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1.
Angew Chem Int Ed Engl ; 60(16): 8792-8797, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33533101

RESUMO

A revised structure of natural 14-mer cyclic depsipeptide MA026, isolated from Pseudomonas sp. RtlB026 in 2002 was established by physicochemical analysis with HPLC, MS/MS, and NMR and confirmed by total solid-phase synthesis. The revised structure differs from that previously reported in that two amino acid residues, assigned in error, have been replaced. Synthesized MA026 with the revised structure showed a tight junction (TJ) opening activity like that of the natural one in a cell-based TJ opening assay. Bioinformatic analysis of the putative MA026 biosynthetic gene cluster (BGC) of RtIB026 demonstrated that the stereochemistry of each amino acid residue in the revised structure can be reasonably explained. Phylogenetic analysis with xantholysin BGC indicates an exceptionally high homology (ca. 90 %) between xantholysin and MA026. The TJ opening activity of MA026 when binding to claudin-1 is a key to new avenues for transdermal administration of large hydrophilic biologics.


Assuntos
Produtos Biológicos/metabolismo , Depsipeptídeos/biossíntese , Família Multigênica , Pseudomonas/genética , Produtos Biológicos/química , Depsipeptídeos/química , Depsipeptídeos/genética , Conformação Molecular
2.
Biochem Biophys Res Commun ; 355(2): 520-5, 2007 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-17303079

RESUMO

Previously, we demonstrated that capsaicin induces tight-junction (TJ) opening in human intestinal Caco-2 cells. In order to clarify the mechanism underlying the TJ opening action of capsaicin, we performed a proteomics study on capsaicin-treated Caco-2 cells. Phosphorylated cofilin was decreased significantly by capsaicin treatment. In addition, capsaicin induced Ca2+ influx in Caco-2 cells and there was a clear correlation between Ca2+) influx and cofilin dephosphorylation (activation). The Ca2+-chelating reagent EGTA blocked the cofilin dephosphorylation induced by both capsaicin and ionomycin, suggesting that the dephosphorylation was mediated by Ca2+ influx. Finally, transepithelial electrical resistance measurements showed that TJ opening accompanied cofilin dephosphorylation. Our data suggest that TJ opening is mediated by cofilin dephosphorylation, which is caused by capsaicin stimuli, including Ca2+ influx. This is the first report of capsaicin action via the dephosphorylation of cofilin in human intestinal cells.


Assuntos
Capsaicina/farmacologia , Cofilina 1/metabolismo , Intestinos/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Western Blotting , Células CACO-2 , Cálcio/metabolismo , Eletroforese em Gel Bidimensional , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citologia , Transporte de Íons , Fosfoproteínas/metabolismo , Fosforilação , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Junções Íntimas/metabolismo
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