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In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology
The L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene encodes an important mitochondrial enzyme. However, its altered activity results in excessive levels of L-2-hydroxyglutarate, which results in diverse psychiatric features of intellectual disability. In the current study, we executed an in-silico...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028441/ https://www.ncbi.nlm.nih.gov/pubmed/35456504 http://dx.doi.org/10.3390/genes13040698 |
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author | Muzammal, Muhammad Di Cerbo, Alessandro Almusalami, Eman M. Farid, Arshad Khan, Muzammil Ahmad Ghazanfar, Shakira Al Mohaini, Mohammed Alsalman, Abdulkhaliq J. Alhashem, Yousef N. Al Hawaj, Maitham A. Alsaleh, Abdulmonem A. |
author_facet | Muzammal, Muhammad Di Cerbo, Alessandro Almusalami, Eman M. Farid, Arshad Khan, Muzammil Ahmad Ghazanfar, Shakira Al Mohaini, Mohammed Alsalman, Abdulkhaliq J. Alhashem, Yousef N. Al Hawaj, Maitham A. Alsaleh, Abdulmonem A. |
author_sort | Muzammal, Muhammad |
collection | PubMed |
description | The L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene encodes an important mitochondrial enzyme. However, its altered activity results in excessive levels of L-2-hydroxyglutarate, which results in diverse psychiatric features of intellectual disability. In the current study, we executed an in-silico analysis of all reported L2HGDH missense and nonsense variants in order to investigate their biological significance. Among the superimposed 3D models, the highest similarity index for a wild-type structure was shown by the mutant Glu336Lys (87.26%), while the lowest similarity index value was shown by Arg70* (10.00%). Three large active site pockets were determined using protein active site prediction, in which the 2nd largest pocket was shown to encompass the substrate L-2-hydroxyglutarate (L2HG) binding residues, i.e., 89Gln, 195Tyr, 402Ala, 403Gly and 404Val. Moreover, interactions of wild-type and mutant L2HGDH variants with the close functional interactor D2HGDH protein resulted in alterations in the position, number and nature of networking residues. We observed that the binding of L2HG with the L2HGDH enzyme is affected by the nature of the amino acid substitution, as well as the number and nature of bonds between the substrate and protein molecule, which are able to affect its biological activity. |
format | Online Article Text |
id | pubmed-9028441 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-90284412022-04-23 In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology Muzammal, Muhammad Di Cerbo, Alessandro Almusalami, Eman M. Farid, Arshad Khan, Muzammil Ahmad Ghazanfar, Shakira Al Mohaini, Mohammed Alsalman, Abdulkhaliq J. Alhashem, Yousef N. Al Hawaj, Maitham A. Alsaleh, Abdulmonem A. Genes (Basel) Article The L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene encodes an important mitochondrial enzyme. However, its altered activity results in excessive levels of L-2-hydroxyglutarate, which results in diverse psychiatric features of intellectual disability. In the current study, we executed an in-silico analysis of all reported L2HGDH missense and nonsense variants in order to investigate their biological significance. Among the superimposed 3D models, the highest similarity index for a wild-type structure was shown by the mutant Glu336Lys (87.26%), while the lowest similarity index value was shown by Arg70* (10.00%). Three large active site pockets were determined using protein active site prediction, in which the 2nd largest pocket was shown to encompass the substrate L-2-hydroxyglutarate (L2HG) binding residues, i.e., 89Gln, 195Tyr, 402Ala, 403Gly and 404Val. Moreover, interactions of wild-type and mutant L2HGDH variants with the close functional interactor D2HGDH protein resulted in alterations in the position, number and nature of networking residues. We observed that the binding of L2HG with the L2HGDH enzyme is affected by the nature of the amino acid substitution, as well as the number and nature of bonds between the substrate and protein molecule, which are able to affect its biological activity. MDPI 2022-04-15 /pmc/articles/PMC9028441/ /pubmed/35456504 http://dx.doi.org/10.3390/genes13040698 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Muzammal, Muhammad Di Cerbo, Alessandro Almusalami, Eman M. Farid, Arshad Khan, Muzammil Ahmad Ghazanfar, Shakira Al Mohaini, Mohammed Alsalman, Abdulkhaliq J. Alhashem, Yousef N. Al Hawaj, Maitham A. Alsaleh, Abdulmonem A. In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology |
title | In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology |
title_full | In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology |
title_fullStr | In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology |
title_full_unstemmed | In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology |
title_short | In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology |
title_sort | in silico analysis of the l-2-hydroxyglutarate dehydrogenase gene mutations and their biological impact on disease etiology |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028441/ https://www.ncbi.nlm.nih.gov/pubmed/35456504 http://dx.doi.org/10.3390/genes13040698 |
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