Biosynthesis of indocarbazostatin B, incorporation of D-[U-13C] glucose and L-[2-13C] tryptophan.

High incorporation of D-[U-13C] glucose and L-[indole-2-13C] 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.