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Updated: Jul 18, 2026

Profiling of Methyltransferases and Other S-adenosyl-L-homocysteine-binding Proteins by Capture Compound Mass Spectrometry (CCMS)
Published on: December 20, 2010
Natural product diversification using a non-natural cofactor analogue of S-adenosyl-L-methionine
Changsheng Zhang1, Rachel L Weller, Jon S Thorson
1Laboratory for Biosynthetic Chemistry, University of Wisconsin National Cooperative Drug Discovery Group, Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705-2222, USA.
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.
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