16526-56-0Relevant academic research and scientific papers
RImN and Cfr are Radical SAM Enzymes Involved in Methylation of Ribosomal RNA
Yan, Feng,Lamarre, Jacqueline M.,Roehrich, Rene,Wiesner, Jochen,Jomaa, Hassan,Markin, Alexander S.,Fujimori, Danica Galonic
, p. 3953 - 3964 (2010)
Posttranscriptional modifications of ribosomal RNA (rRNA) nucleotides are a common mechanism of modulating the ribosome's function and conferring bacterial resistance to ribosome-targeting antibiotics. One such modification is methylation of an adenosine nucleotide within the peptidyl transferase center of the ribosome mediated by the endogenous methyltransferase RImN and its evolutionarily related resistance enzyme Cfr. These methyltransferases catalyze methyl transfer to aromatic carbon atoms of the adenosine within a complex 23S rRNA substrate to form the 2,8-dimethylated product. RImN and Cfr are members of the Radical SAM superfamily and contain the characteristic cysteine-rich CX3CX2C motif. We demonstrate that both enzymes are capable of accommodating the requisite [4Fe-4S] cluster. S-Adenosylmethionine (SAM) is both the methyl donor and the source of a 5′-deoxyadenosyl radical, which activates the substrate for methylation. Detailed analyses of the rRNA requirements show that the enzymes can utilize proteinfree 23S rRNA as a substrate, but not the fully assembled large ribosomal subunit, suggesting that the methylations take place during the assembly of the ribosome. The key recognition elements in the 23S rRNA are helices 90-92 and the adjacent single stranded RNA that encompasses A2503. To our knowledge, this study represents the first in vitro description of a methyl transfer catalyzed by a member of the Radical SAM superfamily, and it expands the catalytic repertoire of this diverse enzyme class. Furthermore, by providing information on both the timing of methylation and its substrate requirements, our findings have important implications for the functional consequences of Cfr-mediated modification of rRNA in the acquisition of antibiotic resistance.
Discovery of new S-adenosylmethionine decarboxylase inhibitors for the treatment of Human African Trypanosomiasis (HAT)
Hirth, Bradford,Barker Jr., Robert H.,Celatka, Cassandra A.,Klinger, Jeffrey D.,Liu, Hanlan,Nare, Bakela,Nijjar, Amarjit,Phillips, Margaret A.,Sybertz, Edmund,Willert, Erin K.,Xiang, Yibin
scheme or table, p. 2916 - 2919 (2010/02/28)
Modification of the structure of trypanosomal AdoMetDC inhibitor 1 (MDL73811) resulted in the identification of a new inhibitor 7a, which features a methyl substituent at the 8-position. Compound 7a exhibits improved potencies against both the trypanosomal AdoMetDC enzyme and parasites, and better blood brain barrier penetration than 1.
INHIBITORS OF S-ADENOSYL-L-METHIONINE DECARBOXYLASE
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Page/Page column 29-30, (2009/01/23)
Novel mechanism-based inhibitors of S-adenosyl-L-methionine decarboxylase are provided. These compounds of formula (1) inhibit the life cycle of trypanosomes, and are useful to treat subjects infected with African trypanosomes. The invention includes pharmaceutical compositions and methods of using the compounds of formula (1).
Antiviral Activity of C-Alkylated Purine Nucleosides Obtained by Cross-Coupling with Tetraalkyltin Reagents
Aerschot, Arthur A. Van,Mamos, Petros,Weyns, Nancy J.,Ikeda, Satoru,Clercq, Erik De,Herdewijn, Piet A.
, p. 2938 - 2942 (2007/10/02)
2-, 6-, And 8-alkylated (methyl, ethyl, and vinyl) adenosine analogues were synthesized by a palladium-catalyzed cross-coupling of a tetraalkyltin with the halogenated purine nucleosides.The synthesis of the 8-substituted analogues was accomplished using a transient protection procedure.The 6-alkylated-9-β-D-ribofuranosylpurines as well as 2-ethyladenosine were cytotoxic at relatively low concentrations (0.8-10 μg/mL). 8-Methyladenosine was a potent and selective inhibitor of vaccinia virus, whereas 8-ethyl- and 8-vinyladenosine were specifically inhibitory to respiratory syncytial virus. 8-Vinyladenosine displayed particular activity against herpes simplex virus (type 1).
Novel adenosine derivatives and pharmaceutical composition containing them as an active ingredient
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, (2008/06/13)
Novel adenosine compounds of the formula (I): STR1 wherein R1, R2 and R3 are hydrogen or a lower alkyl group; X is hydrogen, a lower alkyl group, an amino group or halogen; and Y is hydrogen or a lower alkyl group, exhibit utility as antihypertensive agents.
Unusual Competition between Nitrogen and Carbon Methylation of Nucleosides by Methyl Radical in Various Aqueous Media
Zady, Mona F.,Wong, John L.
, p. 2373 - 2377 (2007/10/02)
Five nucleosides, adenosine, guanosine, cytidine, thymidine, and uridine, were allowed to react with methyl radical produced by homolysis of tert-butyl peracetate.The extent and sites of reaction exhibited a marked dependence on the pH of the aqueous medium.In the region of pH 1-4, the major products arose from C-methylation of the nucleosides.The purines were more reactive than the pyrimidines under these acidic conditions.In the pH range of 4-10, the extent of C-methylation decreased steadily with increasing pH while N-methylated products arising from methylationof the ring nitrogen and/or exocyclic amino groups predominated.In this pH range, the pyrimidine nucleosides were the more reactive.Beyond pH 10, the extent of methylation diminished in all cases as decomposition of tert-butyl peracetate became rampant.The C-methylation occurs by way of an addition mechanism while N-methylation appears to proceed via radical abstraction of a hydrogen from the N-H group followed by combination with methyl radical.The implications of these reactivity and methylation patterns in radical carcinogenesis are discussed.
