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Experimental Neurology Nov 2021In addition to DNA methylation, reversible epigenetic modification occurring in RNA has been discovered recently. The most abundant type of RNA methylation is... (Review)
Review
In addition to DNA methylation, reversible epigenetic modification occurring in RNA has been discovered recently. The most abundant type of RNA methylation is N6-methyladenosine (m6A) modification, which is dynamically regulated by methylases ("writers"), demethylases ("erasers") and m6A-binding proteins ("readers"). As an essential posttranscriptional regulator, m6A can control mRNA splicing, processing, stability, export and translation. Recent studies have revealed that m6A modification has the strongest tissue specificity for brain tissue and plays crucial roles in central nervous system (CNS) injures by affecting its downstream target genes or non-coding RNAs. This review focuses on the expression and function of m6A regulatory proteins in CNS trauma in vitro and in vivo. We also highlight the latest insights into the molecular mechanisms of pathological damage in the CNS. Understanding m6A dynamics, functions, and machinery will yield an opportunity for designing and developing novel therapeutic agents for CNS injuries.
Topics: Adenosine; Animals; Central Nervous System; Epigenesis, Genetic; Humans; RNA
PubMed: 34339678
DOI: 10.1016/j.expneurol.2021.113829 -
Critical Reviews in Toxicology Sep 2020Recent advances in the field of RNA modifications and long non-coding RNAs (lncRNAs) have provided substantial evidence on important biological functions. LncRNAs are... (Review)
Review
Recent advances in the field of RNA modifications and long non-coding RNAs (lncRNAs) have provided substantial evidence on important biological functions. LncRNAs are defined as longer than 200 nucleotides which are not translated into proteins. The term "epitranscriptome" refers to all modifications in RNA types. Adenine-6 methylation (mA) is the most common, dynamic and prominent modifications in coding and non-coding RNAs and has critical and previously unappreciated functional roles. Accumulation evidence indicated the association between RNA m6A modification and cancer and nonmalignant diseases. Recent studies reported that several lncRNAs including and - are subject to mA modification. It can be suggested that lncRNAs modified by mA modification have substantive roles in diseases. Currently limited data are available regarding how environmental exposure affects mA-modified lncRNAs. Furthermore, we do not know the interaction of environmental exposure and mA-modified lncRNAs in development of adverse human health outcomes. Thus, in this systematic review, we aimed to present the data of the studies that reported a significant association between environmental exposure and expression/DNA methylation of mA-modified long non-coding RNAs.
Topics: Adenosine; Environmental Exposure; Humans; Neoplasms; RNA, Long Noncoding
PubMed: 32924714
DOI: 10.1080/10408444.2020.1812511 -
Progress in Biophysics and Molecular... 2022Inosine is one of the most common post-transcriptional modifications. Since its discovery, it has been noted for its ability to contribute to non-Watson-Crick... (Review)
Review
Inosine is one of the most common post-transcriptional modifications. Since its discovery, it has been noted for its ability to contribute to non-Watson-Crick interactions within RNA. Rapidly accumulating evidence points to the widespread generation of inosine through hydrolytic deamination of adenosine to inosine by different classes of adenosine deaminases. Three naturally occurring methyl derivatives of inosine, i.e., 1-methylinosine, 2'-O-methylinosine and 1,2'-O-dimethylinosine are currently reported in RNA modification databases. These modifications are expected to lead to changes in the structure, folding, dynamics, stability and functions of RNA. The importance of the modifications is indicated by the strong conservation of the modifying enzymes across organisms. The structure, binding and catalytic mechanism of the adenosine deaminases have been well-studied, but the underlying mechanism of the catalytic reaction is not very clear yet. Here we extensively review the existing data on the occurrence, biogenesis and functions of inosine and its methyl derivatives in RNA. We also included the structural and thermodynamic aspects of these modifications in our review to provide a detailed and integrated discussion on the consequences of A-to-I editing in RNA and the contribution of different structural and thermodynamic studies in understanding its role in RNA. We also highlight the importance of further studies for a better understanding of the mechanisms of the different classes of deamination reactions. Further investigation of the structural and thermodynamic consequences and functions of these modifications in RNA should provide more useful information about their role in different diseases.
