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Immunology Jun 2024The cross-regulation of immunity and metabolism is currently a research hotspot in life sciences and immunology. Metabolic immunology plays an important role in... (Review)
Review
The cross-regulation of immunity and metabolism is currently a research hotspot in life sciences and immunology. Metabolic immunology plays an important role in cutting-edge fields such as metabolic regulatory mechanisms in immune cell development and function, and metabolic targets and immune-related disease pathways. Protein post-translational modification (PTM) is a key epigenetic mechanism that regulates various biological processes and highlights metabolite functions. Currently, more than 400 PTM types have been identified to affect the functions of several proteins. Among these, metabolic PTMs, particularly various newly identified histone or non-histone acylation modifications, can effectively regulate various functions, processes and diseases of the immune system, as well as immune-related diseases. Thus, drugs aimed at targeted acylation modification can have substantial therapeutic potential in regulating immunity, indicating a new direction for further clinical translational research. This review summarises the characteristics and functions of seven novel lysine acylation modifications, including succinylation, S-palmitoylation, lactylation, crotonylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation and malonylation, and their association with immunity, thereby providing valuable references for the diagnosis and treatment of immune disorders associated with new acylation modifications.
PubMed: 38866391
DOI: 10.1111/imm.13822 -
Molecular & Cellular Proteomics : MCP Jun 2024Histone post-translational modifications (PTMs) have crucial roles in a multitude of cellular processes, and their aberrant levels have been linked with numerous...
Histone post-translational modifications (PTMs) have crucial roles in a multitude of cellular processes, and their aberrant levels have been linked with numerous diseases, including cancer. Although histone PTM investigations have focused so far on methylations and acetylations, alternative long-chain acylations emerged as new dimension, as they are linked to cellular metabolic states and affect gene expression through mechanisms distinct from those regulated by acetylation. Mass spectrometry (MS) is the most powerful, comprehensive and unbiased method to study histone PTMs. However, typical MS-based protocols for histone PTM analysis do not allow identification of naturally occurring propionylation and butyrylation. Here, we present improved state-of-the-art sample preparation and analysis protocols to quantitate these classes of modifications. After testing different derivatization methods coupled to protease digestion, we profiled common histone PTMs and histone acylations in seven mouse tissues and human normal and tumor breast clinical samples, obtaining a map of propionylations and butyrylations found in different tissue contexts. A quantitative histone PTM analysis also revealed a contribution of histone acylations in discriminating different tissues, also upon perturbation with antibiotics, and breast cancer samples from the normal counterpart. Our results show that profiling only classical modifications is limiting and highlight the importance of using sample preparation methods that allows the analysis of the widest possible spectrum of histone modifications, paving the way for deeper insights into their functional significance in cellular processes and disease states.
PubMed: 38866077
DOI: 10.1016/j.mcpro.2024.100799 -
Journal of Chemical Information and... Jun 2024Epigenetic modifications of histone N-terminal tails play a critical role in regulating the chromatin structure and biological processes such as transcription and DNA...
Epigenetic modifications of histone N-terminal tails play a critical role in regulating the chromatin structure and biological processes such as transcription and DNA repair. One of the key post-translational modifications (PTMs) is the acetylation of lysine residues on histone tails. Epigenetic modifications are ubiquitous in the development of diseases, such as cancer and neurological disorders. Histone H2B tails are critical regulators of nucleosome dynamics, biological processes, and certain diseases. Here, we report all-atomistic molecular dynamics (MD) simulations of the nucleosome to demonstrate that acetylation of the histone tails changes their conformational space and interaction with DNA. We perform simulations of H2B tails, critical regulators of gene regulation, in both the lysine-acetylated (ACK) and unacetylated wild type (WT) states. To explore the effects of salt concentration, we use two different NaCl concentrations to perform simulations at microsecond time scales. Salt can modulate the effects of electrostatic interactions between the DNA phosphate backbone and histone tails. Upon acetylation, H2B tails shift their secondary structure helical propensity. The number of contacts between the DNA and the H2B tail decreases. We characterize the conformational dynamics of the H2B tails by principal component analysis (PCA). The ACK tails become more compact at increased salt concentrations, but conformations from the WT tails display the most contacts with DNA at both salt concentrations. Mainly, H2B acetylation may increase the DNA accessibility for regulatory proteins to bind, which can aid in gene regulation and NCP stability.
