Abstract
AT2433, an indolocarbazole antitumor antibiotic, is structurally distinguished by its aminodideoxypentose-containing disaccharide and asymmetrically halogenated N-methylated aglycon. Cloning and sequence analysis of AT2433 gene cluster and comparison of this locus with that encoding for rebeccamycin and the gene cluster encoding calicheamicin present an opportunity to study the aminodideoxypentose biosynthesis via comparative genomics. The locus was confirmed via in vitro biochemical characterization of two methyltransferases-one common to AT2433 and rebeccamycin, the other unique to AT2433-as well as via heterologous expression and in vivo bioconversion experiments using the AT2433 N-glycosyltransferase. Preliminary studies of substrate tolerance for these three enzymes reveal the potential to expand upon the enzymatic diversification of indolocarbazoles. Moreover, this work sets the stage for future studies regarding the origins of the indolocarbazole maleimide nitrogen and indolocarbazole asymmetry.
Original language | English |
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Pages (from-to) | 733-743 |
Number of pages | 11 |
Journal | Chemistry and Biology |
Volume | 13 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2006 |
Bibliographical note
Funding Information:This work was supported in part by National Institutes of Health grants CA84374, AI52218, and GM70637, and a National Cooperative Drug Discovery Group grant from the National Cancer Institute (U19 CA113297). J.S.T. is a Romnes fellow. The authors want to thank Professors Peng George Wang (The Ohio State University) and David L. Van Vranken (UC Irvine) for graciously providing materials and Drs. Byron R. Griffith and Aqeel Ahmed for technical assistance. The authors also wish to acknowledge the Analytical Instrumentation Center of the School of Pharmacy, UW-Madison, for MS and NMR support.
Funding
This work was supported in part by National Institutes of Health grants CA84374, AI52218, and GM70637, and a National Cooperative Drug Discovery Group grant from the National Cancer Institute (U19 CA113297). J.S.T. is a Romnes fellow. The authors want to thank Professors Peng George Wang (The Ohio State University) and David L. Van Vranken (UC Irvine) for graciously providing materials and Drs. Byron R. Griffith and Aqeel Ahmed for technical assistance. The authors also wish to acknowledge the Analytical Instrumentation Center of the School of Pharmacy, UW-Madison, for MS and NMR support.
Funders | Funder number |
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National Cooperative Drug Discovery Group | |
National Institutes of Health (NIH) | GM70637, CA84374, AI52218 |
National Childhood Cancer Registry – National Cancer Institute | U19 CA113297 |
Keywords
- CHEMBIO
- MICROBIO
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmacology
- Drug Discovery
- Clinical Biochemistry