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Quercetin-3-Rutinoside Blocks the Disassembly of Cholera Toxin by Protein Disulfide Isomerase

1
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
2
Department of Physics, College of Sciences, University of Central Florida, Orlando, FL 32816, USA
*
Author to whom correspondence should be addressed.
Current address: Department of Pathology and Lab Medicine, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Toxins 2019, 11(8), 458; https://doi.org/10.3390/toxins11080458
Received: 5 July 2019 / Revised: 24 July 2019 / Accepted: 2 August 2019 / Published: 4 August 2019
(This article belongs to the Section Bacterial Toxins)
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Abstract

Protein disulfide isomerase (PDI) is mainly located in the endoplasmic reticulum (ER) but is also secreted into the bloodstream where its oxidoreductase activity is involved with thrombus formation. Quercetin-3-rutinoside (Q3R) blocks this activity, but its inhibitory mechanism against PDI is not fully understood. Here, we examined the potential inhibitory effect of Q3R on another process that requires PDI: disassembly of the multimeric cholera toxin (CT). In the ER, PDI physically displaces the reduced CTA1 subunit from its non-covalent assembly in the CT holotoxin. This is followed by CTA1 dislocation from the ER to the cytosol where the toxin interacts with its G protein target for a cytopathic effect. Q3R blocked the conformational change in PDI that accompanies its binding to CTA1, which, in turn, prevented PDI from displacing CTA1 from its holotoxin and generated a toxin-resistant phenotype. Other steps of the CT intoxication process were not affected by Q3R, including PDI binding to CTA1 and CT reduction by PDI. Additional experiments with the B chain of ricin toxin found that Q3R could also disrupt PDI function through the loss of substrate binding. Q3R can thus inhibit PDI function through distinct mechanisms in a substrate-dependent manner. View Full-Text
Keywords: AB toxin; cholera toxin; inhibitor; polyphenol; protein disulfide isomerase; ricin; rutin hydrate AB toxin; cholera toxin; inhibitor; polyphenol; protein disulfide isomerase; ricin; rutin hydrate
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Guyette, J.; Cherubin, P.; Serrano, A.; Taylor, M.; Abedin, F.; O’Donnell, M.; Burress, H.; Tatulian, S.A.; Teter, K. Quercetin-3-Rutinoside Blocks the Disassembly of Cholera Toxin by Protein Disulfide Isomerase. Toxins 2019, 11, 458.

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