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Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer
Congenital hypothyroidism is one of the most common preventable endocrine disorders associated with thyroid dysgenesis or dyshormonogenesis. Thyroid peroxidase (TPO) gene defect is mainly responsible for dyshormonogenesis; a defect in the thyroid hormone biosynthesis pathway. In Bangladesh, there is...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10497151/ https://www.ncbi.nlm.nih.gov/pubmed/37699049 http://dx.doi.org/10.1371/journal.pone.0291386 |
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author | Begum, Mst. Noorjahan Mahtarin, Rumana Ahmed, Sinthyia Shahriar, Imrul Hossain, Shekh Rezwan Mia, Md. Waseque Qadri, Syed Saleheen Qadri, Firdausi Mannoor, Kaiissar Akhteruzzaman, Sharif |
author_facet | Begum, Mst. Noorjahan Mahtarin, Rumana Ahmed, Sinthyia Shahriar, Imrul Hossain, Shekh Rezwan Mia, Md. Waseque Qadri, Syed Saleheen Qadri, Firdausi Mannoor, Kaiissar Akhteruzzaman, Sharif |
author_sort | Begum, Mst. Noorjahan |
collection | PubMed |
description | Congenital hypothyroidism is one of the most common preventable endocrine disorders associated with thyroid dysgenesis or dyshormonogenesis. Thyroid peroxidase (TPO) gene defect is mainly responsible for dyshormonogenesis; a defect in the thyroid hormone biosynthesis pathway. In Bangladesh, there is limited data regarding the genetic etiology of Congenital Hypothyroidism (CH). The present study investigates the impact of the detected mutations (p.Ala373Ser, and p.Thr725Pro) on the TPO dimer protein. We have performed sequential molecular docking of H(2)O(2) and I(-) ligands with both monomers of TPO dimer to understand the iodination process in thyroid hormone biosynthesis. Understanding homodimer interactions at the atomic level is a critical challenge to elucidate their biological mechanisms of action. The docking results reveal that mutations in the dimer severely disrupt its catalytic interaction with essential ligands. Molecular dynamics simulation has been performed to validate the docking results, thus realizing the consequence of the mutation in the biological system’s mimic. The dynamics results expose that mutations destabilize the TPO dimer protein. Finally, principal component analysis exhibits structural and energy profile discrepancies in wild-type and mutant dimers. The findings of this study highlight that the mutations in TPO protein can critically affect the dimer structure and loss of enzymatic activity is persistent. Other factors also might influence the hormone synthesis pathway, which is under investigation. |
format | Online Article Text |
id | pubmed-10497151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-104971512023-09-13 Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer Begum, Mst. Noorjahan Mahtarin, Rumana Ahmed, Sinthyia Shahriar, Imrul Hossain, Shekh Rezwan Mia, Md. Waseque Qadri, Syed Saleheen Qadri, Firdausi Mannoor, Kaiissar Akhteruzzaman, Sharif PLoS One Research Article Congenital hypothyroidism is one of the most common preventable endocrine disorders associated with thyroid dysgenesis or dyshormonogenesis. Thyroid peroxidase (TPO) gene defect is mainly responsible for dyshormonogenesis; a defect in the thyroid hormone biosynthesis pathway. In Bangladesh, there is limited data regarding the genetic etiology of Congenital Hypothyroidism (CH). The present study investigates the impact of the detected mutations (p.Ala373Ser, and p.Thr725Pro) on the TPO dimer protein. We have performed sequential molecular docking of H(2)O(2) and I(-) ligands with both monomers of TPO dimer to understand the iodination process in thyroid hormone biosynthesis. Understanding homodimer interactions at the atomic level is a critical challenge to elucidate their biological mechanisms of action. The docking results reveal that mutations in the dimer severely disrupt its catalytic interaction with essential ligands. Molecular dynamics simulation has been performed to validate the docking results, thus realizing the consequence of the mutation in the biological system’s mimic. The dynamics results expose that mutations destabilize the TPO dimer protein. Finally, principal component analysis exhibits structural and energy profile discrepancies in wild-type and mutant dimers. The findings of this study highlight that the mutations in TPO protein can critically affect the dimer structure and loss of enzymatic activity is persistent. Other factors also might influence the hormone synthesis pathway, which is under investigation. Public Library of Science 2023-09-12 /pmc/articles/PMC10497151/ /pubmed/37699049 http://dx.doi.org/10.1371/journal.pone.0291386 Text en © 2023 Begum et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://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 Begum, Mst. Noorjahan Mahtarin, Rumana Ahmed, Sinthyia Shahriar, Imrul Hossain, Shekh Rezwan Mia, Md. Waseque Qadri, Syed Saleheen Qadri, Firdausi Mannoor, Kaiissar Akhteruzzaman, Sharif Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer |
title | Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer |
title_full | Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer |
title_fullStr | Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer |
title_full_unstemmed | Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer |
title_short | Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer |
title_sort | investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10497151/ https://www.ncbi.nlm.nih.gov/pubmed/37699049 http://dx.doi.org/10.1371/journal.pone.0291386 |
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