The Dynamic Structure of Jadomycin B and the Amino Acid Incorporation Step of Its Biosynthesis

Rix, Uwe; Zheng, Jianting; Rix, Lily; Greenwell, Lisa; Yang, Keqian; Rohr, Jürgen

doi:10.1021/ja031724o

Cited by 80 publications

(98 citation statements)

References 10 publications

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“…33−35 When subjected to shock conditions (ethanol), the bacteria switches natural product production to JdDS (structure found in Figure 2B). 36,37 We have found that this compound is produced at higher levels than is JdB, allowing for straightforward detection by LC-MS/MS analysis. All three strains were successful in utilizing the D-serine minimal media as a nutrient source, growing to comparable OD 600 values ( Figure 1B).…”

Section: ■ Introductionmentioning

confidence: 97%

JadX is a Disparate Natural Product Binding Protein

Robertson¹,

Forget²,

Martinez-Farina³

et al. 2016

J. Am. Chem. Soc.

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Vous avez des questions? Nous pouvons vous aider. Pour communiquer directement avec un auteur, consultez la première page de la revue dans laquelle son article a été publié afin de trouver ses coordonnées. Si vous n'arrivez pas à les repérer, communiquez avec nous à PublicationsArchive-ArchivesPublications@nrc-cnrc.gc.ca. Questions? Contact the NRC Publications Archive team atPublicationsArchive-ArchivesPublications@nrc-cnrc.gc.ca. If you wish to email the authors directly, please see the first page of the publication for their contact information. NRC Publications Archive Archives des publications du CNRCThis publication could be one of several versions: author's original, accepted manuscript or the publisher's version. / La version de cette publication peut être l'une des suivantes : la version prépublication de l'auteur, la version acceptée du manuscrit ou la version de l'éditeur. NRC Publications Record / Notice d'Archives des publications de CNRC:http://nparc.cisti-icist.nrc-cnrc.gc.ca/eng/view/object/?id=1cef32c4-4c83-4b35-af83-2602ff6d1af3 http://nparc.cisti-icist.nrc-cnrc.gc.ca/fra/voir/objet/?id=1cef32c4-4c83-4b35-af83-2602ff6d1af3JadX is a Disparate Natural Product Binding Protein ABSTRACT: We report that JadX, a protein of previously undetermined function coded for in the jadomycin biosynthetic gene cluster of Streptomyces venezuelae ISP5230, affects both chloramphenicol and jadomycin production levels in blocked mutants. Characterization of recombinant JadX through protein−ligand interactions by chemical shift perturbation and WaterLOGSY NMR spectroscopy resulted in the observation of binding between JadX and a series of jadomycins and between JadX and chloramphenicol, another natural product produced by S. venezuelae ISP5230. These results suggest JadX to be an unusual class of natural product binding protein involved in binding structurally disparate natural products. The ability for JadX to bind two different natural products in vitro and the ability to affect production of these secondary metabolites in vivo suggest a potential role in regulation or signaling. This is the first example of functional characterization of these JadX-like proteins, and provides insight into a previously unobserved regulatory process.

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Section: ■ Introductionmentioning

confidence: 97%

JadX is a Disparate Natural Product Binding Protein

Robertson¹,

Forget²,

Martinez-Farina³

et al. 2016

J. Am. Chem. Soc.

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“…The phenanthridine ring system is plausibly derived by condensation of an amino acid with the postulated acid/ aldehyde intermediate (5), formed during angucyclic ring opening (7,9). Strengthening this possibility is the formation of jadomycin analogues when different amino acids are supplied as precursors (10,11). Until now, the only oxygenase gene identified in the jad biosynthetic cluster (Fig.…”

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confidence: 99%

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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“…As we have reported [10], by directed biosynthesis eleven new jadomycins were produced. Five of them including compounds 2, 3, 4, 5, and 6 were characterized by NMR.…”

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confidence: 86%

“…During its biosynthesis, an angucyclinone intermediate undergoes oxidative cleavage at ring B and an L-isoleucine is incorporated to generate the unique pentacyclic core of the jadomycin aglycon [8,9]. By substituting L-isoleucine in the jadomycin B production medium with other amino acids, eleven new jadomycin derivatives were generated [10]. Five of them ( Fig.…”

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confidence: 99%

“…1), designated jadomycins Ala (2), F (3), V (4), S (5) and T (6), which has incorporated alanine, phenylalanine, valine, serine and threonine, respectively, were characterized in detail [10]. The diastereomeric mixture with 3a-S and 3a-R configuration found for these jadomycins derivatives along with the observed dynamic equilibrium (found for compound 1, 2, 3, and 4) and the fact that various amino acids with different side chains can be incorporated into the jadomycin skeleton strongly support our hypothesis that the incorporation of amino acid most likely occurs nonenzymatically [10]. This exemplifies the potential to use jadomycin scaffold to generate novel structure modifications on the oxazolone ring.…”

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confidence: 99%

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Cytotoxic Activities of New Jadomycin Derivatives

et al. 2005

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Cytotoxic activities of jadomycin B and five new jadomycin derivatives against four cancer cell lines (HepG2, IM-9, IM-9/Bcl-2 and H460) were evaluated. Jadomycin S was most potent against HepG2, IM-9 and IM-9/Bcl-2 while jadomycin F was most potent against H460. Their potencies correlated with the degrees of apoptosis induced. Structure-activity-relationship analyses clearly demonstrate that the side chains of the oxazolone ring derived from the incorporated amino acids make a significant impact on biological activity. Therefore, jadomycin offers an ideal scaffold to manipulate structure and could be exploited to make many novel bioactive compounds with altered activities.

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The Dynamic Structure of Jadomycin B and the Amino Acid Incorporation Step of Its Biosynthesis

Cited by 80 publications

References 10 publications

JadX is a Disparate Natural Product Binding Protein

JadX is a Disparate Natural Product Binding Protein

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

Cytotoxic Activities of New Jadomycin Derivatives

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