ChemBioChem

Cover image for Vol. 18 Issue 22

Editor: Meghan Campbell; Editorial Board Chairs: Thomas Carell, Donald Hilvert, Barbara Imperiali

Online ISSN: 1439-7633

Associated Title(s): ChemCatChem, ChemMedChem, ChemPhysChem, ChemSusChem

7_02/2006Cover Picture: Design, Synthesis, and Preliminary Biological Evaluation of a DNA Methyltransferase-Directed Alkylating Agent (ChemBioChem 2/2006)

The cover picture shows the envisioned pathways for how the DNA methyltransferase, M.HhaI, can use either S-adenosyl-l-methionine (SAM; left) or an unnatural aziridinium cofactor (right). The aziridinium ion is proposed to arise in situ from the appropriately functionalized 5' N-mustard precursor. By virtue of its structural similarity to SAM, this highly reactive alkylating agent is bound by a methyltransferase (MTase) and delivered to a specific DNA nucleobase (extrahelical cytosine colored by atom). The stick structures (center) depict the envisioned approach of SAM vs. the proposed aziridinium intermediate to an M.HhaI DNA substrate within the M.HhaI active site. We thank Peter Anderson for assistance in generating the modeling images. The DNA substrate and cofactor structures were adapted from coordinates for the ternary structure of M.HhaI in complex with duplex DNA and S-adenosyl-homocysteine (RCSB PDB). Detailed information regarding this new synthetic DNA alkylating agent and MTase-driven DNA alkylation is reported by S. Rajski and R. Weller on p. 243 ff.

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