Topics: Adenosine; Inosine; RNA; RNA Editing
PubMed: 35065168
DOI: 10.1016/j.pbiomolbio.2022.01.001 -
Current Opinion in Structural Biology Aug 2021RNA undergoes extensive biochemical modification following transcription. In addition to RNA splicing, transcripts are processed by a suite of enzymes that alter the... (Review)
Review
RNA undergoes extensive biochemical modification following transcription. In addition to RNA splicing, transcripts are processed by a suite of enzymes that alter the chemical structure of different nucleobases. Broadly termed as 'RNA editing,' these modifications impart significant functional changes to translation, localization, and stability of individual transcripts within the cell. These changes are dynamic and required for a number of critical cellular processes, and dysregulation of these pathways is responsible for several disease states. Accurately detecting, measuring, and mapping different RNA modifications across the transcriptome is vital to understanding their broader functions as well as leveraging these events as diagnostic biomarkers. Here, we review recent advances in profiling several types of RNA modifications, with particular emphasis on adenosine-to-inosine (A-to-I) and N-methyladenosine (mA) RNA editing. We especially highlight approaches that utilize proteins to detect or enrich modified RNA transcripts before sequencing, and we summarize recent insights yielded from these techniques.
Topics: Adenosine; Inosine; RNA; RNA Editing; Transcriptome
PubMed: 33445115
DOI: 10.1016/j.sbi.2020.12.006 -
Harnessing methylation and AdoMet-utilising enzymes for selective modification in cascade reactions.Organic & Biomolecular Chemistry May 2021Enzyme-mediated methylation is a very important reaction in nature, yielding a wide range of modified natural products, diversifying small molecules and fine-tuning the... (Review)
Review
Enzyme-mediated methylation is a very important reaction in nature, yielding a wide range of modified natural products, diversifying small molecules and fine-tuning the activity of biomacromolecules. The field has attracted much attention over the recent years and interesting applications of the dedicated enzymes in biocatalysis and biomolecular labelling have emerged. In this review article, we summarise the concepts and recent advances in developing (chemo)-enzymatic cascades for selective methylation, alkylation and photocaging as tools to study biological methylation and as biotransformations to generate site-specifically alkylated products.
Topics: S-Adenosylmethionine
PubMed: 33949607
DOI: 10.1039/d1ob00354b -
The Journal of Organic Chemistry Nov 2019In search of a new template for anti-hepatitis C virus (HCV) agents, we designed and synthesized the 2'--methyl-4'-selenopyrimidine and -purine nucleosides and their...
In search of a new template for anti-hepatitis C virus (HCV) agents, we designed and synthesized the 2'--methyl-4'-selenopyrimidine and -purine nucleosides and their phosphoramidate prodrugs to replace a furanose oxygen of anti-HCV nucleos(t)ides with a selenium atom on the basis that selenium is a chemical isostere of oxygen. These nucleosides are expected to show different physicochemical properties such as better lipophilicity which might enhance the penetration across cell membranes and the conformational constraint induced by a bulky selenium atom in the sugar ring. The 2'--methyl-4'-selenopyrimidine and -purine nucleosides and were synthesized from 2--methyl-d-ribono-γ-lactone () via construction of 2--methyl-d-selenosugar through -4 epimerization and S2 cyclization with Se as key steps. The key 4'-selenosugar was converted to the 2'--methyl-4'-selenopyrimidine and -purine nucleosides using Pummerer-type rearrangement and Vorbrüggen glycosylation, respectively. In addition, the ProTide strategy has been applied to synthesize the adenine and uracil phosphoramidate derivatives and to overcome the limitations associated with parent nucleosides such as inefficient conversion to their corresponding 5'-monophosphate form and poor cellular uptake. The regio- and stereochemistry of 4'-selenonucleosides were confirmed by 2D NOESY NMR spectroscopy and X-ray crystallography. None of the final pyrimidine and purine nucleosides and their prodrugs exhibited significant anti-HCV activity up to 100 μM.
Topics: Antiviral Agents; Hepacivirus; Microbial Sensitivity Tests; Molecular Conformation; Nucleosides; Organoselenium Compounds
PubMed: 31608633
DOI: 10.1021/acs.joc.9b01462 -
Reviews in Endocrine & Metabolic... Dec 2021Type 2 diabetes has been a global health challenge over the decades and is among the leading causes of death. Several treatment approaches have been developed, but more... (Review)
Review
Type 2 diabetes has been a global health challenge over the decades and is among the leading causes of death. Several treatment approaches have been developed, but more effective and new therapies are still needed. The role of adenosine in glucose and lipid homeostasis has offered a different therapeutic approach. Adenosine mediates its physiological role through the activation of adenosine receptors. These adenosine receptors have been implicated in glucose and lipid homeostasis. The ability of agonists and antagonists of adenosine receptors to activate or inhibit the adenosine signalling cascade and thereby affecting the balance of glucose and lipid homeostasis has challenged the studies of agonists and antagonists of adenosine receptors, both preclinical and clinical, as potential anti-diabetic drugs. This review provides a background on different anti-diabetic therapeutic approaches, outlining the role of adenosine receptors in glucose and lipid homeostasis, and mechanisms underlying the action of agonists/antagonists of adenosine receptors as a therapeutic potential towards type 2 diabetes.
