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A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism
The different steps of the human Top1 (topoisomerase I) catalytic cycle have been analysed in the presence of a pentacyclic-diquinoid synthetic compound. The experiments indicate that it efficiently inhibits the cleavage step of the enzyme reaction, fitting well into the catalytic site. Surprisingly...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590572/ https://www.ncbi.nlm.nih.gov/pubmed/23368812 http://dx.doi.org/10.1042/BSR20120118 |
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author | Arnò, Barbara Coletta, Andrea Tesauro, Cinzia Zuccaro, Laura Fiorani, Paola Lentini, Sara Galloni, Pierluca Conte, Valeria Floris, Barbara Desideri, Alessandro |
author_facet | Arnò, Barbara Coletta, Andrea Tesauro, Cinzia Zuccaro, Laura Fiorani, Paola Lentini, Sara Galloni, Pierluca Conte, Valeria Floris, Barbara Desideri, Alessandro |
author_sort | Arnò, Barbara |
collection | PubMed |
description | The different steps of the human Top1 (topoisomerase I) catalytic cycle have been analysed in the presence of a pentacyclic-diquinoid synthetic compound. The experiments indicate that it efficiently inhibits the cleavage step of the enzyme reaction, fitting well into the catalytic site. Surprisingly the compound, when incubated with the binary topoisomerase–DNA cleaved complex, helps the enzyme to remove itself from the cleaved DNA and close the DNA gap, increasing the religation rate. The compound also induces the religation of the stalled enzyme–CPT (camptothecin)–DNA ternary complex. Analysis of the molecule docked over the binary complex, together with its chemical properties, suggests that the religation enhancement is due to the presence on the compound of two oxygen atoms that act as hydrogen acceptors. This property facilitates the deprotonation of the 5′ DNA end, suggesting that this is the limiting step in the topoisomerase religation mechanism. |
format | Online Article Text |
id | pubmed-3590572 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-35905722013-03-12 A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism Arnò, Barbara Coletta, Andrea Tesauro, Cinzia Zuccaro, Laura Fiorani, Paola Lentini, Sara Galloni, Pierluca Conte, Valeria Floris, Barbara Desideri, Alessandro Biosci Rep Original Paper The different steps of the human Top1 (topoisomerase I) catalytic cycle have been analysed in the presence of a pentacyclic-diquinoid synthetic compound. The experiments indicate that it efficiently inhibits the cleavage step of the enzyme reaction, fitting well into the catalytic site. Surprisingly the compound, when incubated with the binary topoisomerase–DNA cleaved complex, helps the enzyme to remove itself from the cleaved DNA and close the DNA gap, increasing the religation rate. The compound also induces the religation of the stalled enzyme–CPT (camptothecin)–DNA ternary complex. Analysis of the molecule docked over the binary complex, together with its chemical properties, suggests that the religation enhancement is due to the presence on the compound of two oxygen atoms that act as hydrogen acceptors. This property facilitates the deprotonation of the 5′ DNA end, suggesting that this is the limiting step in the topoisomerase religation mechanism. Portland Press Ltd. 2013-03-07 /pmc/articles/PMC3590572/ /pubmed/23368812 http://dx.doi.org/10.1042/BSR20120118 Text en © 2013 The Author(s). http://creativecommons.org/licenses/by-nc/2.5/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Paper Arnò, Barbara Coletta, Andrea Tesauro, Cinzia Zuccaro, Laura Fiorani, Paola Lentini, Sara Galloni, Pierluca Conte, Valeria Floris, Barbara Desideri, Alessandro A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism |
title | A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism |
title_full | A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism |
title_fullStr | A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism |
title_full_unstemmed | A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism |
title_short | A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism |
title_sort | small organic compound enhances the religation reaction of human topoisomerase i and identifies crucial elements for the religation mechanism |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590572/ https://www.ncbi.nlm.nih.gov/pubmed/23368812 http://dx.doi.org/10.1042/BSR20120118 |
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