Abstracts (poster) - Wissenschaft Online

Wibke Peters, Thomas Macherey, Mike Duisken, Sophie Willnow, Bernhard Lüscher,
Elmar Weinhold
New S-Adenosyl-L-methionine Analogues to Investigate the
Methylome
DNA and protein methyltransferases (MTases) play crucial roles in setting epigenetic
marks on DNA and histone proteins. They catalyse the transfer of the activated methyl
group from the ubiquitous cofactor S-adenosyl-L-methionine (AdoMet or SAM) to specific
residues within their substrates. Since the methyl group is not an attractive reporter
group, we have synthesised two new classes of AdoMet analogues which serve as
efficient cofactors for sequence-specific DNA functionalisation and labelling.
In the first class of cofactor analogues the amino acid side chain of AdoMet is replaced
with an aziridinyl residue and reporter groups are attached to the adenine ring.[1,2]
DNA MTase-catalysed nucleophilic aziridine ring opening leads to sequence-specific
coupling of the whole aziridine cofactor with DNA and hence to covalent DNA labelling. In
the second class of cofactor analogues the methyl group of AdoMet is replaced with
extended carbon chains carrying an unsaturated bond in beta-position to the sulfonium
center.[3,4] The unsaturared bond is essential and leads to efficient transfer of the
extended side chain to DNA.
We have extended this work to protein MTases and find that the latter AdoMet analogues
also function as cofactors for histone MTases. These analogues are used to transfer
bioorthogonal chemical groups for modification by click chemistry and provide a new
chemical tool to label proteins and identify targets of protein MTases.
Literature
[1] Pljevaljcic, F. Schmidt, E. Weinhold, Sequence-specific Methyltransferase-Induced
Labeling of DNA (SMILing DNA), ChemBioChem 2004, 5, 265–269.
[2] Pljevaljcic, F. Schmidt, A. J. Scheidig, R. Lurz, E. Weinhold, Quantitative labeling of
long plasmid DNA with nanometer precision, ChemBioChem 2007, 8, 1516–1519.
[3] C. Dalhoff, G. Lukinavicius, S. Klimasauskas, E. Weinhold, Direct transfer of
extended groups from synthetic cofactors by DNA methyltransferases, Nat. Chem. Biol.
2006, 2, 31–32.
[4] G. Lukinavicius, V. Lapiene, Z. Stasevskij, C. Dalhoff, E. Weinhold, S. Klimasauskas,
Targeted labeling of DNA by methyltransferase-directed Transfer of Activated Groups
(mTAG), J. Am. Chem. Soc. 2007, 129, 2758–2759.
contact:
Professor Elmar Weinhold
RWTH Aachen University
Institute of Organic Chemistry
elmar.weinhold@oc.rwth-aachen.de
Landoltweg 1
52056 Aachen (Germany)
additional information
Mike Duisken, LECO Instrumente GmbH, 41199 Mönchengladbach, Germany; Bernhard Lüscher,
Institute of Biochemistry, Division of Biochemistry and Molecular Biology, RWTH Aachen University
Hospital, 52074 Aachen, Germany.