Abstract
S-Adenosyl-L-methionine (AdoMet) is the major methyl donor for biological methylation reactions catalyzed by methyltransferases. We report the first chemical synthesis of AdoMet analogs with extended carbon chains replacing the methyl group and their evaluation as cofactors for all three classes of DNA methyltransferases. Extended groups containing a double or triple bond in the β position to the sulfonium center were transferred onto DNA in a catalytic and sequence-specific manner, demonstrating a high utility of such synthetic cofactors for targeted functionalization of biopolymers.
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Acknowledgements
The authors are grateful to E. Merkiene and M. Čaikovskij for constructing the Q82A variant of M.HhaI, F. Grygas and R. Gerasimaite for technical assistance and K. Glensk for preparing M.TaqI. We thank V. Gabelica and F. Rosu for performing high-resolution ESI-MS measurements at the Center for Analysis of Residues in Traces (CART), laboratory of E. De Pauw, University of Liège, Belgium. C.D. thanks the Deutsche Forschungsgemeinschaft for a stipend within the Graduiertenkolleg 440. This work was supported by grants from VolkswagenStiftung, the Howard Hughes Medical Institute and the Ministry of Science and Education of Lithuania.
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Supplementary information
Supplementary Fig. 1
HPLC analysis of chemically and enzymatically synthesized S-adenosyl-L-ethionine. (PDF 363 kb)
Supplementary Fig. 2
Analysis of enzymatic transalkylation reactions by DNA MTases. (PDF 1450 kb)
Supplementary Fig. 3
Analysis of transalkylation products formed in duplex oligodeoxynucleotides. (PDF 472 kb)
Supplementary Fig. 4
Blockage of restriction endonuclease cleavage at overlapping sites on DNA by enzymatic incorporation of extended groups. (PDF 232 kb)
Supplementary Table 1
ESI-MS analysis of synthetic AdoMet analogs and modified nucleosides formed after enzymatic transalkylations with DNA MTases. (PDF 98 kb)
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Dalhoff, C., Lukinavičius, G., Klimas̆auskas, S. et al. Direct transfer of extended groups from synthetic cofactors by DNA methyltransferases. Nat Chem Biol 2, 31–32 (2006). https://doi.org/10.1038/nchembio754
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DOI: https://doi.org/10.1038/nchembio754
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