On the histone lysine methyltransferase activity of fungal metabolite chaetocin.
Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 an...
| প্রধান লেখক: | , , , , , , , , , , , |
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| বিন্যাস: | Journal article |
| ভাষা: | English |
| প্রকাশিত: |
2013
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| _version_ | 1826261351216971776 |
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| author | Cherblanc, F Chapman, K Reid, J Borg, A Sundriyal, S Alcazar-Fuoli, L Bignell, E Demetriades, M Schofield, C DiMaggio, P Brown, R Fuchter, M |
| author_facet | Cherblanc, F Chapman, K Reid, J Borg, A Sundriyal, S Alcazar-Fuoli, L Bignell, E Demetriades, M Schofield, C DiMaggio, P Brown, R Fuchter, M |
| author_sort | Cherblanc, F |
| collection | OXFORD |
| description | Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally related analogues. Our results reveal that only the structurally unique ETP core is required for inhibition, and such inhibition is time-dependent and irreversible (in the absence of DTT), ultimately resulting in protein denaturation. Mass spectrometric data provide a molecular basis for this effect, demonstrating covalent adduct formation between 1 and the protein. This provides a potential rationale for the selectivity observed in the inhibition of a variety of HKMTs by 1 in vitro and has implications for the activity of ETPs against these important epigenetic targets. |
| first_indexed | 2024-03-06T19:20:01Z |
| format | Journal article |
| id | oxford-uuid:19c20c44-79eb-48ce-bb47-ce171bb48ce1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:20:01Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:19c20c44-79eb-48ce-bb47-ce171bb48ce12022-03-26T10:50:46ZOn the histone lysine methyltransferase activity of fungal metabolite chaetocin.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:19c20c44-79eb-48ce-bb47-ce171bb48ce1EnglishSymplectic Elements at Oxford2013Cherblanc, FChapman, KReid, JBorg, ASundriyal, SAlcazar-Fuoli, LBignell, EDemetriades, MSchofield, CDiMaggio, PBrown, RFuchter, MHistone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally related analogues. Our results reveal that only the structurally unique ETP core is required for inhibition, and such inhibition is time-dependent and irreversible (in the absence of DTT), ultimately resulting in protein denaturation. Mass spectrometric data provide a molecular basis for this effect, demonstrating covalent adduct formation between 1 and the protein. This provides a potential rationale for the selectivity observed in the inhibition of a variety of HKMTs by 1 in vitro and has implications for the activity of ETPs against these important epigenetic targets. |
| spellingShingle | Cherblanc, F Chapman, K Reid, J Borg, A Sundriyal, S Alcazar-Fuoli, L Bignell, E Demetriades, M Schofield, C DiMaggio, P Brown, R Fuchter, M On the histone lysine methyltransferase activity of fungal metabolite chaetocin. |
| title | On the histone lysine methyltransferase activity of fungal metabolite chaetocin. |
| title_full | On the histone lysine methyltransferase activity of fungal metabolite chaetocin. |
| title_fullStr | On the histone lysine methyltransferase activity of fungal metabolite chaetocin. |
| title_full_unstemmed | On the histone lysine methyltransferase activity of fungal metabolite chaetocin. |
| title_short | On the histone lysine methyltransferase activity of fungal metabolite chaetocin. |
| title_sort | on the histone lysine methyltransferase activity of fungal metabolite chaetocin |
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