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

被引:58
作者
Zhang, CS
Weller, RL
Thorson, JS
Rajski, SR
机构
[1] Univ Wisconsin, Sch Pharm, Pharmaceut Sci Div, Madison, WI 53705 USA
[2] Univ Wisconsin, Dept Chem, Madison, WI 53705 USA
[3] Univ Wisconsin, Lab Biosynth Chem, Natl Cooperat Drug Discovery Grp, Madison, WI 53705 USA
关键词
D O I
10.1021/ja056231t
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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. Copyright © 2006 American Chemical Society.
引用
收藏
页码:2760 / 2761
页数:2
相关论文
共 19 条
[1]   Conversion of DNA methyltransferases into azidonucleosidyl transferases via synthetic cofactors [J].
Comstock, LR ;
Rajski, SR .
NUCLEIC ACIDS RESEARCH, 2005, 33 (05) :1644-1652
[2]   NMR-STUDIES OF THE CONJUGATION OF MECHLORETHAMINE WITH GLUTATHIONE [J].
GAMCSIK, MP ;
HAMILL, TG ;
COLVIN, M .
JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (03) :1009-1014
[3]   Conformational control in the rebeccamycin class of indolocarbazole glycosides [J].
Gilbert, EJ ;
Chisholm, JD ;
Van Vranken, DL .
JOURNAL OF ORGANIC CHEMISTRY, 1999, 64 (15) :5670-5676
[4]   Formation of unusual sugars: Mechanistic studies and biosynthetic applications [J].
He, XMM ;
Liu, HW .
ANNUAL REVIEW OF BIOCHEMISTRY, 2002, 71 :701-754
[5]   Characterization of two polyketide methyltransferases involved in the biosynthesis of the antitumor drug mithramycin by Streptomyces argillaceus [J].
Lozano, MJF ;
Remsing, LL ;
Quirós, LM ;
Braña, AF ;
Fernández, E ;
Sánchez, C ;
Méndez, C ;
Rohr, J ;
Salas, JA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (05) :3065-3074
[6]   Glycosyltransferases involved in the biosynthesis of biologically active natural products that contain oligosaccharides [J].
Luzhetskyy, A ;
Vente, A ;
Bechthold, A .
MOLECULAR BIOSYSTEMS, 2005, 1 (02) :117-126
[7]  
Pignot M, 1998, ANGEW CHEM INT EDIT, V37, P2888, DOI 10.1002/(SICI)1521-3773(19981102)37:20<2888::AID-ANIE2888>3.0.CO
[8]  
2-4
[9]  
Prudhomme Michelle, 2004, Current Medicinal Chemistry - Anti-Cancer Agents, V4, P509
[10]   Deciphering the late steps in the biosynthesis of the anti-tumour indolocarbazole staurosporine:: sugar donor substrate flexibility of the StaG glycosyltransferase [J].
Salas, AP ;
Zhu, LL ;
Sánchez, C ;
Braña, AF ;
Rohr, J ;
Méndez, C ;
Salas, JA .
MOLECULAR MICROBIOLOGY, 2005, 58 (01) :17-27