Biosynthesis of Staurosporine, 2. Incorporation of Tryptophan

Meksuriyen, Duangdeun; Cordell, Geoffrey A.

doi:10.1021/np50059a013

Cited by 57 publications

(67 citation statements)

References 15 publications

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“…The 13 C NMR of 9 showed the distinctly enriched signals at C-12a (relative intensity 17.7) and C-12b (relative intensity 11.5) with a couple of strong doublet signals (J 12a,12b ϭ76.5 Hz) as shown in Table 2 and Fig. 3, thereby establishing that 9 was produced from two intact tryptophan units as in the case of staurosporine biosynthesis [9] (Fig. 4).…”

Section: C-labeled Indocarbazostatin B (8) Incorporation Of D-[u-mentioning

confidence: 81%

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

et al. 2005

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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.

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Section: C-labeled Indocarbazostatin B (8) Incorporation Of D-[u-mentioning

confidence: 81%

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

et al. 2005

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“…Interest in the indolocarbazole-containing natural products, including rebeccamycin and related antibiotics K-252a and staurosporine (21), is due to their potent inhibition of protein kinase C and promising spectrum of antitumor activity (38). In some cases, a sugar moiety linked to one or both indole nitrogen atoms of the indolocarbazole core is required for biological activity (Fig.…”

mentioning

confidence: 99%

Molecular Analysis of the Rebeccamycin l -Amino Acid Oxidase from Lechevalieria aerocolonigenes ATCC 39243

2005

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Rebeccamycin, a member of the tryptophan-derived indolocarbazole family, is produced by Lechevalieria aerocolonigenes ATCC 39243. The biosynthetic pathway that specifies biosynthesis of this important metabolite is comprised of 11 genes spanning 18 kb of DNA. A presumed early enzyme involved in elaboration of the rebeccamycin aglycone is encoded by rebO, located at the left-hand region of the reb gene cluster. The deduced protein product, RebO (51.9 kDa), is an L-amino acid oxidase (L-AAO) that has 27% identity to an L-AAO from Scomber japonicus (animal, mackerel) and is a member of the family of FAD-dependent oxidase enzymes. In order to study the biochemical properties of this key enzyme, the rebO gene was overexpressed and purified from Escherichia coli. Biochemical characterization showed that RebO is dimeric, with a molecular mass of approximately 101 kDa. Further analysis revealed that the enzyme contains a noncovalently bound FAD cofactor and is reoxidized at the expense of molecular oxygen by producing one molecule of hydrogen peroxide. Based on kinetic studies, RebO shows significant preference for 7-chloro-L-tryptophan, suggesting its likely role as the natural early pathway substrate. Furthermore, the native RebO enzyme has evident, albeit limited, flexibility as shown by bioconversion studies with unnatural substrates. This work provides the first analysis of a structural enzyme involved in construction of this important class of indolocarbazole natural products.Over the past 50 years, many antibacterial, antifungal, and anticancer agents have been identified from secondary metabolites isolated from soil microorganisms. In particular, actinomycetes produce a wide variety of bioactive natural products. Based on phylogenetic analysis from 16S rRNA gene sequences (18), Lechevalieria aerocolonigenes ATCC 39243 is a member of the family Pseudonocardiaceae and is the producer of the indolocarbazole antitumor antibiotic rebeccamycin (Fig.

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“…strain 11 [36]. Staurosporine possesses inhibitory activity against fungi and yeasts but has no significant effects on bacteria [28,34]. Furthermore, staurosporine exhibits strong inhibitory activities against protein kinase C, as well as inhibition of platelet aggregation, the blocking of growth phases in cancer cells and the reversal of multidrug resistance [46].…”

Section: Structural Elucidation Of the Antifungal Compoundmentioning

confidence: 99%

Streptomyces scabiei subsp. xuchangensis, A NOVEL STREPTOMYCETE ISOLATE FOR STAUROSPORINE PRODUCTION AND A WHEAT TAKE-ALL CONTROL AGENT

Cai-yi¹,

ZHENG²,

Shen³

et al. 2012

Int J of Micr Res

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Abstract-The streptomycete strain SCY114 was isolated from a soil sample of Xuchang in Henan province, China. It possessed smooth grey spores borne in rectiflexible and spiral chains and was capable of using all of the International Streptomyces Project sugars. The melting temperature and G+C content were 81.8℃ and 61.6 mol%, respectively. The level of 16S rRNA gene sequence similarity between strain SCY114 and S. scabies ATCC49173 was 99.8%. However, the values of DNA-DNA relatedness between strain SCY114 and S. scabies ATCC49173 was 65.2%, and the strain SCY114 did not exhibit pathogenicity towards potato plants. Based on the phenotypic and genotypic evidence, strain SCY114 was identified as a subspecies of the Streptomyces scabiei, for which the name Streptomyces scabiei subsp. xuchangensis is proposed. Strain SCY114 strongly inhibited the in vitro mycelial growth of Gaeumannomyces graminis var. tritici as well as various other plant pathogenic fungi. The filtered culture broth of strain SCY114 was substantially more effective at controlling wheat take-all compared to the silthiofam, and the disease was reduced by 78.2%. An antifungal antibiotic was isolated from the fermentation broth of strain SCY114 using a series of chromatographic procedures. The molecular formula of the antibiotic was determined to be C28H26N4O3, and on the basis of the NMR data, the antibiotic was confirmed to be staurosporine.

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Biosynthesis of Staurosporine, 2. Incorporation of Tryptophan

Cited by 57 publications

References 15 publications

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

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

Molecular Analysis of the Rebeccamycin l -Amino Acid Oxidase from Lechevalieria aerocolonigenes ATCC 39243

Streptomyces scabiei subsp. xuchangensis, A NOVEL STREPTOMYCETE ISOLATE FOR STAUROSPORINE PRODUCTION AND A WHEAT TAKE-ALL CONTROL AGENT

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