyme activity in vivo (8).…”

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confidence: 99%

Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells

Liu

Lin

Darwanto

et al. 2009

Journal of Biological Chemistry

114

131

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“…4,5 Recently Zhao and co-workers discovered a number of new modified amino acids in histones. [6][7][8] Some of these were also detected in proteins other than histones, raising the possibility that they are of more widespread importance. [9][10][11] The new post-translational modifications (PTMs) are acylated derivatives of lysine at the e-amino position.…”

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confidence: 99%

Synthesis of ε-N-propionyl-, ε-N-butyryl-, and ε-N-crotonyl-lysine containing histone H3 using the pyrrolysine system

2013

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Recently new lysine modifications were detected in histones and other proteins. Using the pyrrolysine amber suppression system we genetically inserted three of the new amino acids e-N-propionyl-, e-N-butyryl-, and e-N-crotonyl-lysine site specifically into histone H3. The lysine at position 9 (H3 K9), which is known to be highly modified in chromatin, was replaced by these unnatural amino acids.The histone code is based on the post-translational modification of critical amino acid residues in different histones. Among these, lysine acetylations and methylations are the most abundant and affect the transcriptional status of the genes associated with the corresponding histones. [1][2][3] The role of these modifications is sequence dependent. Typically acetylation is associated with transcriptionally active genes, while methylation induces transcriptional silencing. 4,5 Recently Zhao and co-workers discovered a number of new modified amino acids in histones. [6][7][8] Some of these were also detected in proteins other than histones, raising the possibility that they are of more widespread importance. [9][10][11] The new post-translational modifications (PTMs) are acylated derivatives of lysine at the e-amino position. The acylation partners are propionic acid, butyric acid, malonic acid, succinic acid, crotonic acid or fatty acids. A common characteristic of these compounds is that they are key metabolic intermediates that typically exist as CoA activated thioester species in the cell. 12 It is currently not clear how these newly discovered PTMs are biosynthetically established within the histones and we do not fully understand if and how they influence genetic processes.So far no specific deacylases for e-N-propionyl-or e-Nbutyryl-lysine have been identified. However Sirt5, a member of NAD-dependent sirtuins is able to specifically deacylate e-Nmalonyl-and e-N-succinyllysine. 11 Recently it was discovered that HDAC3 exhibits decrotonylase activity in vitro 13 and it was found that lysine crotonylation activates genes even in a globally repressive environment. 7,14 In order to enable investigation of the new lysine derivatives in histones it is essential to generate histones that contain these amino acids site specifically. 15 In this direction semi-synthetic chemical ligation based methods 16,17 were utilized and chemical methods were employed to generate acetyllysine (Kac) and methylated-lysines or derivatives thereof. [18][19][20][21] Chin and co-workers reported the introduction of Kac into H3 K56 22 using the pyrrolysine system. This system was also employed for the synthesis of monomethyl-and dimethyl-lysine containing histones. 23,24 Schultz et al. recently described the synthesis of histone H2B containing e-N-crotonyllysine at position K11 using an evolved pyrrolysyl-tRNA synthetase from Methanosarcina barkeri. 25 Here we show that the pyrrolysine system can be used to insert e-N-propionyl-(Kpr, 1), e-N-butyryl-(Kbu, 2), and e-Ncrotonyl-lysine (Kcr, 3) into histones at critical positions such as H3 K9 using...

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“…Members of three different KAT families catalyze lysine acylation in vitro: p300/CBP catalyzes propionylation, butyrylation, and crotonylation of histones and p53 (Chen et al, 2007;Sabari et al, 2015), yeast Esa1, a member of the MYST family of acetyltransferases, catalyzes propionylation of histone H4 peptides (Berndsen et al, 2007), and human P/CAF, which is closely related by sequence homology to Gcn5, catalyzes propionylation of histone H3 peptides (Leemhuis et al, 2008). Some KATs are clearly promiscuous with regards to acyl chain identity, but the mechanisms employed by acyltransferases to discriminate between different acyl-CoA molecules are still largely unknown.…”

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confidence: 99%

Structural basis for acyl group discrimination by human Gcn5L2

Ringel

Wolberger

2016

Preprint

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Gcn5 is a conserved acetyltransferase that regulates transcription by acetylating the Nterminal tails of histones. Motivated by recent studies identifying a chemically diverse array of lysine acyl modifications in vivo, we examined the acyl chain specificity of the acetyltransferase, human Gcn5 (Gcn5L2). Whereas Gcn5L2 robustly catalyzes lysine acetylation, the acyltransferase activity of Gcn5L2 gets progressively weaker with increasing acyl chain length. To understand how Gcn5 discriminates between different acyl-CoA molecules, we determined structures of the catalytic domain of human Gcn5L2 bound to propionyl-CoA and butyryl-CoA. Although the active site of Gcn5L2 can accommodate propionyl-CoA and butyryl-CoA without major structural rearrangements, butyryl-CoA adopts a conformation incompatible with catalysis that obstructs the path of the incoming lysine residue and acts as a competitive inhibitor for Gcn5L2 versus acetyl-CoA. These structures demonstrate how Gcn5L2 discriminates between acyl chain donors and explain why Gcn5L2 has weak activity for acyl moieties that are larger than an acetyl group.

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Lysine Propionylation and Butyrylation Are Novel Post-translational Modifications in Histones

Cited by 619 publications

References 31 publications

Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells

Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells

Synthesis of ε-N-propionyl-, ε-N-butyryl-, and ε-N-crotonyl-lysine containing histone H3 using the pyrrolysine system

Structural basis for acyl group discrimination by human Gcn5L2

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