Topics: Molecular Dynamics Simulation; Histones; Nucleosomes; DNA; Acetylation; Protein Conformation; Principal Component Analysis
PubMed: 38865599
DOI: 10.1021/acs.jcim.4c00059 -
Journal of the American Chemical Society Jun 2024The catalytic cross-coupling of identical or similar functional groups is a cornerstone strategy for carbon-carbon bond formation, as exemplified by renowned methods,...
The catalytic cross-coupling of identical or similar functional groups is a cornerstone strategy for carbon-carbon bond formation, as exemplified by renowned methods, such as olefin cross-metathesis, Kolbe electrolysis, and various cross-electrophile couplings. However, similar methodologies for coupling aldehydes─fundamental building blocks in organic synthesis─remain underdeveloped. While the benzoin-type condensation, first reported in 1832, offers a reliable route for aldehyde dimerization, the chemo- and enantioselective cross-coupling of nonidentical yet similar aldehydes remains an unsolved challenge. Herein, we report a unified platform enabling highly chemo- and enantioselective cross-coupling of aldehydes. By leveraging nickel photoredox catalysis in tandem with discrete activation strategies for each aldehyde, this mechanistically distinct approach facilitates the enantioselective union of an aldehyde-derived α-oxy radical with an acyl radical, photocatalytically generated from a distinct aldehyde. This novel strategy enables modular access to enantioenriched α-oxygenated ketones with two minimally differentiated aliphatic substituents, a feat not achievable with existing chemocatalytic or biocatalytic techniques. The synthetic utility of this method is demonstrated by its application in the streamlined asymmetric synthesis of various medicinally relevant molecules. Additionally, mechanistic investigations rationalize the versatility of nickel photoredox catalysis to exploit new pathways for addressing long-standing synthetic challenges.
PubMed: 38864298
DOI: 10.1021/jacs.4c03164 -
Acetylation of histones and non-histone proteins is not a mere consequence of ongoing transcription.Nature Communications Jun 2024In all eukaryotes, acetylation of histone lysine residues correlates with transcription activation. Whether histone acetylation is a cause or consequence of...
In all eukaryotes, acetylation of histone lysine residues correlates with transcription activation. Whether histone acetylation is a cause or consequence of transcription is debated. One model suggests that transcription promotes the recruitment and/or activation of acetyltransferases, and histone acetylation occurs as a consequence of ongoing transcription. However, the extent to which transcription shapes the global protein acetylation landscapes is not known. Here, we show that global protein acetylation remains virtually unaltered after acute transcription inhibition. Transcription inhibition ablates the co-transcriptionally occurring ubiquitylation of H2BK120 but does not reduce histone acetylation. The combined inhibition of transcription and CBP/p300 further demonstrates that acetyltransferases remain active and continue to acetylate histones independently of transcription. Together, these results show that histone acetylation is not a mere consequence of transcription; acetyltransferase recruitment and activation are uncoupled from the act of transcription, and histone and non-histone protein acetylation are sustained in the absence of ongoing transcription.
Topics: Acetylation; Histones; Transcription, Genetic; Humans; Ubiquitination; p300-CBP Transcription Factors; Protein Processing, Post-Translational; Histone Acetyltransferases; Lysine
PubMed: 38862536
DOI: 10.1038/s41467-024-49370-2 -
Genomics, Proteomics & Bioinformatics May 2024Lysine post-translational modifications (PTMs) are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental... (Review)
Review
Lysine post-translational modifications (PTMs) are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins. Dysregulation of lysine PTMs is implicated in many diseases, and targeting lysine PTM regulatory factors, including writers, erasers, and readers, has become an effective strategy for disease therapy. The continuing development of mass spectrometry (MS) technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of PTMs. The global characterization of lysine PTMs is crucial for deciphering the regulatory networks, molecular functions, and mechanisms of action of lysine PTMs. In this review, we focus on lysine PTMs, and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS technologies. We also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy.
Topics: Protein Processing, Post-Translational; Lysine; Humans; Histones; Animals; Proteomics
PubMed: 38862432
DOI: 10.1093/gpbjnl/qzae019 -
Journal of Asian Natural Products... Jun 2024Twenty 3-acyloxymaltol/ethyl maltol derivatives ( and ) were synthesized and evaluated for their anti-oomycete activity against , respectively. Among all of twenty...
