The Oxidative Ring Cleavage in Jadomycin Biosynthesis: A Multistep Oxygenation Cascade in a Biosynthetic Black Box

Rix, Uwe; Wang, Chenchen; Chen, Yihua; Lipata, Fredilyn; Rix, Lily; Greenwell, Lisa; Vining, L. C.; Yang, Keqian; Rohr, Jürgen

doi:10.1002/cbic.200400395

Cited by 64 publications

(81 citation statements)

References 29 publications

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“…This may be due to the dehydration activity of JadF demands an appropriate context (together with JadGH?). Evidence in support of this inference is that, besides dehydrorabelomycin (7) and L-digitoxosyl-dehydorabelomycin (8), rabelomycin was also accumulated in the jadG in-frame deletion mutant (20), indicating the dehydration activity of JadF partially depends on its interaction with JadG. Post-PKS aromatization is a common phenomenon in angucycline and other aromatic polyketide biosynthetic pathways, e.g.…”

Section: Discussionmentioning

confidence: 93%

“…However, the jadG inactivation mutant accumulated three C-12 monooxygenated compounds (20), and VS668 (jadH disrupted) mainly yielded 2,3-dehydro-UWM6, an angucyclic compound without quinone moiety, implying JadH, instead of JadG, catalyzed the C-12 monooxygenation (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

“…After fractionation of the crude extract by semipreparative high performance liquid chromatography (HPLC), the main product was isolated and its structure was elucidated by NMR, as described elsewhere (20).…”

Section: Isolation and Structural Characterization Of The Productmentioning

confidence: 99%

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Functional Analyses of Oxygenases in Jadomycin Biosynthesis and Identification of JadH as a Bifunctional Oxygenase/Dehydrase

Chen

Wang

Greenwell

et al. 2005

Journal of Biological Chemistry

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A novel angucycline metabolite, 2,3-dehydro-UWM6, was identified in a jadH mutant of Streptomyces venezuelae ISP5230. Both UWM6 and 2,3-dehydro-UWM6 could be converted to jadomycin A or B by a ketosynthase ␣ (jadA) mutant of S. venezuelae. These angucycline intermediates were also converted to jadomycin A by transformant of the heterologous host Streptomyces lividans expressing the jadFGH oxygenases in vivo and by its cell-free extracts in vitro; thus the three gene products JadFGH are implicated in catalysis of the postpolyketide synthase biosynthetic reactions converting UWM6 to jadomycin aglycone. Genetic and biochemical analyses indicate that JadH possesses dehydrase activity, not previously associated with polyketide-modifying oxygenase. Since the formation of aromatic polyketides often requires multiple dehydration steps, bifunctionality of oxygenases modifying aromatic polyketides may be a general phenomenon.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Functional Analyses of Oxygenases in Jadomycin Biosynthesis and Identification of JadH as a Bifunctional Oxygenase/Dehydrase

Chen

Wang

Greenwell

et al. 2005

Journal of Biological Chemistry

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“…UV-Vis spectra of purified jadomycin derivatives were recorded using a Shimadzu BioSpec-mini UV-Vis spectrophotometer. NMR spectra were recorded on a Varian Unity VNS 600 NMR spectrometer ( 1 H at 600 MHz, 13 C at 150 MHz, Varian, Walnut Creek, CA, USA). Spectra were collected in CDCl 3 or dimethyl sulfoxide (DMSO)-d 6 .…”

Section: General Proceduresmentioning

confidence: 99%

“…Three oxygenases, JadF, JadG and JadH, have been implicated in the ring cleavage and amino-acid insertion process. [10][11][12][13] JadH was shown to be a FAD-dependent bifunctional hydroxylase/dehydrase in vitro, 10,14 catalyzing C-12 monooxygenation and 4a,12b-dehydration of 2,3-dehydro-UWM6, whereas the functions of JadF and JadG are still not clear.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the cytotoxic activity of new jadomycin derivatives reveals the potential to improve its selectivity against tumor cells

et al. 2012

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The jadomycins are a unique family of angucycline-derived antibiotics with interesting cytotoxic activities. In this work, six new jadomycin derivatives were produced in vivo by providing non-natural amino acids in fermentation media. They were further purified and identified by MS and NMR analyses. The cytotoxicities of these derivatives were evaluated against tumor cell lines MCF-7 and HCT116, as well as the normal human microvascular epithelial cells. The derivatives with alkyl side chains showed similar levels of cytotoxicity as jadomycin B and other known derivatives with nonpolar side chains, with IC 50 ranging from 1.3 to 10 lM; but the activities are not selective as these compounds also showed similar levels of cytotoxicity toward the normal human microvascular epithelial cells in the same concentration range. For the first time, derivatives with amino side chains (jadomycin Orn and K) were prepared and evaluated. Significantly, jadomycin Orn showed differential activity against normal and tumor cell lines. This result points to a new direction to modify jadomycin structure. The insights on the structure-activity relationship of jadomycins will guide further efforts to generate new and improved jadomycin derivatives against tumor cells.

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2015

Biosynthesis of Heterocycles

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The Oxidative Ring Cleavage in Jadomycin Biosynthesis: A Multistep Oxygenation Cascade in a Biosynthetic Black Box

Cited by 64 publications

References 29 publications

Functional Analyses of Oxygenases in Jadomycin Biosynthesis and Identification of JadH as a Bifunctional Oxygenase/Dehydrase

Functional Analyses of Oxygenases in Jadomycin Biosynthesis and Identification of JadH as a Bifunctional Oxygenase/Dehydrase

Evaluation of the cytotoxic activity of new jadomycin derivatives reveals the potential to improve its selectivity against tumor cells

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