Switching the Switch: Ligand Induced Disulfide Formation in HDAC8
Human histone deacetylase 8 is a well‐recognized target for T‐cell lymphoma and particularly childhood neuroblastoma. PD‐404,182 was shown to be a selective covalent inhibitor of HDAC8 that forms mixed disulfides with several cysteine residues and is also able to transform thiol groups to thiocyanat...
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| Veröffentlicht in: | Chemistry : a European journal 2020-10, Vol.26 (58), p.13249-13255 |
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| creator | Jänsch, Niklas Sugiarto, Wisely Oki Muth, Marius Kopranovic, Aleksandra Desczyk, Charlotte Ballweg, Matthias Kirschhöfer, Frank Brenner‐Weiss, Gerald Meyer‐Almes, Franz‐Josef |
| description | Human histone deacetylase 8 is a well‐recognized target for T‐cell lymphoma and particularly childhood neuroblastoma. PD‐404,182 was shown to be a selective covalent inhibitor of HDAC8 that forms mixed disulfides with several cysteine residues and is also able to transform thiol groups to thiocyanates. Moreover, HDAC8 was shown to be regulated by a redox switch based on the reversible formation of a disulfide bond between cysteines Cys102 and Cys153. This study on the distinct effects of PD‐404,182 on HDAC8 reveals that this compound induces the dose‐dependent formation of intramolecular disulfide bridges. Therefore, the inhibition mechanism of HDAC8 by PD‐404,182 involves both, covalent modification of thiols as well as ligand mediated disulfide formation. Moreover, this study provides a deep molecular insight into the regulation mechanism of HDAC8 involving several cysteines with graduated capability to form reversible disulfide bridges.
Regulated by a redox switch: PD‐404,182 has been evaluated as an isoenzyme selective covalent inhibitor of HDAC8. HDAC8 belongs to the enzyme family of zinc‐dependent histone deacetylases and is known to be regulated by a redox switch. The enzyme plays an important role in several cancer diseases and particularly childhood neuroblastoma. This study provides deep insight in how HDAC8 enzyme activity is regulated by disulfide bonds induced by PD‐404,182. |
| doi_str_mv | 10.1002/chem.202001712 |
| format | Article |
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Regulated by a redox switch: PD‐404,182 has been evaluated as an isoenzyme selective covalent inhibitor of HDAC8. HDAC8 belongs to the enzyme family of zinc‐dependent histone deacetylases and is known to be regulated by a redox switch. The enzyme plays an important role in several cancer diseases and particularly childhood neuroblastoma. This study provides deep insight in how HDAC8 enzyme activity is regulated by disulfide bonds induced by PD‐404,182.</description><identifier>ISSN: 0947-6539</identifier><identifier>EISSN: 1521-3765</identifier><identifier>DOI: 10.1002/chem.202001712</identifier><identifier>PMID: 32428298</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Bridges ; Chemistry ; Children ; covalent inhibitors ; cysteine ; HDAC8 ; Histone deacetylase ; Ligands ; Lymphoma ; Mixed disulfides ; Neuroblastoma ; redox switch ; sulfenamides ; Target recognition ; Thiocyanates ; Thiols</subject><ispartof>Chemistry : a European journal, 2020-10, Vol.26 (58), p.13249-13255</ispartof><rights>2020 The Authors. Published by Wiley-VCH GmbH</rights><rights>2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5052-c4d057a1eebfb4aff0884d968c4c68bd1cfaed13e4106013dfbfcb2cffa7f5293</citedby><cites>FETCH-LOGICAL-c5052-c4d057a1eebfb4aff0884d968c4c68bd1cfaed13e4106013dfbfcb2cffa7f5293</cites><orcidid>0000-0002-1001-3249</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fchem.202001712$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fchem.202001712$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32428298$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jänsch, Niklas</creatorcontrib><creatorcontrib>Sugiarto, Wisely Oki</creatorcontrib><creatorcontrib>Muth, Marius</creatorcontrib><creatorcontrib>Kopranovic, Aleksandra</creatorcontrib><creatorcontrib>Desczyk, Charlotte</creatorcontrib><creatorcontrib>Ballweg, Matthias</creatorcontrib><creatorcontrib>Kirschhöfer, Frank</creatorcontrib><creatorcontrib>Brenner‐Weiss, Gerald</creatorcontrib><creatorcontrib>Meyer‐Almes, Franz‐Josef</creatorcontrib><title>Switching the Switch: Ligand Induced Disulfide Formation in HDAC8</title><title>Chemistry : a European journal</title><addtitle>Chemistry</addtitle><description>Human histone deacetylase 8 is a well‐recognized target for T‐cell lymphoma and particularly childhood neuroblastoma. PD‐404,182 was shown to be a selective covalent inhibitor of HDAC8 that forms mixed disulfides with several cysteine residues and is also able to transform thiol groups to thiocyanates. Moreover, HDAC8 was shown to be regulated by a redox switch based on the reversible formation of a disulfide bond between cysteines Cys102 and Cys153. This study on the distinct effects of PD‐404,182 on HDAC8 reveals that this compound induces the dose‐dependent formation of intramolecular disulfide bridges. Therefore, the inhibition mechanism of HDAC8 by PD‐404,182 involves both, covalent modification of thiols as well as ligand mediated disulfide formation. Moreover, this study provides a deep molecular insight into the regulation mechanism of HDAC8 involving several cysteines with graduated capability to form reversible disulfide bridges.
