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Determination of the Bridging Ligand in the Active Site of Tyrosinase
Tyrosinase is a type-3 copper enzyme that is widely distributed in plants, fungi, insects, and mammals. Developing high potent inhibitors against tyrosinase is of great interest in diverse fields including tobacco curing, food processing, bio-insecticides development, cosmetic development, and human...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150207/ https://www.ncbi.nlm.nih.gov/pubmed/29143758 http://dx.doi.org/10.3390/molecules22111836 |
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author | Zou, Congming Huang, Wei Zhao, Gaokun Wan, Xiao Hu, Xiaodong Jin, Yan Li, Junying Liu, Junjun |
author_facet | Zou, Congming Huang, Wei Zhao, Gaokun Wan, Xiao Hu, Xiaodong Jin, Yan Li, Junying Liu, Junjun |
author_sort | Zou, Congming |
collection | PubMed |
description | Tyrosinase is a type-3 copper enzyme that is widely distributed in plants, fungi, insects, and mammals. Developing high potent inhibitors against tyrosinase is of great interest in diverse fields including tobacco curing, food processing, bio-insecticides development, cosmetic development, and human healthcare-related research. In the crystal structure of Agaricus bisporus mushroom tyrosinase, there is an oxygen atom bridging the two copper ions in the active site. It is unclear whether the identity of this bridging oxygen is a water molecule or a hydroxide anion. In the present study, we theoretically determine the identity of this critical bridging oxygen by performing first-principles hybrid quantum mechanics/molecular mechanics/Poisson-Boltzmann-surface area (QM/MM-PBSA) calculations along with a thermodynamic cycle that aim to improve the accuracy. Our results show that the binding with water molecule is energy favored and the QM/MM-optimized structure is very close to the crystal structure, whereas the binding with hydroxide anions causes the increase of energy and significant structural changes of the active site, indicating that the identity of the bridging oxygen must be a water molecule rather than a hydroxide anion. The different binding behavior between water and hydroxide anions may explain why molecules with a carboxyl group or too many negative charges have lower inhibitory activity. In light of this, the design of high potent active inhibitors against tyrosinase should satisfy both the affinity to the copper ions and the charge neutrality of the entire molecule. |
format | Online Article Text |
id | pubmed-6150207 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61502072018-11-13 Determination of the Bridging Ligand in the Active Site of Tyrosinase Zou, Congming Huang, Wei Zhao, Gaokun Wan, Xiao Hu, Xiaodong Jin, Yan Li, Junying Liu, Junjun Molecules Article Tyrosinase is a type-3 copper enzyme that is widely distributed in plants, fungi, insects, and mammals. Developing high potent inhibitors against tyrosinase is of great interest in diverse fields including tobacco curing, food processing, bio-insecticides development, cosmetic development, and human healthcare-related research. In the crystal structure of Agaricus bisporus mushroom tyrosinase, there is an oxygen atom bridging the two copper ions in the active site. It is unclear whether the identity of this bridging oxygen is a water molecule or a hydroxide anion. In the present study, we theoretically determine the identity of this critical bridging oxygen by performing first-principles hybrid quantum mechanics/molecular mechanics/Poisson-Boltzmann-surface area (QM/MM-PBSA) calculations along with a thermodynamic cycle that aim to improve the accuracy. Our results show that the binding with water molecule is energy favored and the QM/MM-optimized structure is very close to the crystal structure, whereas the binding with hydroxide anions causes the increase of energy and significant structural changes of the active site, indicating that the identity of the bridging oxygen must be a water molecule rather than a hydroxide anion. The different binding behavior between water and hydroxide anions may explain why molecules with a carboxyl group or too many negative charges have lower inhibitory activity. In light of this, the design of high potent active inhibitors against tyrosinase should satisfy both the affinity to the copper ions and the charge neutrality of the entire molecule. MDPI 2017-10-27 /pmc/articles/PMC6150207/ /pubmed/29143758 http://dx.doi.org/10.3390/molecules22111836 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zou, Congming Huang, Wei Zhao, Gaokun Wan, Xiao Hu, Xiaodong Jin, Yan Li, Junying Liu, Junjun Determination of the Bridging Ligand in the Active Site of Tyrosinase |
title | Determination of the Bridging Ligand in the Active Site of Tyrosinase |
title_full | Determination of the Bridging Ligand in the Active Site of Tyrosinase |
title_fullStr | Determination of the Bridging Ligand in the Active Site of Tyrosinase |
title_full_unstemmed | Determination of the Bridging Ligand in the Active Site of Tyrosinase |
title_short | Determination of the Bridging Ligand in the Active Site of Tyrosinase |
title_sort | determination of the bridging ligand in the active site of tyrosinase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150207/ https://www.ncbi.nlm.nih.gov/pubmed/29143758 http://dx.doi.org/10.3390/molecules22111836 |
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