Myxochelins Target Human 5-Lipoxygenase

Schieferdecker, Sebastian; König, Stefanie; Koeberle, Andreas; Dahse, Hans‐Martin; Werz, Oliver; Nett, Markus

doi:10.1021/np500909b

Cited by 31 publications

(35 citation statements)

References 29 publications

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“…We recently described the isolation of the catechol siderophore myxochelin A from the predatory bacterium Pyxidicoccus fallax HKI727 . The natural product strongly suppressed the growth of K‐562 leukemia cells and pharmacological characterization revealed human 5‐LO as the molecular target, which was inhibited with an IC 50 of 1.9 μ m in a cell‐free assay . The active site of human 5‐LO contains a non‐heme iron, which serves as an electron donor (Fe 2+ ) or acceptor (Fe 3+ ) during catalysis .…”

Section: Structures Of Lysinol‐derived Myxochelin Analogues and Theirmentioning

confidence: 99%

“…[7] The naturalp roduct strongly suppressedt he growth of K-562 leukemiac ells and pharmacological character-ization revealed human 5-LO as the molecular target, which was inhibited with an IC 50 of 1.9 mm in ac ell-free assay. [7] The active site of human 5-LO contains an on-heme iron, which serves as an electron donor (Fe 2 + )o ra cceptor( Fe 3 + )d uring catalysis. [8][9][10] Our original assumption that the inhibition of human5 -LO was solely due to the complexation of this active site iron by myxochelinA could be disproven by structure activity relationship (SAR) studies of myxochelind erivatives which were generated by precursor-directedb iosynthesis.…”

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confidence: 98%

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Myxochelin‐Inspired 5‐Lipoxygenase Inhibitors: Synthesis and Biological Evaluation

et al. 2016

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A total of 48 analogues of the natural product myxochelin A were prepared and evaluated for their inhibitory effects on human 5-lipoxygenase in both cell-free and cell-based assays. Structure-activity relationship analysis revealed that the secondary alcohol function and only chiral center of myxochelin A is not required for biological activity. By expanding the diaminoalkane linker of the two aromatic residues it was possible to generate a myxochelin derivative with superior activity against 5-lipoxygenase in intact cells.

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Section: Structures Of Lysinol‐derived Myxochelin Analogues and Theirmentioning

confidence: 99%

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confidence: 98%

Myxochelin‐Inspired 5‐Lipoxygenase Inhibitors: Synthesis and Biological Evaluation

et al. 2016

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“…Pseudochelin A is a catechol siderophore that is structurally closely related to the myxochelins (10,13) and hyalachelins (14). In this study, we identified a gene cluster for pseudochelin A biosynthesis in P. piscicida S2040 and we demonstrated that a single enzyme, MxcM, is needed to provide a myxochelin-producing bacterium the potential for pseudochelin biosynthesis.…”

Section: Discussionmentioning

confidence: 81%

“…In recent years, myxobacteria have gained increasing attention due to their enormous potential as producers of secondary metabolites with antifungal, antibacterial, and cytotoxic activities (7)(8)(9). To maintain their iron homeostasis, many myxobacteria produce catechol siderophores, such as the myxochelins (10)(11)(12)(13) or the structurally related hyalachelins (14). Although the myxochelins are generally regarded as myxobacterial siderophores, they were occasionally also described for other bacteria.…”

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Engineering Pseudochelin Production in Myxococcus xanthus

Korp

Winand

Sester

et al. 2018

Appl Environ Microbiol

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Myxobacteria utilize the catechol natural products myxochelin A and B in order to maintain their iron homeostasis. Recently, the production of these siderophores was reported from the marine bacterium S2040, along with a new myxochelin derivative named pseudochelin A. The latter features a characteristic imidazoline moiety, which was proposed to originate from an intramolecular condensation reaction of the β-aminoethyl amide group in myxochelin B. To identify the enzyme catalyzing this conversion, we compared the myxochelin regulons of two myxobacterial strains, which solely produce myxochelin A and B, with S2040. This approach revealed a gene exclusive to the myxochelin regulon in S2040, coding for an enzyme of the amidohydrolase superfamily. To prove that this enzyme is indeed responsible for the postulated conversion, the reaction was reconstituted using a hexahistidyl-tagged recombinant protein made in and myxochelin B as substrate. To test the production of pseudochelin A under conditions, the amidohydrolase gene was cloned into the myxobacterial plasmid pZJY156 and placed under the control of a copper-inducible promoter. The resulting vector was introduced into the myxobacterium DSM16526, a native producer of myxochelin A and B. Following the induction with copper, the myxobacterial expression strain was found to synthesize small quantities of pseudochelin A. Replacement of the copper-inducible promoter with the constitutive promoter led to increased production levels in , which facilitated the isolation and subsequent structural verification of the heterologously produced compound. In this study, an enzyme for imidazoline formation in pseudochelin biosynthesis was identified. Evidence for the involvement of this enzyme in the postulated reaction was obtained after reconstitution. Furthermore, the function of this enzyme was also demonstrated by transferring the corresponding gene into the bacterium , which thereby became a producer of pseudochelin A. Aside from clarifying the molecular basis of imidazoline formation in siderophore biosynthesis, we describe the heterologous expression of a gene in a myxobacterium without its chromosomal integration. Due to its metabolic proficiency, represents an interesting alternative to established host systems for the reconstitution and manipulation of biosynthetic pathways. Since the plasmid used in this study is easily adaptable for the expression of other enzymes as well, we expand the conventional expression strategy for myxobacteria, which is based on the integration of biosynthetic genes into the host genome.

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“…Pyxidicoccus sp. in this study produces compounds that are inhibitory to pancreatic (MIA PaCa-2) and prostate (PC-3) cancer cell lines, whereas a secondary metabolite from P. fallax has been associated with inhibition of leukemic cells by Schieferdecker et al (2015). In the present investigation, the extract from M. fulvus (S199) exhibited the inhibition of PC-3 (prostate cancer) and HeLa (cervical cancer) cells which have not been documented in the cytotoxicity profile of the metabolite isolated from M. fulvus in a study by Ahn et al (1999).…”

Section: Discussionmentioning

confidence: 91%

Molecular and functional characterization of myxobacteria isolated from soil in India

et al. 2017

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This study reports the isolation of myxobacteria from soil collected from plains in north India. Based on the morphology and 16S rDNA sequence, the isolated myxobacteria were identified as Corallococcus sp., Pyxidicoccus sp., Myxococcus sp., Cystobacter sp. and Archangium sp. The myxobacteria were functionally characterized to assess their ability to produce antibacterial and anticancer metabolites. The isolates were found to be functionally versatile as they produced extracellular bioactive molecules that exhibited high frequency of activities against Bacillus cereus, Mycobacterium smegmatis, Enterobacter cloacae and Pseudomonas syringae. The strains also showed cytotoxic activity against the human cancer cell lines of liver, pancreas, prostrate, bone and cervix. These results indicate the importance of isolating diverse strains of myxobacteria from unexplored habitats to find novel bioactive compounds. Moreover, the bioactive molecules explored in this study are predominantly hydrophilic compounds, obviating the limitations of solubility-related aspect of drug discovery.

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Myxochelins Target Human 5-Lipoxygenase

Cited by 31 publications

References 29 publications

Myxochelin‐Inspired 5‐Lipoxygenase Inhibitors: Synthesis and Biological Evaluation

Myxochelin‐Inspired 5‐Lipoxygenase Inhibitors: Synthesis and Biological Evaluation

Engineering Pseudochelin Production in Myxococcus xanthus

Molecular and functional characterization of myxobacteria isolated from soil in India

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