Global Analysis of Lysine 2-Hydroxyisobutyrylome upon SAHA Treatment and Its Relationship with Acetylation and Crotonylation

Wu, Qiulian; Li, Ke; Wang, Chi; Fan, Pingsheng; Wu, Zhiwei; Xu, Xiaoling

doi:10.1021/acs.jproteome.8b00289

“…The lysine modifications are not limited to ubiquitination, acetylation, and methylation. For example, lysine modifications by other acyl groups [159][160][161][162] have also received great attention; few selective modulators for these modifications are known. In addition, the protein modifications are only a part of chemical modification of biomolecules in physiological condition.…”

Section: Resultsmentioning

confidence: 99%

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

Itoh

¹

2020

CHEMICAL & PHARMACEUTICAL BULLETIN

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Enzymatic and post-translational modifications (PTMs) such as ubiquitination, acetylation, and methylation occur at lysine residues. The PTMs play critical roles in the regulation of the protein functions, and thus, various cellular processes. In addition, aberrations of the PTMs are associated with various diseases, such as cancer and neurodegenerative disorders. Therefore, we hypothesized that modulation of the PTMs and normalization of the PTM abnormalities could be useful as methods to control various cellular mechanisms and as a therapeutic strategy, respectively. To modulate the PTMs, we have focused on lysine-modifying enzymes and have pursued drug discovery researches on ubiquitination inducers, lysine deacetylase (KDAC) inhibitors, and lysine demethylase (KDM) inhibitors. For the identification of the modulators, we have used not only conventional drug design, such as structure-based drug design (SBDD) and ligand-based drug design (LBDD), but also "strategic chemistry approaches," such as drug design based on enzyme catalytic mechanism. As a result, we have identified several modulators which have pharmacological effects in animal models or in cellular studies. In this review, focusing on the drug design based on enzyme catalytic mechanism, our drug discovery researches have been discussed.

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“…Since the discovery of phosphorylation, many new PTMs have been identi ed over the years, such as crotonylation, propionylation, malonylation, butyrylation, succinylation, glutarylation, βhydroxybutyrylation and 2-hydroxyisobutyrylation [9]. PTMs have been found in different pathologic conditions in SLE [10,11].…”

Section: Discussionmentioning

confidence: 99%

Proteome analysis of lysine 2-hydroxyisobutyrylation in the peripheral blood of systemic lupus erythematosus patients

Zhou

¹

,

Hua

²

,

Zhang

³

et al. 2020

Preprint

0

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organs, the pathogenic mechanism is related to many factors, but the specific pathogenic mechanism has not been clarified yet. Protein lysine modifications play important roles in gene regulation, transcription, metabolism and other biological processes. The lysine 2-hydroxyisobutyrylation(K hib ) histone mark has recently been discovered as a novel protein modification. In this study, patients in the active SLE group were examined (N=8), while the control group was healthy (N=20).Utilizing antibody-based affinity enrichment and nano-HPLC/MS/MS analyses of K hib peptides, we identified 156 upregulated proteins(fold change>1.5),124 downregulated proteins(fold change<1/1.5), including 220 K hib sites that were upregulated and 187 K hib sites that were downregulated. Our data demonstrate that proteins with K hib sites were localized in the cytoplasm. Functional enrichment analysis revealed that proteins with K hib sites are broadly involved in a wide range of biological processes, cellular components and molecular functions. The 03010 Ribosome pathways may exert important influence on the SLE pathogenic mechanism, according to a KEGG analysis. The functional analysis of K hib is of value for important future investigations of SLE pathogenesis.

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“…Since the discovery of phosphorylation, many new PTMs have been identified over the years, such as crotonylation, propionylation, malonylation, butyrylation, succinylation, glutarylation, βhydroxybutyrylation and 2-hydroxyisobutyrylation (Wu et al 2018). PTMs have been found in different pathologic conditions in SLE (Lu et al 2016;Zavala-Cerna et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Proteome analysis of lysine 2-hydroxyisobutyrylation in the peripheral blood of systemic lupus erythematosus patients

Zhou

¹

,

Lin

²

,

Zhang

³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organs, the pathogenic mechanism is related to many factors, but the specific pathogenic mechanism has not been clarified yet. Protein lysine modifications play important roles in gene regulation, transcription, metabolism and other biological processes. The lysine 2-hydroxyisobutyrylation(K hib ) histone mark has recently been discovered as a novel protein modification. In this study, patients in the active SLE group were examined (N=8), while the control group was healthy (N=20).Utilizing antibody-based affinity enrichment and nano-HPLC/MS/MS analyses of K hib peptides, we identified 156 upregulated proteins(fold change>1.5),124 downregulated proteins(fold change<1/1.5), including 220 K hib sites that were upregulated and 187 K hib sites that were downregulated. Our data demonstrate that proteins with K hib sites were localized in the cytoplasm. Functional enrichment analysis revealed that proteins with K hib sites are broadly involved in a wide range of biological processes, cellular components and molecular functions. The 03010 Ribosome pathways may exert important influence on the SLE pathogenic mechanism, according to a KEGG analysis. The functional analysis of K hib is of value for important future investigations of SLE pathogenesis.

show abstract

Global Analysis of Lysine 2-Hydroxyisobutyrylome upon SAHA Treatment and Its Relationship with Acetylation and Crotonylation

Cited by 26 publications

References 21 publications

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

Proteome analysis of lysine 2-hydroxyisobutyrylation in the peripheral blood of systemic lupus erythematosus patients

Proteome analysis of lysine 2-hydroxyisobutyrylation in the peripheral blood of systemic lupus erythematosus patients

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