Mapping the Intramolecular Communications among Different Glutamate Dehydrogenase States Using Molecular Dynamics
Glutamate dehydrogenase (GDH) is a ubiquitous enzyme that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate. It acts as an important branch-point enzyme between carbon and nitrogen metabolisms. Due to the multifaceted roles of GDH in cancer, hyperinsulinism/hyperammonemi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/6/798 |
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| author | Shaherin Basith Balachandran Manavalan Tae Hwan Shin Gwang Lee |
| author_facet | Shaherin Basith Balachandran Manavalan Tae Hwan Shin Gwang Lee |
| author_sort | Shaherin Basith |
| collection | DOAJ |
| description | Glutamate dehydrogenase (GDH) is a ubiquitous enzyme that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate. It acts as an important branch-point enzyme between carbon and nitrogen metabolisms. Due to the multifaceted roles of GDH in cancer, hyperinsulinism/hyperammonemia, and central nervous system development and pathologies, tight control of its activity is necessitated. To date, several GDH structures have been solved in its closed form; however, intrinsic structural information in its open and apo forms are still deficient. Moreover, the allosteric communications and conformational changes taking place in the three different GDH states are not well studied. To mitigate these drawbacks, we applied unbiased molecular dynamic simulations (MD) and network analysis to three different GDH states i.e., apo, active, and inactive forms, for investigating their modulatory mechanisms. In this paper, based on MD and network analysis, crucial residues important for signal transduction, conformational changes, and maps of information flow among the different GDH states were elucidated. Moreover, with the recent findings of allosteric modulators, an allosteric wiring illustration of GDH intramolecular signal transductions would be of paramount importance to obtain the process of this enzyme regulation. The structural insights gained from this study will pave way for large-scale screening of GDH regulators and could support researchers in the design and development of new and potent GDH ligands. |
| first_indexed | 2024-03-10T10:58:31Z |
| format | Article |
| id | doaj.art-65da74a05b084bc9b271fcb072bf18e5 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T10:58:31Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-65da74a05b084bc9b271fcb072bf18e52023-11-21T21:41:53ZengMDPI AGBiomolecules2218-273X2021-05-0111679810.3390/biom11060798Mapping the Intramolecular Communications among Different Glutamate Dehydrogenase States Using Molecular DynamicsShaherin Basith0Balachandran Manavalan1Tae Hwan Shin2Gwang Lee3Department of Physiology, School of Medicine, Ajou University, Suwon 16499, KoreaDepartment of Physiology, School of Medicine, Ajou University, Suwon 16499, KoreaDepartment of Physiology, School of Medicine, Ajou University, Suwon 16499, KoreaDepartment of Physiology, School of Medicine, Ajou University, Suwon 16499, KoreaGlutamate dehydrogenase (GDH) is a ubiquitous enzyme that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate. It acts as an important branch-point enzyme between carbon and nitrogen metabolisms. Due to the multifaceted roles of GDH in cancer, hyperinsulinism/hyperammonemia, and central nervous system development and pathologies, tight control of its activity is necessitated. To date, several GDH structures have been solved in its closed form; however, intrinsic structural information in its open and apo forms are still deficient. Moreover, the allosteric communications and conformational changes taking place in the three different GDH states are not well studied. To mitigate these drawbacks, we applied unbiased molecular dynamic simulations (MD) and network analysis to three different GDH states i.e., apo, active, and inactive forms, for investigating their modulatory mechanisms. In this paper, based on MD and network analysis, crucial residues important for signal transduction, conformational changes, and maps of information flow among the different GDH states were elucidated. Moreover, with the recent findings of allosteric modulators, an allosteric wiring illustration of GDH intramolecular signal transductions would be of paramount importance to obtain the process of this enzyme regulation. The structural insights gained from this study will pave way for large-scale screening of GDH regulators and could support researchers in the design and development of new and potent GDH ligands.https://www.mdpi.com/2218-273X/11/6/798glutamate dehydrogenaseenzymemolecular dynamicsnetwork analysisallosteryregulation |
| spellingShingle | Shaherin Basith Balachandran Manavalan Tae Hwan Shin Gwang Lee Mapping the Intramolecular Communications among Different Glutamate Dehydrogenase States Using Molecular Dynamics Biomolecules glutamate dehydrogenase enzyme molecular dynamics network analysis allostery regulation |
| title | Mapping the Intramolecular Communications among Different Glutamate Dehydrogenase States Using Molecular Dynamics |
| title_full | Mapping the Intramolecular Communications among Different Glutamate Dehydrogenase States Using Molecular Dynamics |
| title_fullStr | Mapping the Intramolecular Communications among Different Glutamate Dehydrogenase States Using Molecular Dynamics |
| title_full_unstemmed | Mapping the Intramolecular Communications among Different Glutamate Dehydrogenase States Using Molecular Dynamics |
| title_short | Mapping the Intramolecular Communications among Different Glutamate Dehydrogenase States Using Molecular Dynamics |
| title_sort | mapping the intramolecular communications among different glutamate dehydrogenase states using molecular dynamics |
| topic | glutamate dehydrogenase enzyme molecular dynamics network analysis allostery regulation |
| url | https://www.mdpi.com/2218-273X/11/6/798 |
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