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Nucleic Acids Research May 2021Deazapurine nucleosides such as 3-deazaadenosine (c3A) are crucial for atomic mutagenesis studies of functional RNAs. They were the key for our current mechanistic...
Deazapurine nucleosides such as 3-deazaadenosine (c3A) are crucial for atomic mutagenesis studies of functional RNAs. They were the key for our current mechanistic understanding of ribosomal peptide bond formation and of phosphodiester cleavage in recently discovered small ribozymes, such as twister and pistol RNAs. Here, we present a comprehensive study on the impact of c3A and the thus far underinvestigated 3-deazaguanosine (c3G) on RNA properties. We found that these nucleosides can decrease thermodynamic stability of base pairing to a significant extent. The effects are much more pronounced for 3-deazapurine nucleosides compared to their constitutional isomers of 7-deazapurine nucleosides (c7G, c7A). We furthermore investigated base pair opening dynamics by solution NMR spectroscopy and revealed significantly enhanced imino proton exchange rates. Additionally, we solved the X-ray structure of a c3A-modified RNA and visualized the hydration pattern of the minor groove. Importantly, the characteristic water molecule that is hydrogen-bonded to the purine N3 atom and always observed in a natural double helix is lacking in the 3-deazapurine-modified counterpart. Both, the findings by NMR and X-ray crystallographic methods hence provide a rationale for the reduced pairing strength. Taken together, our comparative study is a first major step towards a comprehensive understanding of this important class of nucleoside modifications.
Topics: Base Pairing; Crystallography, X-Ray; Mutagenesis; Purines; RNA; RNA Stability; Thermodynamics; Tubercidin
PubMed: 33856457
DOI: 10.1093/nar/gkab256 -
Clinical Biochemistry Jun 2021Recently, the enzyme nudix hydrolase 15 (NUDT15) has been identified as an additional component of the thiopurine metabolism pathway. NUDT15 (also known as MTH2)... (Review)
Review
Recently, the enzyme nudix hydrolase 15 (NUDT15) has been identified as an additional component of the thiopurine metabolism pathway. NUDT15 (also known as MTH2) catalyzes the dephosphorylation of 6-thioguanosine triphosphate (6-TGTP) and 6-thio-deoxyguanosine triphosphate (6-TdGTP), which is the active metabolite of thiopurine medications. Thiopurine compounds, which were first synthesized in the 1950s, are widely used in the treatment of childhood leukemia, inflammatory bowel disease, and autoimmune disorders. For many years, TPMT has been recognized as an enzyme that is involved in thiopurine metabolism, and interindividual variation in TPMT activity has been known to contribute to differences in risk of thiopurine toxicity. Genetic variation that leads to decreased NUDT15 activity has been recognized as an additional contributor, beyond TPMT, to thiopurine toxicity. In some populations, including Asian and Latino populations, NUDT15 genetic variants are more common than TPMT variants, making this a significant biomarker of toxicity. Clinical genetic testing is now available for a subset of NUDT15 variants, representing a remarkably fast translation from bench to bedside. This review will focus on NUDT15 - from discovery to clinical implementation.
Topics: Asian People; Hispanic or Latino; Humans; Inflammatory Bowel Diseases; Methyltransferases; Mutation; Pharmacogenomic Variants; Purine Nucleosides; Pyrophosphatases; Thionucleosides
PubMed: 33675810
DOI: 10.1016/j.clinbiochem.2021.02.007 -
Nature Jun 2020The nature of the first genetic polymer is the subject of major debate. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of...
The nature of the first genetic polymer is the subject of major debate. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of the prebiotic era-that is, prior to the dawn of life-other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA. Such a theory streamlines the eventual 'genetic takeover' of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life.