Regulated by a redox switch: PD‐404,182 has been evaluated as an isoenzyme selective covalent inhibitor of HDAC8. HDAC8 belongs to the enzyme family of zinc‐dependent histone deacetylases and is known to be regulated by a redox switch. The enzyme plays an important role in several cancer diseases and particularly childhood neuroblastoma. This study provides deep insight in how HDAC8 enzyme activity is regulated by disulfide bonds induced by PD‐404,182.</description><subject>Bridges</subject><subject>Chemistry</subject><subject>Children</subject><subject>covalent inhibitors</subject><subject>cysteine</subject><subject>HDAC8</subject><subject>Histone deacetylase</subject><subject>Ligands</subject><subject>Lymphoma</subject><subject>Mixed disulfides</subject><subject>Neuroblastoma</subject><subject>redox switch</subject><subject>sulfenamides</subject><subject>Target recognition</subject><subject>Thiocyanates</subject><subject>Thiols</subject><issn>0947-6539</issn><issn>1521-3765</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNqFkctP3DAQhy1UBAvttccqUi9csoyfsXuotFoei7RVD23PluPHrlHi0DgB8d8TtLC0vfQ0Gs03n2b0Q-gjhjkGIOd269s5AQKAK0wO0AxzgktaCf4OzUCxqhScqmN0kvMtAChB6RE6poQRSZScocWPhzjYbUybYtj6Ytd9KdZxY5IrbpIbrXfFRcxjE6LzxVXXt2aIXSpiKlYXi6V8jw6DabL_8FJP0a-ry5_LVbn-fn2zXKxLy4GT0jIHvDLY-zrUzIQAUjKnhLTMClk7bIPxDlPPMAjA1IU62JrYEEwVOFH0FH3dee_GuvXO-jT0ptF3fWxN_6g7E_XfkxS3etPd60ooopicBGcvgr77Pfo86DZm65vGJN-NWRMGnEIliJjQz_-gt93Yp-m9ieIY44pIPFHzHWX7Lufeh_0xGPRzOvo5Hb1PZ1r49OcLe_w1jglQO-AhNv7xPzq9XF1-e5M_AcLOm_M</recordid><startdate>20201015</startdate><enddate>20201015</enddate><creator>Jänsch, Niklas</creator><creator>Sugiarto, Wisely Oki</creator><creator>Muth, Marius</creator><creator>Kopranovic, Aleksandra</creator><creator>Desczyk, Charlotte</creator><creator>Ballweg, Matthias</creator><creator>Kirschhöfer, Frank</creator><creator>Brenner‐Weiss, Gerald</creator><creator>Meyer‐Almes, Franz‐Josef</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1001-3249</orcidid></search><sort><creationdate>20201015</creationdate><title>Switching the Switch: Ligand Induced Disulfide Formation in HDAC8</title><author>Jänsch, Niklas ; Sugiarto, Wisely Oki ; Muth, Marius ; Kopranovic, Aleksandra ; Desczyk, Charlotte ; Ballweg, Matthias ; Kirschhöfer, Frank ; Brenner‐Weiss, Gerald ; Meyer‐Almes, Franz‐Josef</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5052-c4d057a1eebfb4aff0884d968c4c68bd1cfaed13e4106013dfbfcb2cffa7f5293</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Bridges</topic><topic>Chemistry</topic><topic>Children</topic><topic>covalent inhibitors</topic><topic>cysteine</topic><topic>HDAC8</topic><topic>Histone deacetylase</topic><topic>Ligands</topic><topic>Lymphoma</topic><topic>Mixed disulfides</topic><topic>Neuroblastoma</topic><topic>redox switch</topic><topic>sulfenamides</topic><topic>Target recognition</topic><topic>Thiocyanates</topic><topic>Thiols</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jänsch, Niklas</creatorcontrib><creatorcontrib>Sugiarto, Wisely Oki</creatorcontrib><creatorcontrib>Muth, Marius</creatorcontrib><creatorcontrib>Kopranovic, Aleksandra</creatorcontrib><creatorcontrib>Desczyk, Charlotte</creatorcontrib><creatorcontrib>Ballweg, Matthias</creatorcontrib><creatorcontrib>Kirschhöfer, Frank</creatorcontrib><creatorcontrib>Brenner‐Weiss, Gerald</creatorcontrib><creatorcontrib>Meyer‐Almes, Franz‐Josef</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Chemistry : a European journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jänsch, Niklas</au><au>Sugiarto, Wisely Oki</au><au>Muth, Marius</au><au>Kopranovic, Aleksandra</au><au>Desczyk, Charlotte</au><au>Ballweg, Matthias</au><au>Kirschhöfer, Frank</au><au>Brenner‐Weiss, Gerald</au><au>Meyer‐Almes, Franz‐Josef</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Switching the Switch: Ligand Induced Disulfide Formation in HDAC8</atitle><jtitle>Chemistry : a European journal</jtitle><addtitle>Chemistry</addtitle><date>2020-10-15</date><risdate>2020</risdate><volume>26</volume><issue>58</issue><spage>13249</spage><epage>13255</epage><pages>13249-13255</pages><issn>0947-6539</issn><eissn>1521-3765</eissn><abstract>Human histone deacetylase 8 is a well‐recognized target for T‐cell lymphoma and particularly childhood neuroblastoma. 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| subjects | Bridges Chemistry Children covalent inhibitors cysteine HDAC8 Histone deacetylase Ligands Lymphoma Mixed disulfides Neuroblastoma redox switch sulfenamides Target recognition Thiocyanates Thiols |
| title | Switching the Switch: Ligand Induced Disulfide Formation in HDAC8 |
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