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Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation

Toxic metals are known to inhibit DNA repair but the underlying mechanisms of inhibition are still not fully understood. DNA repair enzymes such as human uracil-DNA glycosylase (hUNG) perform the initial step in the base excision repair (BER) pathway. In this work, we showed that cadmium [Cd(II)], a...

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Autores principales: Gokey, Trevor, Hang, Bo, Guliaev, Anton B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156901/
https://www.ncbi.nlm.nih.gov/pubmed/27974818
http://dx.doi.org/10.1038/srep39137
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author Gokey, Trevor
Hang, Bo
Guliaev, Anton B.
author_facet Gokey, Trevor
Hang, Bo
Guliaev, Anton B.
author_sort Gokey, Trevor
collection PubMed
description Toxic metals are known to inhibit DNA repair but the underlying mechanisms of inhibition are still not fully understood. DNA repair enzymes such as human uracil-DNA glycosylase (hUNG) perform the initial step in the base excision repair (BER) pathway. In this work, we showed that cadmium [Cd(II)], a known human carcinogen, inhibited all activity of hUNG at 100 μM. Computational analyses based on 2 μs equilibrium, 1.6 μs steered molecular dynamics (SMD), and QM/MM MD determined that Cd(II) ions entered the enzyme active site and formed close contacts with both D145 and H148, effectively replacing the catalytic water normally found in this position. Geometry refinement by density functional theory (DFT) calculations showed that Cd(II) formed a tetrahedral structure with D145, P146, H148, and one water molecule. This work for the first time reports Cd(II) inhibition of hUNG which was due to replacement of the catalytic water by binding the active site D145 and H148 residues. Comparison of the proposed metal binding site to existing structural data showed that D145:H148 followed a general metal binding motif favored by Cd(II). The identified motif offered structural insights into metal inhibition of other DNA repair enzymes and glycosylases.
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spelling pubmed-51569012016-12-20 Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation Gokey, Trevor Hang, Bo Guliaev, Anton B. Sci Rep Article Toxic metals are known to inhibit DNA repair but the underlying mechanisms of inhibition are still not fully understood. DNA repair enzymes such as human uracil-DNA glycosylase (hUNG) perform the initial step in the base excision repair (BER) pathway. In this work, we showed that cadmium [Cd(II)], a known human carcinogen, inhibited all activity of hUNG at 100 μM. Computational analyses based on 2 μs equilibrium, 1.6 μs steered molecular dynamics (SMD), and QM/MM MD determined that Cd(II) ions entered the enzyme active site and formed close contacts with both D145 and H148, effectively replacing the catalytic water normally found in this position. Geometry refinement by density functional theory (DFT) calculations showed that Cd(II) formed a tetrahedral structure with D145, P146, H148, and one water molecule. This work for the first time reports Cd(II) inhibition of hUNG which was due to replacement of the catalytic water by binding the active site D145 and H148 residues. Comparison of the proposed metal binding site to existing structural data showed that D145:H148 followed a general metal binding motif favored by Cd(II). The identified motif offered structural insights into metal inhibition of other DNA repair enzymes and glycosylases. Nature Publishing Group 2016-12-15 /pmc/articles/PMC5156901/ /pubmed/27974818 http://dx.doi.org/10.1038/srep39137 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Gokey, Trevor
Hang, Bo
Guliaev, Anton B.
Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation
title Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation
title_full Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation
title_fullStr Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation
title_full_unstemmed Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation
title_short Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation
title_sort cadmium(ii) inhibition of human uracil-dna glycosylase by catalytic water supplantation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156901/
https://www.ncbi.nlm.nih.gov/pubmed/27974818
http://dx.doi.org/10.1038/srep39137
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