Natural product diversification using a non-natural cofactor analogue of S-adenosyl-L-methionine.

Changsheng Zhang, Rachel L Weller, Jon S Thorson, Scott R Rajski

Index: J. Am. Chem. Soc. 128(9) , 2760-1, (2006)

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Abstract

Adenosine analogues bearing either 5'-aziridine or 5'-N-mustard electrophiles are methyltransferase-dependent DNA alkylating agents. We present here a novel synthetic cofactor bearing a pendant 5'-amino acid N-mustard. Unlike previously studied synthetic cofactors, this material is very efficiently used by the natural product biosynthetic enzyme rebeccamycin methyltransferase (RebM) to generate a number of new rebeccamycin analogues. These data promote the notion that natural product methyltransferases can be used with non-natural cofactors to enhance the molecular diversity of natural product analogues for drug discovery. To our knowledge, this is the first documentation of a biological methyltransferase, other than DNA methyltransferases, that can exploit such synthetic cofactors.