Catalytic Mechanism of DNA Topoisomerase IB
Type IB topoisomerases and tyrosine recombinases are structurally homologous strand transferases that act through DNA-(3′-phosphotyrosyl)-enzyme intermediates. A constellation of conserved amino acids (Arg-130, Lys-167, Arg-223, and His-265 in vaccinia topoisomerase) catalyzes transesterification of...
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| Veröffentlicht in: | Molecular cell 2000-06, Vol.5 (6), p.1035-1041 |
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| creator | Krogh, Berit O Shuman, Stewart |
| description | Type IB topoisomerases and tyrosine recombinases are structurally homologous strand transferases that act through DNA-(3′-phosphotyrosyl)-enzyme intermediates. A constellation of conserved amino acids (Arg-130, Lys-167, Arg-223, and His-265 in vaccinia topoisomerase) catalyzes transesterification of tyrosine to the scissile phosphodiester. We used 5′-bridging phosphorothiolate-modified DNAs to implicate Lys-167 as a general acid catalyst. The lower pK
a of the 5′-S leaving group versus 5′-O restored activity to the K167A mutant, whereas there was no positive thio effect for mutants R223A and H265A. The lysine is located atop a flexible hairpin loop, and it shifts into the minor groove upon DNA binding. Coupling of conformational changes in a general acid loop to covalent catalysis of phosphoryl transfer is one of several mechanistic features shared by the topoisomerase/recombinase and protein phosphatase superfamilies. |
| doi_str_mv | 10.1016/S1097-2765(00)80268-3 |
| format | Article |
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a of the 5′-S leaving group versus 5′-O restored activity to the K167A mutant, whereas there was no positive thio effect for mutants R223A and H265A. The lysine is located atop a flexible hairpin loop, and it shifts into the minor groove upon DNA binding. Coupling of conformational changes in a general acid loop to covalent catalysis of phosphoryl transfer is one of several mechanistic features shared by the topoisomerase/recombinase and protein phosphatase superfamilies.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/S1097-2765(00)80268-3</identifier><identifier>PMID: 10911997</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Substitution ; Arginine - genetics ; Arginine - metabolism ; Base Sequence ; Catalysis ; Conserved Sequence - genetics ; DNA - genetics ; DNA - metabolism ; DNA Topoisomerases, Type I - chemistry ; DNA Topoisomerases, Type I - genetics ; DNA Topoisomerases, Type I - metabolism ; Histidine - genetics ; Histidine - metabolism ; Kinetics ; Lysine - genetics ; Lysine - metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Tyrosine - metabolism ; Vaccinia virus - enzymology ; Viral Proteins - chemistry ; Viral Proteins - genetics ; Viral Proteins - metabolism</subject><ispartof>Molecular cell, 2000-06, Vol.5 (6), p.1035-1041</ispartof><rights>2000 Cell Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-6b22dffdae6907455f4271ac891df721500a910358e44032b48aeb06bc43dd013</citedby><cites>FETCH-LOGICAL-c439t-6b22dffdae6907455f4271ac891df721500a910358e44032b48aeb06bc43dd013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S1097-2765(00)80268-3$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10911997$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Krogh, Berit O</creatorcontrib><creatorcontrib>Shuman, Stewart</creatorcontrib><title>Catalytic Mechanism of DNA Topoisomerase IB</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>Type IB topoisomerases and tyrosine recombinases are structurally homologous strand transferases that act through DNA-(3′-phosphotyrosyl)-enzyme intermediates. A constellation of conserved amino acids (Arg-130, Lys-167, Arg-223, and His-265 in vaccinia topoisomerase) catalyzes transesterification of tyrosine to the scissile phosphodiester. We used 5′-bridging phosphorothiolate-modified DNAs to implicate Lys-167 as a general acid catalyst. The lower pK
a of the 5′-S leaving group versus 5′-O restored activity to the K167A mutant, whereas there was no positive thio effect for mutants R223A and H265A. The lysine is located atop a flexible hairpin loop, and it shifts into the minor groove upon DNA binding. Coupling of conformational changes in a general acid loop to covalent catalysis of phosphoryl transfer is one of several mechanistic features shared by the topoisomerase/recombinase and protein phosphatase superfamilies.