Topics: Adenosine; Cytidine; DNA; Evolution, Chemical; Origin of Life; Oxidation-Reduction; Purine Nucleosides; Pyrimidine Nucleosides; RNA; Uridine
PubMed: 32494078
DOI: 10.1038/s41586-020-2330-9 -
Infectious Disorders Drug Targets 2018Ebola virus (EBOV) was discovered for the first time in 1976. It belongs to the family Filoviridae, which causes hemorrhagic fever that could lead to death in a few... (Review)
Review
Ebola virus (EBOV) was discovered for the first time in 1976. It belongs to the family Filoviridae, which causes hemorrhagic fever that could lead to death in a few days. West Africa faced a major outbreak where symptoms appeared in the form of chills, myalgia, fever, diarrhea, and vomiting, and the disease finally reached a severe state as a result of hemorrhagic complications and failure of multiple organs. EBOV spreads by contact with body fluids of an infected person such as blood, saliva, urine, and seminal fluid, and also spreads by a contact with contaminated surfaces. Viral infection depends on the virus and host defenses. When the virus invades the body, the immune system becomes activated in an attempt to neutralize it. However, if this fails, EBOV viral infection spreads and leads to impaired innate and adaptive immune responses and uncontrollable viral replication. Consequently, the symptomatic patient is isolated and various medicinal regimens such as BCX-4430n TKM- EBOV are used, to cure EBOV, though, a specific treatment is not available. Accordingly, the aim of the present review is to survey and summarize the recent literature pertaining to the outbreak of EBOV, systematic infection of the human body, along with transmission and treatment. In addition, the review also aims to identify areas that need more research and development in combatting this dangerous virus. In the meantime, it should be noted that there is no fully FDA approved drug to treat infections by this virus. Therefore, there is a pressing need to focus on drug discovery along with public awareness to effectively manage any outbreaks in the future.
Topics: Adenine; Adenosine; Africa, Western; Animals; Antiviral Agents; Disease Outbreaks; Drug Discovery; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Immune System; Purine Nucleosides; Pyrrolidines; Virus Replication
PubMed: 28820067
DOI: 10.2174/1871526517666170817100828 -
Current Atherosclerosis Reports Nov 2014Oxidative stress due to an excess of reactive oxygen species (ROS) may play a role in the development and progression of cardiovascular disease (CVD).... (Review)
Review
Oxidative stress due to an excess of reactive oxygen species (ROS) may play a role in the development and progression of cardiovascular disease (CVD). 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a marker of oxidative DNA damage caused by ROS. This review aimed to assess the association between 8-OHdG and CVD by reviewing the literature. Studies in human subjects using either plasma or urine to determine 8-OHdG concentrations were surveyed. Eighteen relevant studies were found, of which 13 were case-control studies and five had a prospective design. Without exception, the case-control studies showed significant positive associations between 8-OHdG and CVD. In agreement, two prospective studies showed a significant association of 8-OHdG and heart failure. Furthermore, two prospective studies found a significant association between 8-OHdG and stroke, and finally, one prospective study showed a borderline significant (p = 0.08) association between coronary artery disease (CAD) patients developing a cardiac event and 8-OHdG concentrations. In conclusion, high levels of 8-OHdG in blood and urine are associated with atherosclerosis and heart failure, but further large prospective studies are needed to investigate 8-OHdG as a predictor for cardiovascular diseases.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Cardiovascular Diseases; Clinical Trials as Topic; DNA Damage; Deoxyguanosine; Humans; Oxidative Stress; Reactive Oxygen Species
PubMed: 25252787
DOI: 10.1007/s11883-014-0452-y -
Frontiers in Bioscience (Landmark... Oct 2023Metazoan adenosine-to-inosine (A-to-I) RNA editing is a highly conserved mechanism that diversifies the transcriptome by post-transcriptionally converting adenosine to... (Review)
Review
Metazoan adenosine-to-inosine (A-to-I) RNA editing is a highly conserved mechanism that diversifies the transcriptome by post-transcriptionally converting adenosine to inosine. Millions of editing sites have been identified in different species and, based on abnormal editing observed in various disorders, it is intuitive to conclude that RNA editing is both functional and adaptive. In this review, we propose the following major points: (1) "Function/functional" only represents a molecular/phenotypic consequence and is not necessarily connected to "adaptation/adaptive"; (2) Adaptive editing should be judged in the light of evolution and emphasize advantages of temporal-spatial flexibility; (3) Adaptive editing could, in theory, be extended from nonsynonymous sites to all potentially functional sites. This review seeks to conceptually bridge the gap between molecular biology and evolutionary biology and provide a more objective understanding on the biological functions and evolutionary significance of RNA editing.
Topics: Animals; RNA; RNA Editing; Adenosine; Inosine; Transcriptome
PubMed: 37919076
DOI: 10.31083/j.fbl2810256 -
ChemMedChem Feb 2024The synthesis and antiproliferative evaluation of novel d-glucopyranuronamide-containing nucleosides is described. Based on our previously reported anticancer...
