Conformational preferences and structural analysis of hypermodified nucleoside, peroxywybutosine (o2yW) found at 37th position in anticodon loop of tRNAPhe and its role in modulating UUC codon-anticodon interactions

Fandilolu, Prayagraj M.; Kamble, Asmita S.; Sambhare, Susmit B.; Sonawane, Kailas D.

doi:10.1016/j.gene.2017.10.072

Cited by 8 publications

(9 citation statements)

References 57 publications

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“…For example, nucleotides in and adjacent to the anticodon sequence are often conserved within tRNA isoacceptor groups ( 46 ), and can be modified to ensure optimal fidelity and efficiency in recognizing certain codon sets. This is true for wild-type tRNA Phe , wherein modified guanine bases in position 34 ( 73 ) of the anticodon and the anticodon-adjacent position 37 ( 74 ) are used to efficiently and accurately decode UUU and UUC codons. Conversely, the tRNA Ser AAA variant we investigated has adenine at 34 and 37, so it is possible that the strong reduction in protein synthesis we observed is due in part to suboptimal codon:anticodon recognition kinetics in the tRNA Ser AAA variant compared to tRNA Phe .…”

Section: Discussionmentioning

confidence: 99%

Formation and persistence of polyglutamine aggregates in mistranslating cells

Lant

Kiri

Duennwald

et al. 2021

Nucleic Acids Research

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In neurodegenerative diseases, including pathologies with well-known causative alleles, genetic factors that modify severity or age of onset are not entirely understood. We recently documented the unexpected prevalence of transfer RNA (tRNA) mutants in the human population, including variants that cause amino acid mis-incorporation. We hypothesized that a mistranslating tRNA will exacerbate toxicity and modify the molecular pathology of Huntington's disease-causing alleles. We characterized a tRNA Pro mutant that mistranslates proline codons with alanine, and tRNA Ser mutants, including a tRNA Ser AGA G35A variant with a phenylalanine anticodon (tRNA Ser AAA ) found in ∼2% of the population. The tRNA Pro mutant caused synthetic toxicity with a deleterious huntingtin poly-glutamine (polyQ) allele in neuronal cells. The tRNA Ser AAA variant showed synthetic toxicity with proteasome inhibition but did not enhance toxicity of the huntingtin allele. Cells mistranslating phenylalanine or proline codons with serine had significantly reduced rates of protein synthesis. Mistranslating cells were slow but effective in forming insoluble polyQ aggregates, defective in protein and aggregate degradation, and resistant to the neuroprotective integrated stress response inhibitor (ISRIB). Our findings identify mistranslating tRNA variants as genetic factors that slow protein aggregation kinetics, inhibit aggregate clearance, and increase drug resistance in cellular models of neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Formation and persistence of polyglutamine aggregates in mistranslating cells

Lant

Kiri

Duennwald

et al. 2021

Nucleic Acids Research

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“…The complex biosynthetic pathway leading to formation of o2yW entails nine intermediate wyosine-family members that function as substrate for the next product. These ancient wyosine-family modifications are exclusively found in tRNA phenylalanine (anticodon GAA) of archaea and eukarya at position 37 ( Figure 4 c), where they play a role in reading-frame maintenance [ 98 , 99 ]. At this position, o2yW modification has been shown to cause RT misincorporation, but the underlying mechanism is not well characterized [ 23 ].…”

Section: Guanosine-derived Modificationsmentioning

confidence: 99%

A Census and Categorization Method of Epitranscriptomic Marks

Mathlin

Pera

Colombo

2020

IJMS

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In the past few years, thorough investigation of chemical modifications operated in the cells on ribonucleic acid (RNA) molecules is gaining momentum. This new field of research has been dubbed “epitranscriptomics”, in analogy to best-known epigenomics, to stress the potential of ensembles of RNA modifications to constitute a post-transcriptional regulatory layer of gene expression orchestrated by writer, reader, and eraser RNA-binding proteins (RBPs). In fact, epitranscriptomics aims at identifying and characterizing all functionally relevant changes involving both non-substitutional chemical modifications and editing events made to the transcriptome. Indeed, several types of RNA modifications that impact gene expression have been reported so far in different species of cellular RNAs, including ribosomal RNAs, transfer RNAs, small nuclear RNAs, messenger RNAs, and long non-coding RNAs. Supporting functional relevance of this largely unknown regulatory mechanism, several human diseases have been associated directly to RNA modifications or to RBPs that may play as effectors of epitranscriptomic marks. However, an exhaustive epitranscriptome’s characterization, aimed to systematically classify all RNA modifications and clarify rules, actors, and outcomes of this promising regulatory code, is currently not available, mainly hampered by lack of suitable detecting technologies. This is an unfortunate limitation that, thanks to an unprecedented pace of technological advancements especially in the sequencing technology field, is likely to be overcome soon. Here, we review the current knowledge on epitranscriptomic marks and propose a categorization method based on the reference ribonucleotide and its rounds of modifications (“stages”) until reaching the given modified form. We believe that this classification scheme can be useful to coherently organize the expanding number of discovered RNA modifications.

