Details
| Original language | English |
|---|---|
| Article number | 2309515 |
| Number of pages | 11 |
| Journal | Advanced science |
| Volume | 11 |
| Issue number | 18 |
| Publication status | Published - 15 May 2024 |
Abstract
The salinilactones, volatile marine natural products secreted from Salinispora arenicola, feature a unique [3.1.0]-lactone ring system and cytotoxic activities through a hitherto unknown mechanism. To find their molecular target, an activity-based protein profiling with a salinilactone-derived probe is applied that disclosed the protein disulfide-isomerases (PDIs) as the dominant mammalian targets of salinilactones, and thioredoxin (TRX1) as secondary target. The inhibition of protein disulfide-isomerase A1 (PDIA1) and TRX1 is confirmed by biochemical assays with recombinant proteins, showing that (1S,5R)-salinilactone B is more potent than its (1R,5S)-configured enantiomer. The salinilactones bound covalently to C53 and C397, the catalytically active cysteines of the isoform PDIA1 according to tandem mass spectrometry. Reactions with a model substrate demonstrated that the cyclopropyl group is opened by an attack of the thiol at C6. Fluorophore labeling experiments showed the cell permeability of a salinilactone-BODIPY (dipyrrometheneboron difluoride) conjugate and its co-localization with PDIs in the endoplasmic reticulum. The study is one of the first to pinpoint a molecular target for a volatile microbial natural product, and it demonstrates that salinilactones can achieve high selectivity despite their small size and intrinsic reactivity.
Keywords
- activity-based protein profiling, natural products, protein disulfide-isomerases, salinilactones, volatiles
ASJC Scopus subject areas
- Medicine(all)
- Medicine (miscellaneous)
- Chemical Engineering(all)
- Materials Science(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Engineering(all)
- Physics and Astronomy(all)
Sustainable Development Goals
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In: Advanced science, Vol. 11, No. 18, 2309515, 15.05.2024.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Activity-Based Protein Profiling Identifies Protein Disulfide-Isomerases as Target Proteins of the Volatile Salinilactones
AU - Jerye, Karoline
AU - Lüken, Helko
AU - Steffen, Anika
AU - Schlawis, Christian
AU - Jänsch, Lothar
AU - Schulz, Stefan
AU - Brönstrup, Mark
N1 - Publisher Copyright: © 2024 The Authors. Advanced Science published by Wiley-VCH GmbH.
PY - 2024/5/15
Y1 - 2024/5/15
N2 - The salinilactones, volatile marine natural products secreted from Salinispora arenicola, feature a unique [3.1.0]-lactone ring system and cytotoxic activities through a hitherto unknown mechanism. To find their molecular target, an activity-based protein profiling with a salinilactone-derived probe is applied that disclosed the protein disulfide-isomerases (PDIs) as the dominant mammalian targets of salinilactones, and thioredoxin (TRX1) as secondary target. The inhibition of protein disulfide-isomerase A1 (PDIA1) and TRX1 is confirmed by biochemical assays with recombinant proteins, showing that (1S,5R)-salinilactone B is more potent than its (1R,5S)-configured enantiomer. The salinilactones bound covalently to C53 and C397, the catalytically active cysteines of the isoform PDIA1 according to tandem mass spectrometry. Reactions with a model substrate demonstrated that the cyclopropyl group is opened by an attack of the thiol at C6. Fluorophore labeling experiments showed the cell permeability of a salinilactone-BODIPY (dipyrrometheneboron difluoride) conjugate and its co-localization with PDIs in the endoplasmic reticulum. The study is one of the first to pinpoint a molecular target for a volatile microbial natural product, and it demonstrates that salinilactones can achieve high selectivity despite their small size and intrinsic reactivity.
AB - The salinilactones, volatile marine natural products secreted from Salinispora arenicola, feature a unique [3.1.0]-lactone ring system and cytotoxic activities through a hitherto unknown mechanism. To find their molecular target, an activity-based protein profiling with a salinilactone-derived probe is applied that disclosed the protein disulfide-isomerases (PDIs) as the dominant mammalian targets of salinilactones, and thioredoxin (TRX1) as secondary target. The inhibition of protein disulfide-isomerase A1 (PDIA1) and TRX1 is confirmed by biochemical assays with recombinant proteins, showing that (1S,5R)-salinilactone B is more potent than its (1R,5S)-configured enantiomer. The salinilactones bound covalently to C53 and C397, the catalytically active cysteines of the isoform PDIA1 according to tandem mass spectrometry. Reactions with a model substrate demonstrated that the cyclopropyl group is opened by an attack of the thiol at C6. Fluorophore labeling experiments showed the cell permeability of a salinilactone-BODIPY (dipyrrometheneboron difluoride) conjugate and its co-localization with PDIs in the endoplasmic reticulum. The study is one of the first to pinpoint a molecular target for a volatile microbial natural product, and it demonstrates that salinilactones can achieve high selectivity despite their small size and intrinsic reactivity.
KW - activity-based protein profiling
KW - natural products
KW - protein disulfide-isomerases
KW - salinilactones
KW - volatiles
UR - http://www.scopus.com/inward/record.url?scp=85186424001&partnerID=8YFLogxK
U2 - 10.1002/advs.202309515
DO - 10.1002/advs.202309515
M3 - Article
AN - SCOPUS:85186424001
VL - 11
JO - Advanced science
JF - Advanced science
SN - 2198-3844
IS - 18
M1 - 2309515
ER -