RebG- and RebM-catalyzed indolocarbazole diversification

Changsheng Zhang, Christoph Albermann, Xun Fu, Noel R. Peters, John D. Chisholm, Guisheng Zhang, Eric J. Gilbert, Peng George Wang, David L. Van Vranken, Jon S. Thorson

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Rebeccamycin and staurosporine represent two broad classes of indolocarbazole glycoside natural products with antitumor properties. Based upon previous sequence annotation and in vivo studies, rebG encodes for the rebeccamycin N-glucosyltransferase, and rebM for the requisite 4′-O-methyltransferase. In the current study, an efficient in vivo biotransformation system for RebG was established in both Streptomyces lividans and Escherichia coli. Bioconversion experiments revealed RebG to glucosylate a set of indolocarbazole surrogates, the products of which could be further modified by in vitro RebM-catalyzed 4′-O-methylation. Both RebG and RebM displayed substrate promiscuity, and evidence for a remarkable lack of RebG regioselectivity in the presence of asymmetric substrates is also provided. In the context of the created indolocarbazole analogues, cytotoxicity assays also highlight the importance of 4′-O-methylotion for their biological activity.

Original languageEnglish (US)
Pages (from-to)795-804
Number of pages10
JournalChemBioChem
Volume7
Issue number5
DOIs
StatePublished - May 1 2006
Externally publishedYes

Keywords

  • Biosynthesis
  • Glycosylation
  • Methylation
  • Rebeccamycin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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    Zhang, C., Albermann, C., Fu, X., Peters, N. R., Chisholm, J. D., Zhang, G., Gilbert, E. J., Wang, P. G., Van Vranken, D. L., & Thorson, J. S. (2006). RebG- and RebM-catalyzed indolocarbazole diversification. ChemBioChem, 7(5), 795-804. https://doi.org/10.1002/cbic.200500504