New Aminocoumarin Antibiotics from a cloQ‐Defective Mutant of the Clorobiocin Producer Streptomyces roseochromogenes DS12.976.

Freitag, Anja; Galm, Ute; Li, Shu‐Ming; Heide, Lutz

doi:10.1002/chin.200436209

Cited by 4 publications

(8 citation statements)

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“…The new compounds were observed in cloQ-defective strains expressing the heterologous amide synthetase CouL, but not in a previously generated cloQ-defective strain expressing CloL [4,9]. This is consistent with the substrate specificities of CloL and CouL, since CouL but not CloL is capable of accepting substituted cinnamic acid substrates.…”

Section: Discussionsupporting

confidence: 77%

“…The amide synthetase CouL could not be replaced by CloL, which catalyzes a very similar reaction but has a different substrate specificity [5,6], since in a cloQdefective strain with intact cloL [9], we could not detect the three new antibiotics described here, even upon specific examination with sensitive LC-MS techniques. However, CouL could be replaced by SimL of simocyclinone biosynthesis [17], cloned into expression vector pUWL201, as is consistent with the reported substrate specificity of SimL.…”

Section: Dependence Of the Formation Of Ferulobiocin 3-chlorocoumaromentioning

confidence: 89%

“…The genetically engineered S. coelicolor M512 strain was pre-cultured for 2 days in YMG medium, for 2 further days in corn starch medium and subsequently for 8ϳ10 days in production medium as described previously [9]. Cultures were treated with petrol ether to remove lipids, and subsequently the antibiotics were extracted with ethyl acetate [9].…”

Section: Fermentation and Preparative Isolation Of New Antibioticsmentioning

confidence: 99%

“…Cultures were treated with petrol ether to remove lipids, and subsequently the antibiotics were extracted with ethyl acetate [9].…”

Section: Fermentation and Preparative Isolation Of New Antibioticsmentioning

confidence: 99%

“…The antibacterial activities of the new compounds were tested against Bacillus subtilis ATCC 14893 in a disc diffusion assay as described previously [9]. Authentic clorobiocin was used as comparison.…”

Section: Antibacterial Activitiesmentioning

confidence: 99%

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New Aminocoumarin Antibiotics Derived from 4-Hydroxycinnamic Acid are Formed after Heterologous Expression of a Modified Clorobiocin Biosynthetic Gene Cluster

Anderle

Kammerer

et al. 2007

J Antibiot

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Three new aminocoumarin antibiotics, termed ferulobiocin, 3-chlorocoumarobiocin and 8Ј-dechloro-3-chlorocoumarobiocin, were isolated from the culture broth of a Streptomyces coelicolor M512 strain expressing a modified clorobiocin biosynthetic gene cluster. Structural analysis showed that these new aminocoumarins were very similar to clorobiocin, with a substituted 4-hydroxycinnamoyl moieties instead of the prenylated 4-hydroxybenzoyl moiety of clorobiocin. The possible biosynthetic origin of these moieties is discussed.

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Section: Discussionsupporting

confidence: 77%

Section: Dependence Of the Formation Of Ferulobiocin 3-chlorocoumaromentioning

confidence: 89%

Section: Fermentation and Preparative Isolation Of New Antibioticsmentioning

confidence: 99%

“…Cultures were treated with petrol ether to remove lipids, and subsequently the antibiotics were extracted with ethyl acetate [9].…”

Section: Fermentation and Preparative Isolation Of New Antibioticsmentioning

confidence: 99%

Section: Antibacterial Activitiesmentioning

confidence: 99%

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New Aminocoumarin Antibiotics Derived from 4-Hydroxycinnamic Acid are Formed after Heterologous Expression of a Modified Clorobiocin Biosynthetic Gene Cluster

Anderle

Kammerer

et al. 2007

J Antibiot

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Optimizing Glycosyltransferase Specificity via “Hot Spot” Saturation Mutagenesis Presents a Catalyst for Novobiocin Glycorandomization

Williams

Goff

Zhang

et al. 2008

Chemistry & Biology

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A comprehensive two-phase "hot spot" saturation mutagenesis strategy for the rapid evolution of glycosyltransferase (GT) specificity for nonnatural acceptors is described. Specifically, the application of a high-throughput screen (based on the fluorescent acceptor umbelliferone) was used to identify key amino acid hot spots that contribute to GT proficiency and/or promiscuity. Saturation mutagenesis of the corresponding hot spots facilitated the utilization of a lower-throughput screen to provide OleD prodigy capable of efficiently glycosylating the nonnatural acceptor novobiocic acid with an array of unique sugars. Incredibly, even in the absence of a high-throughput screen for novobiocic acid glycosylation, this approach rapidly led to improvements in the desired catalytic activity of several hundred-fold.

