Engineering biosynthetic pathways to generate antitumor indolocarbazole derivatives

Abstract

The indolocarbazole family of natural products is a source of lead compounds with potential therapeutic applications in the treatment of cancer and neurodegenerative disorders. Rebeccamycin and staurosporine are two members of this family, which are produced by different actinomycete strains. Although both compounds display antitumor activity, their distinct structural features determine different modes of action: rebeccamycin targets DNA topoisomerase I, while staurosporine is a protein kinase inhibitor. Here we examine the biosyntheses of rebeccamycin and staurosporine while we summarize our recent work concerning (a) identification and characterization of genes involved in the biosynthesis of indolocarbazoles in actinomycetes, and (b) generation of novel indolocarbazole derivatives in microorganisms by combinatorial biosynthesis.

Diversity of culturable actinomycetes in hyper-arid soils of the Atacama Desert, Chile

“…NRPS gene clusters have been detected recently in Lechevalieria species (Ayuso-Sacido and Genilloud 2005) that are involved in the synthesis of antitumor (Onaka 2006;Sanchez et al 2006) and antifungal (Lee et al 2004) compounds. Our own preliminary survey based on a comparison of gene sequence identities with those involved in the synthesis of known bioactive compounds promises that among those encoded by Atacama actinomycetes are novel NRP synthases.…”

Structure and Mechanism of the Rebeccamycin Sugar 4′-O-Methyltransferase RebM

“…1A, 3 and 4) are distinguished by a ␤-glucoside attachment critical for the potent topoisomerase I poisoning effects and notable anticancer activities of this class (5)(6)(7). Biosynthetically the indolocarbazoles are derived from tryptophan, glucose, methionine, and, in the case of the rebeccamycin-type indolocarbazoles, chloride (5,8). The biosynthetic gene clusters encoding 1, 3, and 4 have been reported (9 -11), and a variety of in vitro and in vivo studies have contributed to an understanding of the enzymes responsible for indolocarbazole core biosynthesis (Fig.…”

Pyranose N-Glycosyl Amines: Emerging Targets With Diverse Biological Potential

“…These compounds have very promising activity as antitumor agents [87,88], which is based on their interactions with DNA topoisomerases [89]. Novel approaches to the diversification of the rebeccamycin structure include combinatorial biosynthesis in bacteria [90,91], while enzymes responsible for both enzymatic construction of the indolocarbazole group [92], as well as N-glycosylation [93], have been studied in detail with the latter being used successfully to produce analogs of the natural product. Related studies on the transferase-catalyzed N-glycosylation Cl of the staurosporine aglycone have also been reported [94].…”