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“…In this sense, RM1 has been widely used as the quantum chemical method to refine molecular docking poses, carry out preliminary conformational searches, calculate atomic partial charges and determine ground state geometries of a set of ligands to further perform molecular docking, high throughput screening calculations or SAR studies. Studies of this kind included: the ability of the tariquidar and elacridar to inhibit the multidrug resistance transporter P-glycoprotein; 231 prediction of the partial atomic charges of the thymidylate kinase obtained from variola virus; 232 drug action mechanisms of a set of chloroquine compounds that present antiplasmodial activity against chloroquine-resistant parasites; 233 glycosidase inhibitors, and immunosuppressive agents that are based on γ-hydroxyethyl piperidine iminosugar and N-alkylated derivatives; 234 the use of gamma radiation to degrade the systems phenylethylamine and tyramine; 235 a ternary complex formation in the catalysis of the Trypanosoma cruzi trans-sialidase, which is an important protein for the therapy of Chagas disease by chemotherapy; 236 geometry optimizations and partial atomic charge quantities of the species involved in the inhibition of nerve agents by oxime BI-6 and acetylcholinesterase; 237 evaluation of the ability of the 1,3,4-thiadiazole and s-triazole derivatives as antimicrobial agents; 238 conformational aspects of the modified nucleosides k 2 C (hypermodified nucleoside lysidine) and t 6 A (hypermodified nucleoside N 6 -(N-threonylcarbonyl) adenosine) that are present in the anticodon loop of the tRNA Ile ; 239 structural properties of the system M. tuberculosis enoyl-acyl carrier protein (ACP) reductase-NADH (protonated nicotinamide dinucleotide), as well as its interaction with the diphenyl ether inhibitors; 240 the identification of the inhibitor of the angiotensin converting enzyme; 242 optimization of the geometries of both a set of 1,4-naphthoquinone derivatives that are capable of inhibiting the P2X7 receptor, which is an ATP-gated ion-channel, 247 as well as of the AMCA-peptide-TAMRA system, where AMCA and TAMRA stand, respectively, for 7-amino-4-methyl-3-coumarinylacetic acid and 5-carboxytetramethylrhodamine; 248 partial atomic charge calculations of oximes, such as HI6 and 2-PAM that are nucleophiles capable of reactivating the inhibited human enzyme acetylcholinesterase; 249 structural calculations of peroxywybutosine present in the 37 th position in the anticodon loop of tRNA Phe when both RM1 and multiple molecular dynamics methods were employed; 250 QM/MM calculations on the mechanism of carboxylation of ribulose-1,5-biphosphate, where RM1 was used in QM part; 251 and geometry optimizations of a set of eight 3-phenylcoumarin derivatives with 6,7-or 5,7-dihydroxyl groups, either free or acetylated, bound to the benzopyrone moiety, in order to study modulation of effect or functions of human neutrophils. 252…”

Section: Biological Chemistrymentioning

confidence: 99%

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

Lima¹,

Rocha²,

Freire³

et al. 2018

J. Braz. Chem. Soc.

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In this review, we show improvements to the semiempirical quantum chemical method RM1 and present a wide range of its applications as reported by researchers of various areas, such as theoretical, organic, physical, analytical, and inorganic chemistry, as well as their interfaces with medicinal chemistry, biology, and materials science. Success of RM1 is seemingly due to its ability to predict structural, energetic, electronic and wave function dependent properties of the investigated systems, coupled with its low computational demand required to perform calculations when compared to ab initio and density functional methods. Moreover, RM1 is widely available in several computational chemistry softwares, such as MOPAC, GAMESS, Amber, Spartan, HyperChem, and AMPAC. This review describes various case studies that perhaps can be of interest to researchers who might need a more solid basis from which to expand the frontier of applicability of RM1 to even more complex problems on larger systems.

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Conformational preferences and structural analysis of hypermodified nucleoside, peroxywybutosine (o2yW) found at 37th position in anticodon loop of tRNAPhe and its role in modulating UUC codon-anticodon interactions

Cited by 8 publications

References 57 publications

Formation and persistence of polyglutamine aggregates in mistranslating cells

Formation and persistence of polyglutamine aggregates in mistranslating cells

A Census and Categorization Method of Epitranscriptomic Marks

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

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