A small molecule inhibitor of fungal histone acetyltransferase Rtt109
The histone acetyltransferase R1109 is required for pathogenesis in several clinically important fungal species. Via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of R1109 that does not inhibit other acetyltransferase enzymes such as the yeast Gcn5 or...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-05, Vol.23 (10), p.2853-2859 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Lopes da Rosa, Jessica Bajaj, Vineeta Spoonamore, James Kaufman, Paul D. |
| description | The histone acetyltransferase R1109 is required for pathogenesis in several clinically important fungal species. Via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of R1109 that does not inhibit other acetyltransferase enzymes such as the yeast Gcn5 or human p300 enzymes.
The histone acetyltransferase Rtt109 is the sole enzyme responsible for acetylation of histone H3 lysine 56 (H3K56) in fungal organisms. Loss of Rtt109 renders fungal cells extremely sensitive to genotoxic agents, and prevents pathogenesis in several clinically important species. Here, via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of Rtt109 that does not inhibit other acetyltransferase enzymes. This compound inhibits Rtt109 regardless of which histone chaperone cofactor protein (Asf1 or Vps75) is present, and appears to inhibit Rtt109 via a tight-binding, uncompetitive mechanism. |
| doi_str_mv | 10.1016/j.bmcl.2013.03.112 |
| format | Article |
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The histone acetyltransferase Rtt109 is the sole enzyme responsible for acetylation of histone H3 lysine 56 (H3K56) in fungal organisms. Loss of Rtt109 renders fungal cells extremely sensitive to genotoxic agents, and prevents pathogenesis in several clinically important species. Here, via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of Rtt109 that does not inhibit other acetyltransferase enzymes. This compound inhibits Rtt109 regardless of which histone chaperone cofactor protein (Asf1 or Vps75) is present, and appears to inhibit Rtt109 via a tight-binding, uncompetitive mechanism.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.03.112</identifier><identifier>PMID: 23587423</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>acetylation ; Candida albicans ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; enzymes ; fungi ; genotoxicity ; Histone acetyltransferase ; Histone Acetyltransferases - antagonists & inhibitors ; Histone Acetyltransferases - metabolism ; histones ; lysine ; Molecular Libraries Probe Production Centers Network (MLPCN) ; Molecular Structure ; pathogenesis ; Saccharomyces - enzymology ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins - antagonists & inhibitors ; Saccharomyces cerevisiae Proteins - metabolism ; Small Molecule Libraries - chemical synthesis ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-05, Vol.23 (10), p.2853-2859</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><rights>2013 Elsevier Ltd. All rights reserved. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c479t-5b9ca56548ee1e3014ce5434a40896dbc00b2cb48c159547dcf98f245be03e093</citedby><cites>FETCH-LOGICAL-c479t-5b9ca56548ee1e3014ce5434a40896dbc00b2cb48c159547dcf98f245be03e093</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2013.03.112$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23587423$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lopes da Rosa, Jessica</creatorcontrib><creatorcontrib>Bajaj, Vineeta</creatorcontrib><creatorcontrib>Spoonamore, James</creatorcontrib><creatorcontrib>Kaufman, Paul D.</creatorcontrib><title>A small molecule inhibitor of fungal histone acetyltransferase Rtt109</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The histone acetyltransferase R1109 is required for pathogenesis in several clinically important fungal species. Via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of R1109 that does not inhibit other acetyltransferase enzymes such as the yeast Gcn5 or human p300 enzymes.
