Biosynthesis of Indocarbazostatin B, Incorporation of D-[U-13C] Glucose and L-[2-13C] Tryptophan

Abstract

High incorporation of D-[U-13 C] glucose and L-[indole-2- 13 C] tryptophan into indocarbazostatin B (2) was observed in a biosynthetic study using a mutant strain, Streptomyces sp. MUV-7-8. The original strain, Streptomyces sp. TA-0403 produced a small amount of indocarbazostatin (1) and indocarbazostatin B (2), which displayed potent biological activities. To facilitate biosynthetic studies, we selected high indocarbazostatin producing mutant strains. The first mutants, Streptomyces sp. MUV-6-83 and MUV-6-17, produced indocarbazostatins C (3) and D (4) as well as 1 and 2. When the production medium was supplemented with D-tryptophan, the MUV-6-17 mutant produced K252c (5), whereas when L-tryptophan was added, it produced K252d (6). On further UV treatment of the mutant strain MUV-6-83, we finally obtained a new mutant producer, Streptomyces sp. MUV-7-8, that produced 2 as a major metabolite with higher productivity. This mutant producer enabled us to do a feeding experiment of the envisioned precursors, glucose and tryptophan.

Indolocarbazole natural products: occurrence, biosynthesis, and biological activity

“…As expected, tryptophan was incorporated into the aglycone, while glucose was used for formation of the sugar moiety. 109 The labeling pattern found for the carbohydrate supported previous hypothesis on the biosynthesis of furanosylated ICZs, such as K252a (see Section 3.1.3).…”

“…The MUV-6-83 strain produced 64 as the major metabolite, and was used for feeding experiments with radiolabeled glucose and tryptophan. 109 Feeding with D-[U -13 C]glucose resulted in labeling of all carbons at the carboxysugar moiety, with the exception of C-2 and C-3 (Scheme 6). This labeling pattern agreed with the proposed biosynthetic pathway for furanosylated ICZs, where the six-carbon carboxyfuranose is derived from a benzil → benzilic acid rearrangement of a six-carbon pyranose.…”

Crystal structures and catalytic mechanism of cytochrome P450 StaP that produces the indolocarbazole skeleton

“…9B). However, compounds modified at both C3 and C9 positions have not been isolated (33). These two facts, the existence of asymmetric natural indolocarbazoles, and the highly conserved amino acids in the active site among StaP, RebP, and AtmP, imply that the substrate-binding architecture and the substrate-binding mode have limited the diversity of the indolocarbazole compounds produced by natural bacteria or combinatorial biosynthesis systems.…”

Tandem Gold-Catalyzed Dehydrative Cyclization/Diels–Alder Reactions: Facile Access to Indolocarbazole Alkaloids

“…Both synthetic and naturally occurring variants are known in all three domains . Well-known examples include staurosporine and rebeccamycin, but we were interested in developing an approach that could be applied to the indocarbazostatins, which are nanomolar inhibitors of nerve-growth-factor-induced neurite outgrowth . These are particularly interesting as up-regulated neurotrophic factors have been observed in patients with epilepsy and rat models of Huntington’s disease …”