Topics: Adenosine; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Receptors, Purinergic P1
PubMed: 34165671
DOI: 10.1007/s11154-021-09668-8 -
Molecules (Basel, Switzerland) Aug 2020The arbocyclic nucleosides aristeromycin and neplanocin have been studied as a source for new antiviral agents. A convenient synthesis of C-5'-truncated...
The arbocyclic nucleosides aristeromycin and neplanocin have been studied as a source for new antiviral agents. A convenient synthesis of C-5'-truncated 3-deaza-1',6'-isoneplanocin, which combines the features of antiviral candidates 5'-noraristeromycin and 3-deaza-1',6'-isoneplanocin is reported from (-)-cyclopentenone to give the two C-4' epimers of 5'-nor-3-deaza isoneplanocin. Antiviral assays showed activity against the JC virus (EC = 1.12 µM for (4')-; EC = 59.14 µM for (4')-) and inactivity of both compounds against several DNA and RNA viruses. Both compounds lacked cytotoxicity.
Topics: Adenosine; Antiviral Agents; Humans; JC Virus; RNA Viruses
PubMed: 32854369
DOI: 10.3390/molecules25173865 -
Biochimica Et Biophysica Acta. Reviews... Apr 2021In recent years, the most widely distributed eukaryotic messenger RNA (mRNA) modification, N6-methyladenosine (m6A), has received a large amount of interest, in part due... (Review)
Review
In recent years, the most widely distributed eukaryotic messenger RNA (mRNA) modification, N6-methyladenosine (m6A), has received a large amount of interest, in part due to the development and advances of high-throughput RNA sequencing. The effects of m6A mRNA on tumor progression have been the most widely studied, and large amounts of conflicting data have been reported due to differences in tumor contexts, cell types or cell states. The majority of these studies were related to the significance of m6A mRNA on tumor cells, including on proliferation, stemness, invasion capability, etc. However, it has been noted that tumorigenesis and tumor progression cannot occur without support from the tumor microenvironment (TME), which contains multiple types of stromal cells, such as infiltrating immune cells (IICs), vascular cells, mesenchymal stem cells (MSCs), cancer-associated fibroblasts (CAFs), and various environmental factors. Here, we summarized the contributions of abnormal m6A mRNA in stromal cells within the TME and described the effects of m6A mRNA on TME remodeling.
Topics: Adenosine; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Neoplastic Stem Cells; RNA, Messenger; Tumor Microenvironment
PubMed: 33545295
DOI: 10.1016/j.bbcan.2021.188522 -
Nucleosides, Nucleotides & Nucleic Acids 2022has been reported unable to directly incorporate mononucleotides but instead requires their external dephosphorylation by nucleotidases to the corresponding nucleosides...
has been reported unable to directly incorporate mononucleotides but instead requires their external dephosphorylation by nucleotidases to the corresponding nucleosides prior to their incorporation. Although PA-3 (PA-3), a strain of lactic acid bacteria, has been found to incorporate purine mononucleotides such as adenosine 5'-monophosphate (AMP), it remains unclear whether these bacteria directly incorporate these mononucleotides or incorporate them after dephosphorylation to the corresponding nucleosides. This study evaluated whether PA-3 incorporated radioactively-labeled mononucleotides in the presence or absence of the 5'-nucleotidase inhibitor α,β-methylene ADP (APCP). PA-3 took up C-AMP in the presence of APCP, as well as incorporating P-AMP. Furthermore, radioactivity was detected in the RNA/DNA of bacterial cells cultured in the presence of P-AMP. Taken together, these findings indicated that PA-3 incorporated purine mononucleotides directly rather than after their dephosphorylation to purine nucleosides and that PA-3 utilizes these purine mononucleotides in the synthesis of RNA and DNA. Although additional studies are required to identify purine mononucleotide transporters in PA-3, this study is the first to show that some lactic acid bacteria directly incorporate purine mononucleotides and use them for growth.
Topics: Adenosine Monophosphate; Lactobacillus gasseri; Nucleotidases; Purine Nucleosides
PubMed: 32954967
DOI: 10.1080/15257770.2020.1815768