What is the catalytic mechanism of enzymatic histone n-methyl arginine demethylation and can it be influenced by an external electric field?
Arginine methylation is an important mechanism of epigenetic regulation. Some Fe(II) and 2-oxoglutarate dependent Jumonji-C (JmjC) Nϵ-methyl lysine histone demethylases also have N-methyl arginine demethylase activity. We report combined molecular dynamic (MD) and Quantum Mechanical/Molecular Mechan...
| Main Authors: | , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2021
|
| _version_ | 1797106886074433536 |
|---|---|
| author | Ramanan, R Waheed, SO Schofield, CJ Christov, CZ |
| author_facet | Ramanan, R Waheed, SO Schofield, CJ Christov, CZ |
| author_sort | Ramanan, R |
| collection | OXFORD |
| description | Arginine methylation is an important mechanism of epigenetic regulation. Some Fe(II) and 2-oxoglutarate dependent Jumonji-C (JmjC) Nϵ-methyl lysine histone demethylases also have N-methyl arginine demethylase activity. We report combined molecular dynamic (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) studies on the mechanism of N-methyl arginine demethylation by human KDM4E and compare the results with those reported for N-methyl lysine demethylation by KDM4A. At the KDM4E active site, Glu191, Asn291, and Ser197 form a conserved scaffold that restricts substrate dynamics; substrate binding is also mediated by an out of active site hydrogen-bond between the substrate Ser1 and Tyr178. The calculations imply that in either C−H or N−H potential bond cleaving pathways for hydrogen atom transfer (HAT) during N-methyl arginine demethylation, electron transfer occurs via a σ-channel; the transition state for the N−H pathway is ∼10 kcal/mol higher than for the C−H pathway due to the higher bond dissociation energy of the N−H bond. The results of applying external electric fields (EEFs) reveal EEFs with positive field strengths parallel to the Fe=O bond have a significant barrier-lowering effect on the C−H pathway, by contrast, such EEFs inhibit the N−H activation rate. The overall results imply that KDM4 catalyzed N-methyl arginine demethylation and N-methyl lysine demethylation occur via similar C−H abstraction and rebound mechanisms leading to methyl group hydroxylation, though there are differences in the interactions leading to productive binding of intermediates. |
| first_indexed | 2024-03-07T07:08:49Z |
| format | Journal article |
| id | oxford-uuid:25860102-b09a-4001-b068-9977e3c282aa |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:08:49Z |
| publishDate | 2021 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:25860102-b09a-4001-b068-9977e3c282aa2022-06-06T11:06:32ZWhat is the catalytic mechanism of enzymatic histone n-methyl arginine demethylation and can it be influenced by an external electric field?Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:25860102-b09a-4001-b068-9977e3c282aaEnglishSymplectic ElementsWiley2021Ramanan, RWaheed, SOSchofield, CJChristov, CZArginine methylation is an important mechanism of epigenetic regulation. Some Fe(II) and 2-oxoglutarate dependent Jumonji-C (JmjC) Nϵ-methyl lysine histone demethylases also have N-methyl arginine demethylase activity. We report combined molecular dynamic (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) studies on the mechanism of N-methyl arginine demethylation by human KDM4E and compare the results with those reported for N-methyl lysine demethylation by KDM4A. At the KDM4E active site, Glu191, Asn291, and Ser197 form a conserved scaffold that restricts substrate dynamics; substrate binding is also mediated by an out of active site hydrogen-bond between the substrate Ser1 and Tyr178. The calculations imply that in either C−H or N−H potential bond cleaving pathways for hydrogen atom transfer (HAT) during N-methyl arginine demethylation, electron transfer occurs via a σ-channel; the transition state for the N−H pathway is ∼10 kcal/mol higher than for the C−H pathway due to the higher bond dissociation energy of the N−H bond. The results of applying external electric fields (EEFs) reveal EEFs with positive field strengths parallel to the Fe=O bond have a significant barrier-lowering effect on the C−H pathway, by contrast, such EEFs inhibit the N−H activation rate. The overall results imply that KDM4 catalyzed N-methyl arginine demethylation and N-methyl lysine demethylation occur via similar C−H abstraction and rebound mechanisms leading to methyl group hydroxylation, though there are differences in the interactions leading to productive binding of intermediates. |
| spellingShingle | Ramanan, R Waheed, SO Schofield, CJ Christov, CZ What is the catalytic mechanism of enzymatic histone n-methyl arginine demethylation and can it be influenced by an external electric field? |
| title | What is the catalytic mechanism of enzymatic histone n-methyl arginine demethylation and can it be influenced by an external electric field? |
| title_full | What is the catalytic mechanism of enzymatic histone n-methyl arginine demethylation and can it be influenced by an external electric field? |
| title_fullStr | What is the catalytic mechanism of enzymatic histone n-methyl arginine demethylation and can it be influenced by an external electric field? |
| title_full_unstemmed | What is the catalytic mechanism of enzymatic histone n-methyl arginine demethylation and can it be influenced by an external electric field? |
| title_short | What is the catalytic mechanism of enzymatic histone n-methyl arginine demethylation and can it be influenced by an external electric field? |
| title_sort | what is the catalytic mechanism of enzymatic histone n methyl arginine demethylation and can it be influenced by an external electric field |
| work_keys_str_mv | AT ramananr whatisthecatalyticmechanismofenzymatichistonenmethylargininedemethylationandcanitbeinfluencedbyanexternalelectricfield AT waheedso whatisthecatalyticmechanismofenzymatichistonenmethylargininedemethylationandcanitbeinfluencedbyanexternalelectricfield AT schofieldcj whatisthecatalyticmechanismofenzymatichistonenmethylargininedemethylationandcanitbeinfluencedbyanexternalelectricfield AT christovcz whatisthecatalyticmechanismofenzymatichistonenmethylargininedemethylationandcanitbeinfluencedbyanexternalelectricfield |