Investigation of the impact of nonsynonymous mutations on thyroid peroxidase dimer.

Autor: Begum MN; Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, Bangladesh.; Institute for Developing Science and Health Initiatives (ideSHi), ECB Chattar, Mirpur, Dhaka, Bangladesh.; Virology Laboratory, Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Mohakhali, Dhaka, Bangladesh., Mahtarin R; Institute for Developing Science and Health Initiatives (ideSHi), ECB Chattar, Mirpur, Dhaka, Bangladesh.; Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh., Ahmed S; Division of Computer Aided Drug Design, The Red-Green Research Centre, BICCB, Tejgaon, Dhaka, Bangladesh., Shahriar I; Division of Computer Aided Drug Design, The Red-Green Research Centre, BICCB, Tejgaon, Dhaka, Bangladesh., Hossain SR; Institute for Developing Science and Health Initiatives (ideSHi), ECB Chattar, Mirpur, Dhaka, Bangladesh., Mia MW; Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh., Qadri SS; Institute for Developing Science and Health Initiatives (ideSHi), ECB Chattar, Mirpur, Dhaka, Bangladesh., Qadri F; Institute for Developing Science and Health Initiatives (ideSHi), ECB Chattar, Mirpur, Dhaka, Bangladesh.; Mucosal Immunology and Vaccinology, Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Mohakhali, Dhaka, Bangladesh., Mannoor K; Institute for Developing Science and Health Initiatives (ideSHi), ECB Chattar, Mirpur, Dhaka, Bangladesh., Akhteruzzaman S; Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, Bangladesh.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2023 Sep 12; Vol. 18 (9), pp. e0291386. Date of Electronic Publication: 2023 Sep 12 (Print Publication: 2023).
DOI: 10.1371/journal.pone.0291386
Abstrakt: 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 H2O2 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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Begum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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