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Activity Screening of Carrier Domains within Nonribosomal Peptide Synthetases Using Complex Substrate Mixtures and Large Molecule Mass Spectrometry

et al. 2006

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For screening a pool of potential substrates that load carrier domains found in non-ribosomal peptide synthetases, large molecule mass spectrometry is shown to be an ideal, unbiased assay. Combining the high resolving power of Fourier-Transform Mass Spectrometry with the ability of adenylation domains to select their own substrates, the mass change that takes place upon formation of a covalent intermediate thus identifies the substrate. This assay has an advantage over traditional radiochemical assays in that many substrates, the substrate pool, can be screened simultaneously. Using proteins on the nikkomycin, clorobiocin, coumermycin A 1 , yersiniabactin, pyochelin and enterobactin biosynthetic pathways as proof-of-principle, preferred substrates are readily identified from substrate pools. Furthermore this assay can be used to provide insight into the timing of tailoring events of biosynthetic pathways as demonstrated using the bromination reaction found on the jamaicamide biosynthetic pathway. Finally, this assay can provide insight into the role and function of orphan gene clusters for which the encoded natural product is unknown. This is demonstrated by identifying the substrates for two NRPS modules from the genes pksN and pksJ, that are found on an orphan NRPS/PKS hybrid cluster from Bacillus subtilis. This new assay format is especially timely for activity screening in an era when new types of thiotemplate assembly lines that defy classification are being discovered at an accelerating rate. KeywordsElectrospray Fourier transform mass spectrometry; Non-ribosomal peptide synthetase; Polyketide synthase; Carrier domains; Post-translational modification Almost weekly, new non-ribosomal peptide synthetase (NRPS) gene clusters encoding for proteins that biosynthesize bioactive compounds are discovered (1-4). Since many of the compounds produced by non-ribosomal peptide synthetase (NRPS) as well as polyketide * To whom correspondence should be addressed, kelleher@scs.uiuc.edu, fax number 217 244-8068 and phone number 217 NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2008 October 9. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript synthase (PKS) paradigm have potent medicinal utility or are involved in virulence, and display unusual chemistry, they are of great academic and industrial interest. Therefore we wanted to develop an alternative method for substrate screening to complement the more traditional radioactive assays (5,6). In NRPS and PKS systems, the substrates and intermediates are loaded onto and processed while attached to the pantetheinyl functionality on a carrier domain (7,8).Examples of NRPS or hybrid NRPS/PKS natural products for which substrates load onto carrier domains are: the siderophore pyoverdine (9), a virulence factor excreted by pseudomonads, the antimicrobial agents penicillin (10), vancomycin (11) gramicidin (12) and the antitumor agent calicheamycin (13). With ∼300 genomes sequenced and available in the public ...

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New Aminocoumarin Antibiotics from a cloQ‐Defective Mutant of the Clorobiocin Producer Streptomyces roseochromogenes DS12.976.

Cited by 4 publications

References 1 publication

New Aminocoumarin Antibiotics Derived from 4-Hydroxycinnamic Acid are Formed after Heterologous Expression of a Modified Clorobiocin Biosynthetic Gene Cluster

New Aminocoumarin Antibiotics Derived from 4-Hydroxycinnamic Acid are Formed after Heterologous Expression of a Modified Clorobiocin Biosynthetic Gene Cluster

Optimizing Glycosyltransferase Specificity via “Hot Spot” Saturation Mutagenesis Presents a Catalyst for Novobiocin Glycorandomization

Activity Screening of Carrier Domains within Nonribosomal Peptide Synthetases Using Complex Substrate Mixtures and Large Molecule Mass Spectrometry

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