Bioreduction of Aryl Azides during Mutasynthesis of New Ansamitocins

Mancuso, Lena; Jürjens, Gerrit; Hermane, Jekaterina; Harmrolfs, Kirsten; Eichner, Simone; Fohrer, Jörg; Collisi, Wera; Sasse, Florenz; Kirschning, Andreas

doi:10.1021/ol401989e

Cited by 13 publications

(19 citation statements)

References 51 publications

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“…During our investigation of mutasynthetic options with ansamycin antibiotics, we reported on a unique and unprecedented reductive property of the geldanamycin producer S. hygroscopicus towards aryl azides. Selected examples were transformed into the corresponding anilines 19. We have now found that A. mediterranei is the second microbial source able to reduce the bioorthogonal functional azido group (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

“…Selected examples were transformed into the corresponding anilines. [19] We have now found that A. mediterranei is the second microbial source able to reduce the bioorthogonal functionala zido group (Scheme 3).…”

Section: Mutasynthetic Experimentsmentioning

confidence: 93%

“…The rifamycinso nly form after reduction of the aryl azide and formation of the pyranone 49 strongly indicates that reductionoft he azido group takes place prior to PKS processing, which would be in line with our studies on the geldanamycin producer S. hygroscopicus. [19,20] Secondly,3-hydroxy-5-nitrobenzoic acid 48 was also converted into rifamycin S 1b in trace amounts, which is the first example of an itroarene being reduced by one of the ansamycin producersino ur hands. A. mediterranei exertedamore impressive reductivepowertowards nitro groups when it was supplemented with 3,5-dinitrobenzoic acid 50.A niline 52 was isolated in asimilarly excellent yield as when 3-amino-5-nitrobenzoic acid 51 was fed to the AHBA(À)m utant strain.…”

Section: Mutasynthetic Experimentsmentioning

confidence: 99%

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Evaluation of the Synthetic Potential of an AHBA Knockout Mutant of the Rifamycin Producer Amycolatopsis mediterranei

Bułyszko

Dräger

Klenge

et al. 2015

Chemistry A European J

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Supplementing an AHBA(-) mutant strain of Amycolatopsis mediterranei, the rifamycin producer, with a series of benzoic acid derivatives yielded new tetraketides containing different phenyl groups. These mutasynthetic studies revealed unique reductive properties of A. mediterranei towards nitro- and azidoarenes, leading to the corresponding anilines. In selected cases, the yields of mutaproducts (fermentation products isolated after feeding bacteria with chemically prepared analogs of natural building blocks) obtained are in a range (up to 118 mg L(-1)) that renders them useful as chiral building blocks for further synthetic endeavors. The configuration of the stereogenic centers at C6 and C7 was determined to be 6R,7S for one representative tetraketide. Importantly, processing beyond the tetraketide stage is not always blocked when the formation of the bicyclic naphthalene precursor cannot occur. This was proven by formation of a bromo undecaketide, an observation that has implications regarding the evolutionary development of rifamycin biosynthesis.

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Section: Resultsmentioning

confidence: 99%

Section: Mutasynthetic Experimentsmentioning

confidence: 93%

Section: Mutasynthetic Experimentsmentioning

confidence: 99%

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Evaluation of the Synthetic Potential of an AHBA Knockout Mutant of the Rifamycin Producer Amycolatopsis mediterranei

Bułyszko

Dräger

Klenge

et al. 2015

Chemistry A European J

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“…These components are relatively small, and so metabolic precursors modified with azides and alkynes may be tolerated by the natural biosynthetic machinery of cells. However, certain azides are prone to reduction in the cellular milieu ( Mancuso et al., 2013 ), and the reaction between azides and linear alkynes depends on copper (I) catalysis, which requires optimization to avoid damage to biomolecules ( Hong et al., 2009 ). Strain-promoted reactions between azides and strained alkynes remove the copper dependence ( Agard et al., 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Tagging and Enriching Proteins Enables Cell-Specific Proteomics

Elliott

Bianco

Townsley

et al. 2016

Cell Chemical Biology

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SummaryCell-specific proteomics in multicellular systems and whole animals is a promising approach to understand the differentiated functions of cells and tissues. Here, we extend our stochastic orthogonal recoding of translation (SORT) approach for the co-translational tagging of proteomes with a cyclopropene-containing amino acid in response to diverse codons in genetically targeted cells, and create a tetrazine-biotin probe containing a cleavable linker that offers a way to enrich and identify tagged proteins. We demonstrate that SORT with enrichment, SORT-E, efficiently recovers and enriches SORT tagged proteins and enables specific identification of enriched proteins via mass spectrometry, including low-abundance proteins. We show that tagging at distinct codons enriches overlapping, but distinct sets of proteins, suggesting that tagging at more than one codon enhances proteome coverage. Using SORT-E, we accomplish cell-specific proteomics in the fly. These results suggest that SORT-E will enable the definition of cell-specific proteomes in animals during development, disease progression, and learning and memory.

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“…The processing of 3,5‐diaminobenzoic acid ( 8 ) is especially remarkable because this mutasynthon can easily form ammonium salts, which would hamper transfer through the membrane of S. hygroscopicus . Indeed, in related cases such as mutasynthetic experiments conducted with the AHBA(−) mutant strain of the ansamitocin producer Actinosynnema pretiosum , feeding of 8 did not yield any mutaproduct …”

Section: Resultsmentioning

confidence: 99%

Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

Mohammadi-Ostad-Kalayeh

Stahl

Scheper

et al. 2018

ChemBioChem

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Thirteen new reblastatin derivatives, with alkynyl, amino and fluoro substituents on the aromatic ring, were prepared by a chemo-biosynthetic approach using an AHBA(-) mutant strain of Streptomyces hygroscopicus, the geldanamycin producer. The inhibitory potencies of these mutaproducts and of an extended library of natural products and derivatives were probed with purified heat shock proteins (Hsps), obtained from Leishmania braziliensis (LbHsp90) as well as from human sources (HsHsp90). We determined the activities of potential inhibitors by means of a displacement assay in which fluorescence-labelled ATP competes for the ATP binding sites of Hsps in the presence of the inhibitor in question. The results were compared with those of cell-based assays and, in selected cases, of isothermal titration calorimetry (ITC) measurements. In essence, reblastatin derivatives are also able to bind effectively to the ATP-binding site of LbHsp90, and for selected derivatives, moderate differences in binding to LbHsp90 and HsHsp90 were encountered. This work demonstrates that parasitic heat shock proteins can be developed as potential pharmaceutical targets.

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Bioreduction of Aryl Azides during Mutasynthesis of New Ansamitocins

Cited by 13 publications

References 51 publications

Evaluation of the Synthetic Potential of an AHBA Knockout Mutant of the Rifamycin Producer Amycolatopsis mediterranei

Evaluation of the Synthetic Potential of an AHBA Knockout Mutant of the Rifamycin Producer Amycolatopsis mediterranei

Tagging and Enriching Proteins Enables Cell-Specific Proteomics

Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

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