The histone acetyltransferase Rtt109 is the sole enzyme responsible for acetylation of histone H3 lysine 56 (H3K56) in fungal organisms. Loss of Rtt109 renders fungal cells extremely sensitive to genotoxic agents, and prevents pathogenesis in several clinically important species. Here, via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of Rtt109 that does not inhibit other acetyltransferase enzymes. This compound inhibits Rtt109 regardless of which histone chaperone cofactor protein (Asf1 or Vps75) is present, and appears to inhibit Rtt109 via a tight-binding, uncompetitive mechanism.</description><subject>acetylation</subject><subject>Candida albicans</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>enzymes</subject><subject>fungi</subject><subject>genotoxicity</subject><subject>Histone acetyltransferase</subject><subject>Histone Acetyltransferases - antagonists & inhibitors</subject><subject>Histone Acetyltransferases - metabolism</subject><subject>histones</subject><subject>lysine</subject><subject>Molecular Libraries Probe Production Centers Network (MLPCN)</subject><subject>Molecular Structure</subject><subject>pathogenesis</subject><subject>Saccharomyces - enzymology</subject><subject>Saccharomyces cerevisiae</subject><subject>Saccharomyces cerevisiae Proteins - antagonists & inhibitors</subject><subject>Saccharomyces cerevisiae Proteins - metabolism</subject><subject>Small Molecule Libraries - chemical synthesis</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtLxDAUhYMoOj7-gAvtH2i9aZJOAyLI4AsEwQe4C2l6O5MhbSTpCP57M4yKblydxT3n3MNHyDGFggKtzpZF0xtXlEBZAaygtNwiE8ornjMOYptMQFaQ15K_7pH9GJcAlAPnu2SvZKKe8pJNyNVlFnvtXNZ7h2blMLPDwjZ29CHzXdathrl22cLG0Q-YaYPjhxuDHmKHQUfMHseRgjwkO512EY--9IC8XF89z27z-4ebu9nlfW74VI65aKTRohK8RqTI0hyDgjOuOdSyahsD0JSm4bWhQgo-bU0n667kokFgCJIdkItN79uq6bE1OKQtTr0F2-vwoby26u9lsAs19--KpadUiFRQbgpM8DEG7H6yFNQaqlqqNVS1hqqAqQQ1hU5-f_2JfFNMhtONodNe6XmwUb08pQaRiLOk6-HnGwcmOu8Wg4rG4mCwtQHNqFpv_1vwCUBDkrE</recordid><startdate>20130515</startdate><enddate>20130515</enddate><creator>Lopes da Rosa, Jessica</creator><creator>Bajaj, Vineeta</creator><creator>Spoonamore, James</creator><creator>Kaufman, Paul D.</creator><general>Elsevier Ltd</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20130515</creationdate><title>A small molecule inhibitor of fungal histone acetyltransferase Rtt109</title><author>Lopes da Rosa, Jessica ; Bajaj, Vineeta ; Spoonamore, James ; Kaufman, Paul D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c479t-5b9ca56548ee1e3014ce5434a40896dbc00b2cb48c159547dcf98f245be03e093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>acetylation</topic><topic>Candida albicans</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>enzymes</topic><topic>fungi</topic><topic>genotoxicity</topic><topic>Histone acetyltransferase</topic><topic>Histone Acetyltransferases - antagonists & inhibitors</topic><topic>Histone Acetyltransferases - metabolism</topic><topic>histones</topic><topic>lysine</topic><topic>Molecular Libraries Probe Production Centers Network (MLPCN)</topic><topic>Molecular Structure</topic><topic>pathogenesis</topic><topic>Saccharomyces - enzymology</topic><topic>Saccharomyces cerevisiae</topic><topic>Saccharomyces cerevisiae Proteins - antagonists & inhibitors</topic><topic>Saccharomyces cerevisiae Proteins - metabolism</topic><topic>Small Molecule Libraries - chemical synthesis</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lopes da Rosa, Jessica</creatorcontrib><creatorcontrib>Bajaj, Vineeta</creatorcontrib><creatorcontrib>Spoonamore, James</creatorcontrib><creatorcontrib>Kaufman, Paul D.</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lopes da Rosa, Jessica</au><au>Bajaj, Vineeta</au><au>Spoonamore, James</au><au>Kaufman, Paul D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A small molecule inhibitor of fungal histone acetyltransferase Rtt109</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-05-15</date><risdate>2013</risdate><volume>23</volume><issue>10</issue><spage>2853</spage><epage>2859</epage><pages>2853-2859</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The histone acetyltransferase R1109 is required for pathogenesis in several clinically important fungal species. Via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of R1109 that does not inhibit other acetyltransferase enzymes such as the yeast Gcn5 or human p300 enzymes.
The histone acetyltransferase Rtt109 is the sole enzyme responsible for acetylation of histone H3 lysine 56 (H3K56) in fungal organisms. Loss of Rtt109 renders fungal cells extremely sensitive to genotoxic agents, and prevents pathogenesis in several clinically important species. Here, via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of Rtt109 that does not inhibit other acetyltransferase enzymes. This compound inhibits Rtt109 regardless of which histone chaperone cofactor protein (Asf1 or Vps75) is present, and appears to inhibit Rtt109 via a tight-binding, uncompetitive mechanism.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23587423</pmid><doi>10.1016/j.bmcl.2013.03.112</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2013-05, Vol.23 (10), p.2853-2859 |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | acetylation Candida albicans Dose-Response Relationship, Drug Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology enzymes fungi genotoxicity Histone acetyltransferase Histone Acetyltransferases - antagonists & inhibitors Histone Acetyltransferases - metabolism histones lysine Molecular Libraries Probe Production Centers Network (MLPCN) Molecular Structure pathogenesis Saccharomyces - enzymology Saccharomyces cerevisiae Saccharomyces cerevisiae Proteins - antagonists & inhibitors Saccharomyces cerevisiae Proteins - metabolism Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structure-Activity Relationship |
| title | A small molecule inhibitor of fungal histone acetyltransferase Rtt109 |
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