Catalytic Mechanism and Product Specificity of the Histone Lysine Methyltransferase SET7/9:  An ab Initio QM/MM-FE Study with Multiple Initial Structures

Hu, Po; Zhang, Yingkai

doi:10.1021/ja056153+

Cited by 137 publications

(198 citation statements)

References 52 publications

Supporting

Mentioning

173

Contrasting

Order By: Relevance

“…To better understand why the formation of SDMA is limited, we questioned whether the formation of SDMA in the absence of protein was energetically more costly as compared with MMA and ADMA. Calculations have been applied for studies with protein lysine methyltransferases (PKMTs) suggesting that the energetics of the methyl transfer reactions, at least in part, may determine the product specificity of protein lysine methyltransferases (32)(33)(34)(35). Recent calculations on PRMT1 predicted a more facile ability to form ADMA as compared with MMA, but SDMA formation was not investigated (36).…”

Section: Resultsmentioning

confidence: 99%

A Remodeled Protein Arginine Methyltransferase 1 (PRMT1) Generates Symmetric Dimethylarginine

Gui

Gathiaka

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 99%

A Remodeled Protein Arginine Methyltransferase 1 (PRMT1) Generates Symmetric Dimethylarginine

Gui

Gathiaka

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…Earlier reports have identified SET7/9 as a histone lysine monomethyltransferase, but most of these were in vitro studies (21)(22)(23)40). Further work is needed to determine whether SET7/9 can directly promote Lys 4 trimethylation and whether this can also enhance transcription initiation in vivo.…”

Section: Discussionmentioning

confidence: 99%

Role of the Histone H3 Lysine 4 Methyltransferase, SET7/9, in the Regulation of NF-κB-dependent Inflammatory Genes

Reddy²,

Miao³

et al. 2008

Journal of Biological Chemistry

322

264

View full text Add to dashboard Cite

Nuclear factor -B (NF-B)-regulated inflammatory genes, such as TNF-␣ (tumor necrosis factor-␣), play key roles in the pathogenesis of inflammatory diseases, including diabetes and the metabolic syndrome. However, the nuclear chromatin mechanisms are unclear. We report here that the chromatin histone H3-lysine 4 methyltransferase, SET7/9, is a novel coactivator of NF-B. Gene silencing of SET7/9 with small interfering RNAs in monocytes significantly inhibited TNF-␣-induced inflammatory genes and histone H3-lysine 4 methylation on these promoters, as well as monocyte adhesion to endothelial or smooth muscle cells. Chromatin immunoprecipitation revealed that SET7/9 small interfering RNA could reduce TNF-␣-induced recruitment of NF-B p65 to inflammatory gene promoters. Inflammatory gene induction by ligands of the receptor for advanced glycation end products was also attenuated in SET7/9 knockdown monocytes. In addition, we also observed increased inflammatory gene expression and SET7/9 recruitment in macrophages from diabetic mice. Microarray profiling revealed that, in TNF-␣-stimulated monocytes, the induction of 25% NF-B downstream genes, including the histone H3-lysine 27 demethylase JMJD3, was attenuated by SET7/9 depletion. These results demonstrate a novel role for SET7/9 in inflammation and diabetes.NF-B is a pleiotropic transcription factor that plays a pivotal role in regulating multiple biological functions, such as inflammation, immunity, cell proliferation, and apoptosis (1, 2). NF-B plays an important role in the regulation of proinflammatory genes, such as TNF-␣ (tumor necrosis factor ␣) and MCP-1 (monocyte-chemoattractant protein-1), that are associated with several inflammatory diseases, including atherosclerosis, insulin resistance, metabolic syndrome, and diabetes and its complications (3-7). These genes also lead to monocyte activation associated with these inflammatory diseases.NF-B consists of homo-or heterodimers of different subunits, such as p50, p52, p65/RelA, RelB, and c-Rel, with p65/ RelA and p50 being the most common and well studied (1,8). In most unstimulated cells, NF-B resides in the cytoplasm in an inactive latent form complexed with its inhibitor subunit, IB␣. Multiple extracellular stimuli, including inflammatory cytokines, such as TNF-␣, and ligands of the receptor for advanced glycation end products (RAGE), 2 can induce NF-B activation by promoting IB␣ phosphorylation and its proteasomal degradation (6, 9). The released p65-p50 dimer then translocates to the nucleus, where it binds to the promoters of NF-B-dependent inflammatory genes, such as TNF-␣, MCP-1, and IL-6 (interleukin-6), to induce their expression (2). p65 protein is a key transcriptionally active component of NF-B whose transactivation potential is enhanced by several coactivators, including CREB-binding protein/p300, p/CAF, and SRC1 (10), which have histone acetyltransferase activity, and CARM1, which has arginine methyltransferase activity (11,12). Recently, we showed that histone H3 lysine acetylation is enriched...

show abstract

“…Acetylcholinesterase has been simulated by QM/ MM-FE with an emphasis on the effects of conformational dynamics on the reaction process [130,131]. cAMP-dependent protein kinase [132,133], histone lysine methyltransferase SET7/9 [134,135,136], and bacterial peptide deformylase [137,138] have been studied by the QM/MM-FE method. The reaction mechanism of methane monooxygenase has been explored in detail by Friesner and co-workers [139,140], as well as the P450cam pathway [141].…”

Section: Applications Of Ab Initio Qm/mm Methodsmentioning

confidence: 99%

Free Energies of Chemical Reactions in Solution and in Enzymes with Ab Initio Quantum Mechanics/Molecular Mechanics Methods

Yang

2008

Annu. Rev. Phys. Chem.

417

401

View full text Add to dashboard Cite

Combined QM/MM methods provide an accurate and efficient energetic description of complex chemical and biological systems, leading to significant advances in the understanding of chemical reactions in solution and in enzymes. Progress in QM/MM methodology and application will be reviewed, with a focus on ab initio QM based approaches. Ab initio QM/MM methods capitalize on the accuracy and reliability of the associated quantum mechanical approaches, however at a much higher computational cost compared with semiempirical quantum mechanical approaches. Thus reaction path and activation free energy calculations based on ab initio QM/MM methods encounter unique challenges in simulation timescales and phase space sampling. Recent developments overcoming these challenges and enabling accurate free energy determination for reaction processes in solution and enzymes will be featured in this review, along with applications.

show abstract

Catalytic Mechanism and Product Specificity of the Histone Lysine Methyltransferase SET7/9: An ab Initio QM/MM-FE Study with Multiple Initial Structures

Cited by 137 publications

References 52 publications

A Remodeled Protein Arginine Methyltransferase 1 (PRMT1) Generates Symmetric Dimethylarginine

A Remodeled Protein Arginine Methyltransferase 1 (PRMT1) Generates Symmetric Dimethylarginine

Role of the Histone H3 Lysine 4 Methyltransferase, SET7/9, in the Regulation of NF-κB-dependent Inflammatory Genes

Free Energies of Chemical Reactions in Solution and in Enzymes with Ab Initio Quantum Mechanics/Molecular Mechanics Methods

Contact Info

Product

Resources

About