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Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer
Amyloid formation of the human plasma protein transthyretin (TTR) is associated with several human disorders, including familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis. Dissociation of TTR’s native tetrameric assembly is the rate-limiting step in the conversion into amyloid...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836675/ https://www.ncbi.nlm.nih.gov/pubmed/27093678 http://dx.doi.org/10.1371/journal.pone.0153529 |
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author | Iakovleva, Irina Begum, Afshan Brännström, Kristoffer Wijsekera, Alexandra Nilsson, Lina Zhang, Jin Andersson, Patrik L. Sauer-Eriksson, A. Elisabeth Olofsson, Anders |
author_facet | Iakovleva, Irina Begum, Afshan Brännström, Kristoffer Wijsekera, Alexandra Nilsson, Lina Zhang, Jin Andersson, Patrik L. Sauer-Eriksson, A. Elisabeth Olofsson, Anders |
author_sort | Iakovleva, Irina |
collection | PubMed |
description | Amyloid formation of the human plasma protein transthyretin (TTR) is associated with several human disorders, including familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis. Dissociation of TTR’s native tetrameric assembly is the rate-limiting step in the conversion into amyloid, and this feature presents an avenue for intervention because binding of an appropriate ligand to the thyroxin hormone binding sites of TTR stabilizes the native tetrameric assembly and impairs conversion into amyloid. The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body. In this study we show that the commonly used flame retardant tetrabromobisphenol A (TBBPA) efficiently stabilizes the tetrameric structure of TTR. The X-ray crystal structure shows TBBPA binding in the thyroxine binding pocket with bromines occupying two of the three halogen binding sites. Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP. TBBPA consequently present an interesting scaffold for drug design. Its absorption, metabolism, and potential side-effects are discussed. |
format | Online Article Text |
id | pubmed-4836675 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-48366752016-04-29 Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer Iakovleva, Irina Begum, Afshan Brännström, Kristoffer Wijsekera, Alexandra Nilsson, Lina Zhang, Jin Andersson, Patrik L. Sauer-Eriksson, A. Elisabeth Olofsson, Anders PLoS One Research Article Amyloid formation of the human plasma protein transthyretin (TTR) is associated with several human disorders, including familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis. Dissociation of TTR’s native tetrameric assembly is the rate-limiting step in the conversion into amyloid, and this feature presents an avenue for intervention because binding of an appropriate ligand to the thyroxin hormone binding sites of TTR stabilizes the native tetrameric assembly and impairs conversion into amyloid. The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body. In this study we show that the commonly used flame retardant tetrabromobisphenol A (TBBPA) efficiently stabilizes the tetrameric structure of TTR. The X-ray crystal structure shows TBBPA binding in the thyroxine binding pocket with bromines occupying two of the three halogen binding sites. Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP. TBBPA consequently present an interesting scaffold for drug design. Its absorption, metabolism, and potential side-effects are discussed. Public Library of Science 2016-04-19 /pmc/articles/PMC4836675/ /pubmed/27093678 http://dx.doi.org/10.1371/journal.pone.0153529 Text en © 2016 Iakovleva et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Iakovleva, Irina Begum, Afshan Brännström, Kristoffer Wijsekera, Alexandra Nilsson, Lina Zhang, Jin Andersson, Patrik L. Sauer-Eriksson, A. Elisabeth Olofsson, Anders Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer |
title | Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer |
title_full | Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer |
title_fullStr | Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer |
title_full_unstemmed | Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer |
title_short | Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer |
title_sort | tetrabromobisphenol a is an efficient stabilizer of the transthyretin tetramer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836675/ https://www.ncbi.nlm.nih.gov/pubmed/27093678 http://dx.doi.org/10.1371/journal.pone.0153529 |
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