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Crawford JM, Portmann C, Zhang X, Roeffaers MB, Clardy J
Small molecule perimeter defense in entomopathogenic bacteria
Proceedings of the National Academy of Sciences of the USA 109(27) (2012)
10821-10826
|
a-L-Fucp4NAc-(1-4)-Subst
Subst = (E)-3-[4-oxyphenyl]prop-2-eneisonitrile = SMILES [C-]#[N+]/C=C/c1cc{4}c(O)cc1 |
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Xenorhabdus nematophila
(NCBI TaxID 628,
species name lookup)
Photorhabdus luminescens
(NCBI TaxID 29488,
species name lookup)
Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
NCBI PubMed ID: 22711807Publication DOI: 10.1073/pnas.1201160109Journal NLM ID: 7505876Publisher: National Academy of Sciences
Correspondence: jon_clardy
hms.harvard.edu
Institutions: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA
Two gram-negative insect pathogens, Xenorhabdus nematophila and Photorhabdus luminescens, produce rhabduscin, an amidoglycosyl- and vinyl-isonitrile-functionalized tyrosine derivative. Heterologous expression of the rhabduscin pathway in Escherichia coli, precursor-directed biosynthesis of rhabduscin analogs, biochemical assays, and visualization using both stimulated Raman scattering and confocal fluorescence microscopy established rhabduscin's role as a potent nanomolar-level inhibitor of phenoloxidase, a key component of the insect's innate immune system, as well as rhabduscin's localization at the bacterial cell surface. Stimulated Raman scattering microscopy visualized rhabduscin at the periphery of wild-type X. nematophila cells and E. coli cells heterologously expressing the rhabduscin pathway. Precursor-directed biosynthesis created rhabduscin mimics in X. nematophila pathway mutants that could be accessed at the bacterial cell surface by an extracellular bioorthogonal probe, as judged by confocal fluorescence microscopy. Biochemical assays using both wild-type and mutant X. nematophila cells showed that rhabduscin was necessary and sufficient for potent inhibition (low nM) of phenoloxidases, the enzymes responsible for producing melanin (the hard black polymer insects generate to seal off microbial pathogens). These observations suggest a model in which rhabduscin's physical association at the bacterial cell surface provides a highly effective inhibitor concentration directly at the site of phenoloxidase contact. This class of molecules is not limited to insect pathogens, as the human pathogen Vibrio cholerae also encodes rhabduscin's aglycone, and bacterial cell-coated immunosuppressants could be a general strategy to combat host defenses.
metabolites, Photorhabdus, Xenorhabdus, rhabduscin
Structure type: monomer
Location inside paper: Fig. 1, 1
Trivial name: rhabduscin
Compound class: glycoside
Methods: 13C NMR, 1H NMR, NMR-2D, DNA techniques, biological assays, LC-MS, fluorescence microscopy, enzymatic assay, HR-MS, SRS microscopy
Biological activity: rhabduscin shows low nanomolar-level inhibition (IC50) against both mushroom tyrosinase and insect phenoloxidase, a level roughly three orders of magnitude more potent than the commercial whitening agent kojic acid
Enzymes that release or process the structure: IsnA, IsnB, GT
Synthetic data: chemical
Related record ID(s): 47264, 47266, 47269
NCBI Taxonomy refs (TaxIDs): 628,
29488
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There is only one chemically distinct structure:
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Crawford JM, Portmann C, Zhang X, Roeffaers MB, Clardy J
Small molecule perimeter defense in entomopathogenic bacteria
Proceedings of the National Academy of Sciences of the USA 109(27) (2012)
10821-10826
|
a-L-Rhap-(1-4)-Subst
Subst = (E)-3-[4-oxyphenyl]prop-2-eneisonitrile = SMILES [C-]#[N+]/C=C/c1cc{4}c(O)cc1 |
Show graphically |
Xenorhabdus nematophila
(NCBI TaxID 628,
species name lookup)
Photorhabdus luminescens
(NCBI TaxID 29488,
species name lookup)
Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
NCBI PubMed ID: 22711807Publication DOI: 10.1073/pnas.1201160109Journal NLM ID: 7505876Publisher: National Academy of Sciences
Correspondence: jon_clardy
hms.harvard.edu
Institutions: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA
Two gram-negative insect pathogens, Xenorhabdus nematophila and Photorhabdus luminescens, produce rhabduscin, an amidoglycosyl- and vinyl-isonitrile-functionalized tyrosine derivative. Heterologous expression of the rhabduscin pathway in Escherichia coli, precursor-directed biosynthesis of rhabduscin analogs, biochemical assays, and visualization using both stimulated Raman scattering and confocal fluorescence microscopy established rhabduscin's role as a potent nanomolar-level inhibitor of phenoloxidase, a key component of the insect's innate immune system, as well as rhabduscin's localization at the bacterial cell surface. Stimulated Raman scattering microscopy visualized rhabduscin at the periphery of wild-type X. nematophila cells and E. coli cells heterologously expressing the rhabduscin pathway. Precursor-directed biosynthesis created rhabduscin mimics in X. nematophila pathway mutants that could be accessed at the bacterial cell surface by an extracellular bioorthogonal probe, as judged by confocal fluorescence microscopy. Biochemical assays using both wild-type and mutant X. nematophila cells showed that rhabduscin was necessary and sufficient for potent inhibition (low nM) of phenoloxidases, the enzymes responsible for producing melanin (the hard black polymer insects generate to seal off microbial pathogens). These observations suggest a model in which rhabduscin's physical association at the bacterial cell surface provides a highly effective inhibitor concentration directly at the site of phenoloxidase contact. This class of molecules is not limited to insect pathogens, as the human pathogen Vibrio cholerae also encodes rhabduscin's aglycone, and bacterial cell-coated immunosuppressants could be a general strategy to combat host defenses.
metabolites, Photorhabdus, Xenorhabdus, rhabduscin
Structure type: monomer
Location inside paper: Fig. 1, 2
Trivial name: byelyankacin
Compound class: glycoside
Contained glycoepitopes: IEDB_136105,IEDB_225177,IEDB_885823
Methods: 13C NMR, 1H NMR, NMR-2D, DNA techniques, biological assays, LC-MS, fluorescence microscopy, enzymatic assay, HR-MS, SRS microscopy
Biological activity: byelyankacin shows low nanomolar-level inhibition (IC50) against both mushroom tyrosinase and insect phenoloxidase, a level roughly three orders of magnitude more potent than the commercial whitening agent kojic acid
Enzymes that release or process the structure: IsnA, IsnB, GT
Synthetic data: chemical
Related record ID(s): 47263, 47265, 47267, 47268
NCBI Taxonomy refs (TaxIDs): 628,
29488
Show glycosyltransferases
There is only one chemically distinct structure:
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