Natural product diversification using a non-natural cofactor analogue of S-adenosyl-L-methionine.
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.
Zhang
Changsheng
C
Laboratory 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.
Weller
Rachel L
RL
Thorson
Jon S
JS
Rajski
Scott R
SR
D000478:Alkylation; D001688:Biological Products / Q000138:chemical synthesis*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008780:Methyltransferases / Q000737:chemistry / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000031:analogs & derivatives* / Q000737:chemistry
D001688:Biological Products; D002227:Carbazoles; D007211:Indoles; D012436:S-Adenosylmethionine; C053339:rebeccamycin; D008780:Methyltransferases