Napyradiomycins CNQ525.510B and A80915C target the Hsp90 paralogue Grp94

TitleNapyradiomycins CNQ525.510B and A80915C target the Hsp90 paralogue Grp94
Publication TypeJournal Article
Year of Publication2014
AuthorsFarnaes L., La Clair J.J, Fenical W
JournalOrganic & Biomolecular Chemistry
Volume12
Pagination418-423
Date Published2014/01
Type of ArticleArticle
ISBN Number1477-0520
Accession NumberWOS:000329551800005
Keywordsantibiotics napyradiomycins; cell-death; discovery; fermentation; inhibitor; marine actinomycete; n-terminal domain; naphthablin; physicochemical; properties; Streptomyces
Abstract

The intracellular localization and target of the napyradiomycin congeners CNQ525.510B and A80815C were explored using an immunoaffinity fluorescence (IAF) approach. Semi-synthetic methods were used to prepare probes from napyradiomycin CNQ525.510B and derivative A80815C. The results of confocal microscopy indicated that probes from both natural products localized predominantly within the endoplasmic reticulum (ER) of HCT-116 human colon carcinoma cells. Parallel immunoaffinity precipitation efforts using a monoclonal antibody designed against the IAF tag, resulted in the isolation of an Hsp90 family member. This protein was identified as human Grp94 (hGrp94), by its specific mass spectral signature. This observation was validated by Western blot analyses and by the result of an in vitro Grp94 binding assay. The fact that the napyradiomycins CNQ525.510B and A80815C bind to hGrp94, and their associated probes localize within the ER, suggest the use of these materials as molecular probes for monitoring ER-based chaperone function.

DOI10.1039/c3ob41355a
Short TitleOrg. Biomol. Chem.
Integrated Research Themes: 
Student Publication: 
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