The synthesis and antiproliferative evaluation of novel d-glucopyranuronamide-containing nucleosides is described. Based on our previously reported anticancer d-glucuronamide-based nucleosides, new analogues comprising N/O-dodecyl or N-propargyl substituents at the glucuronamide unit and anomerically-N-linked 2-acetamido-6-chloropurine, 6-chloropurine or 4-(6-chloropurinyl)methyl triazole motifs were synthesized in 4-6 steps starting from acetonide-protected glucofuranurono-6,3-lactone. The methodologies were based on the access to N-substituted glycopyranuronamide precursors, namely 1,2-O-acetyl derivatives or glucuronoamidyl azides for further nucleobase N-glycosylation or 1,3-dipolar cycloaddition with N - and N -propargyl-6-chloropurines, respectively. N-Propargyl glucuronamide-based N -purine nucleosides were converted into (triazolyl)methyl amide-6,6-linked pseudodisaccharide nucleosides via cycloaddition with methyl 6-azido-glucopyranoside. A CuI/Amberlyst A-21 catalytic system employed in the cycloaddition reactions also effected conversion into 6-dimethylaminopurine nucleosides. Antiproliferative evaluation in chronic myeloid leukemia (K562) and breast cancer (MCF-7) cells revealed significant effects exhibited by the synthesized monododecylated purine-containing nucleosides. A N-propargyl 3-O-dodecyl glucuronamide derivative comprising a N -β-linked 6-chloropurine moiety was the most active compound against MCF-7 cells (GI =11.9 μM) while a related α-(purinyl)methyltriazole nucleoside comprising a N -linked 6-chloropurine moiety exhibited the highest activity against K562 cells (GI =8.0 μM). Flow cytometry and immunoblotting analysis of apoptosis-related proteins in K562 cells treated with the N-propargyl 3-O-dodecyl glucuronamide-based N -linked 6-chloropurine nucleoside indicated that it acts via apoptosis induction.
Topics: Humans; Nucleosides; Amides; Purine Nucleosides; Glucuronates
PubMed: 38095428
DOI: 10.1002/cmdc.202300608 -
Current Medicinal Chemistry 2016In this review, we first highlighted on C-methyl-branched nucleosides and nucleotides approved as anti-hepatitis C infection (HCV) drugs, their mechanism of action and... (Review)
Review
In this review, we first highlighted on C-methyl-branched nucleosides and nucleotides approved as anti-hepatitis C infection (HCV) drugs, their mechanism of action and recent progress in the development of new clinical candidates. Then, we report on our attempt to develop several C-methyl nucleosides/tides potentially useful for treatment of various diseases such cancer, pain, epilepsy and glaucoma. Design, synthesis and pharmacological screening of 1'-C-, 2'-C-, 3'-C-methyladenosine or other purine/pyrimidine nucleosides allowed us to discover some promising new molecules. 3'-C-Methyladenosine showed antitumor activity against several human tumor cell lines. We have investigated the mechanism of action of 3;-C-methyladenosine that proved to be an effective inhibitor of ribonucleotide reductase. Moreover, we will also summarize the chemical and biological properties of some of the recent N6-substituted and 5', N6-disubstituted 2'-C-methyladenosine derivatives that were synthetized in our laboratory and evaluated as A1 adenosine receptor agonists. 2-Chloro-2'- C-methyl-N6-cyclopentyladenosine (2'-Me-CCPA), 5'-chloro-5'-deoxy-N6-(±)-(endo-norborn- 2-yl)adenosine (5'Cl5'd-(±)-ENBA) and 2'-C-methyl-5'-chloro-5'-deoxy-N6-(±)-(endonorborn- 2-yl)adenosine (2'-Me-5'Cl5'd-(±)-ENBA) displayed high hA1AR affinity and selectivity. 2'-Me-CCPA and 5'Cl5'd-(±)-ENBA showed significant analgesic properties.
Topics: Adenosine; Adenosine A1 Receptor Agonists; Antineoplastic Agents; Hepacivirus; Hepatitis C; Humans; Molecular Docking Simulation; Multiple Myeloma; Purine Nucleotides; Receptor, Adenosine A1; Structure-Activity Relationship
PubMed: 27356543
DOI: 10.2174/0929867323666160627100755 -
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 -
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