Twenty 3-acyloxymaltol/ethyl maltol derivatives ( and ) were synthesized and evaluated for their anti-oomycete activity against , respectively. Among all of twenty derivatives, more than half of the compounds , , and had anti-oomycete activity higher than the positive control zoxamide (EC = 22.23 mg/L), and the EC values of 18.66, 20.32, 12.80, 16.18, 10.59, 14.98, 16.80, 10.36, 15.32, 12.64, and 13.59 mg/L, respectively. Especially, compounds and exhibited the best anti-oomycete activity against with EC values of 10.59 and 10.36 mg/L, respectively. Overall, hydroxyl group of maltol/ethyl maltol is important active modification site.
PubMed: 38859556
DOI: 10.1080/10286020.2024.2355144 -
Bioorganic & Medicinal Chemistry Letters Sep 20242'-5'-Adenosine linked nucleic acids are crucial components in living cells that play significant roles, including participating in antiviral defense mechanisms by...
2'-5'-Adenosine linked nucleic acids are crucial components in living cells that play significant roles, including participating in antiviral defense mechanisms by facilitating the breakdown of viral genetic material. In this report, we present a chemical derivatization method employing 5-fluoro-2-pyridinoyl-imidazole as the acylation agent, a strategy that can be effectively combined with advanced analytical tools, including Nuclear Magnetic Resonance spectroscopy and Liquid Chromatography-Mass Spectrometry, to enhance the characterization and detection capabilities. This marks the first instance of a simple method designed to detect 2'-5'-adenosine linked nucleic acids. The new method is characterized by its time-saving nature, simplicity, and relative accuracy compared to previous methods.
Topics: Acylation; Adenosine; Nucleic Acids; Imidazoles; Molecular Structure; Magnetic Resonance Spectroscopy; Mass Spectrometry
PubMed: 38857849
DOI: 10.1016/j.bmcl.2024.129847 -
Experimental Cell Research Jul 2024Microtubules are components of the cytoskeleton that perform essential functions in eukaryotes, such as those related to shape change, motility and cell division. In...
Microtubules are components of the cytoskeleton that perform essential functions in eukaryotes, such as those related to shape change, motility and cell division. In this context some characteristics of these filaments are essential, such as polarity and dynamic instability. In trypanosomatids, microtubules are integral to ultrastructure organization, intracellular transport and mitotic processes. Some species of trypanosomatids co-evolve with a symbiotic bacterium in a mutualistic association that is marked by extensive metabolic exchanges and a coordinated division of the symbiont with other cellular structures, such as the nucleus and the kinetoplast. It is already established that the bacterium division is microtubule-dependent, so in this work, it was investigated whether the dynamism and remodeling of these filaments is capable of affecting the prokaryote division. To this purpose, Angomonas deanei was treated with Trichostatin A (TSA), a deacetylase inhibitor, and mutant cells for histone deacetylase 6 (HDAC6) were obtained by CRISPR-Cas9. A decrease in proliferation, an enhancement in tubulin acetylation, as well as morphological and ultrastructural changes, were observed in TSA-treated protozoa and mutant cells. In both cases, symbiont filamentation occurred, indicating that prokaryote cell division is dependent on microtubule dynamism.
Topics: Microtubules; Symbiosis; Cell Division; Trypanosomatina; Hydroxamic Acids; Tubulin; Bacteria; Acetylation; Histone Deacetylase Inhibitors; Histone Deacetylase 6; Cytoskeleton
PubMed: 38857838
DOI: 10.1016/j.yexcr.2024.114126 -
Genomics Jun 2024The investigation of dwarfing rootstocks for the establishment of high-generation seed orchards is a prospective avenue of research. In this investigation, Pinus...
The investigation of dwarfing rootstocks for the establishment of high-generation seed orchards is a prospective avenue of research. In this investigation, Pinus massoniana, Pinus yunnanensis var. pygmaea (P. pygmaea), and P. elliottii seedlings were used as rootstocks for grafting with P. massoniana scions. Grafting P. massoniana onto P. pygmaea rootstock resulted in observable phenotypic alterations in lateral branches, apical buds, and needle length. Certain characteristic metabolites of rootstocks, such as fatty acyls, pregnenolones, steroids, and steroid derivatives, were found to be highly expressed in scions after grafting. RNA-seq analysis revealed MYB-related, SBP, and bHLH demonstrating a significant positive correlation, while C2H2 and Orphans exhibited negative correlations with the differential intensity of metabolites related to lipids and lipid-like molecules. This study offers valuable insights for the establishment of rootstock breeding programs.
PubMed: 38857814
DOI: 10.1016/j.ygeno.2024.110882