</description><subject>Amino Acid Substitution</subject><subject>Arginine - genetics</subject><subject>Arginine - metabolism</subject><subject>Base Sequence</subject><subject>Catalysis</subject><subject>Conserved Sequence - genetics</subject><subject>DNA - genetics</subject><subject>DNA - metabolism</subject><subject>DNA Topoisomerases, Type I - chemistry</subject><subject>DNA Topoisomerases, Type I - genetics</subject><subject>DNA Topoisomerases, Type I - metabolism</subject><subject>Histidine - genetics</subject><subject>Histidine - metabolism</subject><subject>Kinetics</subject><subject>Lysine - genetics</subject><subject>Lysine - metabolism</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Tyrosine - metabolism</subject><subject>Vaccinia virus - enzymology</subject><subject>Viral Proteins - chemistry</subject><subject>Viral Proteins - genetics</subject><subject>Viral Proteins - metabolism</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1PwzAMhiMEYjD4CaCeEAgVnDQf7QmN8TVpwIFxjtLUFUHtOpIOaf-ebt2B20627Oe1pYeQMwo3FKi8_aCQqZgpKS4BrlJgMo2TPXK0GXMq-f62XyMDchzCNwDlIs0OyaBbUJpl6ohcj01rqlXrbPSK9svMXaijpowe3kbRrFk0LjQ1ehMwmtyfkIPSVAFPt3VIPp8eZ-OXePr-PBmPprHlSdbGMmesKMvCoMxAcSFKzhQ1Ns1oUSpGBYDJKCQiRc4hYTlPDeYg8y5eFECTIbno7y5887PE0OraBYtVZebYLINWlAmQAnaCVAmhUiY7UPSg9U0IHku98K42fqUp6LVOvdGp1640gN7o1EmXO98-WOY1Fv9Svb8OuOsB7Hz8OvQ6WIdzi4XzaFtdNG7Hiz8Il4Gy</recordid><startdate>20000601</startdate><enddate>20000601</enddate><creator>Krogh, Berit O</creator><creator>Shuman, Stewart</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7TM</scope><scope>7X8</scope></search><sort><creationdate>20000601</creationdate><title>Catalytic Mechanism of DNA Topoisomerase IB</title><author>Krogh, Berit O ; Shuman, Stewart</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-6b22dffdae6907455f4271ac891df721500a910358e44032b48aeb06bc43dd013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Amino Acid Substitution</topic><topic>Arginine - genetics</topic><topic>Arginine - metabolism</topic><topic>Base Sequence</topic><topic>Catalysis</topic><topic>Conserved Sequence - genetics</topic><topic>DNA - genetics</topic><topic>DNA - metabolism</topic><topic>DNA Topoisomerases, Type I - chemistry</topic><topic>DNA Topoisomerases, Type I - genetics</topic><topic>DNA Topoisomerases, Type I - metabolism</topic><topic>Histidine - genetics</topic><topic>Histidine - metabolism</topic><topic>Kinetics</topic><topic>Lysine - genetics</topic><topic>Lysine - metabolism</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Tyrosine - metabolism</topic><topic>Vaccinia virus - enzymology</topic><topic>Viral Proteins - chemistry</topic><topic>Viral Proteins - genetics</topic><topic>Viral Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Krogh, Berit O</creatorcontrib><creatorcontrib>Shuman, Stewart</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Krogh, Berit O</au><au>Shuman, Stewart</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Catalytic Mechanism of DNA Topoisomerase IB</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2000-06-01</date><risdate>2000</risdate><volume>5</volume><issue>6</issue><spage>1035</spage><epage>1041</epage><pages>1035-1041</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>Type IB topoisomerases and tyrosine recombinases are structurally homologous strand transferases that act through DNA-(3′-phosphotyrosyl)-enzyme intermediates. A constellation of conserved amino acids (Arg-130, Lys-167, Arg-223, and His-265 in vaccinia topoisomerase) catalyzes transesterification of tyrosine to the scissile phosphodiester. We used 5′-bridging phosphorothiolate-modified DNAs to implicate Lys-167 as a general acid catalyst. The lower pK
a of the 5′-S leaving group versus 5′-O restored activity to the K167A mutant, whereas there was no positive thio effect for mutants R223A and H265A. The lysine is located atop a flexible hairpin loop, and it shifts into the minor groove upon DNA binding. Coupling of conformational changes in a general acid loop to covalent catalysis of phosphoryl transfer is one of several mechanistic features shared by the topoisomerase/recombinase and protein phosphatase superfamilies.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>10911997</pmid><doi>10.1016/S1097-2765(00)80268-3</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Access via ScienceDirect (Elsevier); EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Substitution Arginine - genetics Arginine - metabolism Base Sequence Catalysis Conserved Sequence - genetics DNA - genetics DNA - metabolism DNA Topoisomerases, Type I - chemistry DNA Topoisomerases, Type I - genetics DNA Topoisomerases, Type I - metabolism Histidine - genetics Histidine - metabolism Kinetics Lysine - genetics Lysine - metabolism Models, Molecular Molecular Sequence Data Mutation Tyrosine - metabolism Vaccinia virus - enzymology Viral Proteins - chemistry Viral Proteins - genetics Viral Proteins - metabolism |
| title | Catalytic Mechanism of DNA Topoisomerase IB |
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