Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers
Nitric oxide (NO) is a pluripotent regulatory molecule, yet the molecular mechanisms by which it exerts its effects are largely unknown. Few physiologic target molecules of NO have been identified, and even for these, the modifications caused by NO remain uncharacterized. Human glutathione reductase...
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| Veröffentlicht in: | Nature Structural Biology 1998-04, Vol.5 (4), p.267-271 |
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| creator | Becker, Katja Savvides, Savvas N Keese, Michael Schirmer, R. Heiner Karplus, P. Andrew |
| description | Nitric oxide (NO) is a pluripotent regulatory molecule, yet the molecular mechanisms by which it exerts its effects are largely unknown. Few physiologic target molecules of NO have been identified, and even for these, the modifications caused by NO remain uncharacterized. Human glutathione reductase (hGR), a central enzyme of cellular antioxidant defense, is inhibited by S-nitrosoglutathione (GSNO) and by diglutathionyl-dinitroso-iron (DNIC-[GSH]
2
), two
in vivo
transport forms of NO. Here, crystal structures of hGR inactivated by GSNO and DNIC-[GSH]
2
at 1.7 Å resolution provide the first picture of enzyme inactivation by NO-carriers: in GSNO-modified hGR, the active site residue Cys 63 is oxidized to an unusually stable cysteine sulfenic acid (R-SOH), whereas modification with DNIC-[GSH]
2
oxidizes Cys 63 to a cysteine sulfinic acid (R-SO
2
H). Our results illustrate that various forms of NO can mediate distinct chemistry, and that sulfhydryl oxidation must be considered as a major mechanism of NO action. |
| doi_str_mv | 10.1038/nsb0498-267 |
| format | Article |
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2
), two
in vivo
transport forms of NO. Here, crystal structures of hGR inactivated by GSNO and DNIC-[GSH]
2
at 1.7 Å resolution provide the first picture of enzyme inactivation by NO-carriers: in GSNO-modified hGR, the active site residue Cys 63 is oxidized to an unusually stable cysteine sulfenic acid (R-SOH), whereas modification with DNIC-[GSH]
2
oxidizes Cys 63 to a cysteine sulfinic acid (R-SO
2
H). Our results illustrate that various forms of NO can mediate distinct chemistry, and that sulfhydryl oxidation must be considered as a major mechanism of NO action.</description><identifier>ISSN: 1072-8368</identifier><identifier>EISSN: 2331-365X</identifier><identifier>EISSN: 1545-9985</identifier><identifier>DOI: 10.1038/nsb0498-267</identifier><identifier>PMID: 9546215</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Amino Acid Sequence ; Biochemistry ; Biological Microscopy ; Biomedical and Life Sciences ; Computer Simulation ; Crystallography, X-Ray ; Cysteine ; Dithiothreitol - pharmacology ; Glutathione - analogs & derivatives ; Glutathione - chemistry ; Glutathione - pharmacology ; Glutathione Reductase - antagonists & inhibitors ; Glutathione Reductase - chemistry ; Humans ; letter ; Life Sciences ; Membrane Biology ; Models, Molecular ; Molecular Conformation ; Molecular Sequence Data ; Nitric Oxide - chemistry ; Nitric Oxide - pharmacology ; Nitroso Compounds - chemistry ; Nitroso Compounds - pharmacology ; Protein Conformation ; Protein Structure ; S-Nitrosoglutathione ; Software</subject><ispartof>Nature Structural Biology, 1998-04, Vol.5 (4), p.267-271</ispartof><rights>Springer Nature America, Inc. 1998</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c347t-3c8b2a17806e72e3b94b1c8e78dd866584e0355fabada6a6bc319ad7ce76ede53</citedby><cites>FETCH-LOGICAL-c347t-3c8b2a17806e72e3b94b1c8e78dd866584e0355fabada6a6bc319ad7ce76ede53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nsb0498-267$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nsb0498-267$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,778,782,27907,27908,41471,42540,51302</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9546215$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Becker, Katja</creatorcontrib><creatorcontrib>Savvides, Savvas N</creatorcontrib><creatorcontrib>Keese, Michael</creatorcontrib><creatorcontrib>Schirmer, R. Heiner</creatorcontrib><creatorcontrib>Karplus, P. Andrew</creatorcontrib><title>Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers</title><title>Nature Structural Biology</title><addtitle>Nat Struct Mol Biol</addtitle><addtitle>Nat Struct Biol</addtitle><description>Nitric oxide (NO) is a pluripotent regulatory molecule, yet the molecular mechanisms by which it exerts its effects are largely unknown. Few physiologic target molecules of NO have been identified, and even for these, the modifications caused by NO remain uncharacterized. Human glutathione reductase (hGR), a central enzyme of cellular antioxidant defense, is inhibited by S-nitrosoglutathione (GSNO) and by diglutathionyl-dinitroso-iron (DNIC-[GSH]
2
), two
in vivo
transport forms of NO. Here, crystal structures of hGR inactivated by GSNO and DNIC-[GSH]
2
at 1.7 Å resolution provide the first picture of enzyme inactivation by NO-carriers: in GSNO-modified hGR, the active site residue Cys 63 is oxidized to an unusually stable cysteine sulfenic acid (R-SOH), whereas modification with DNIC-[GSH]
2
oxidizes Cys 63 to a cysteine sulfinic acid (R-SO
2
H). Our results illustrate that various forms of NO can mediate distinct chemistry, and that sulfhydryl oxidation must be considered as a major mechanism of NO action.</description><subject>Amino Acid Sequence</subject><subject>Biochemistry</subject><subject>Biological Microscopy</subject><subject>Biomedical and Life Sciences</subject><subject>Computer Simulation</subject><subject>Crystallography, X-Ray</subject><subject>Cysteine</subject><subject>Dithiothreitol - pharmacology</subject><subject>Glutathione - analogs & derivatives</subject><subject>Glutathione - chemistry</subject><subject>Glutathione - pharmacology</subject><subject>Glutathione Reductase - antagonists & inhibitors</subject><subject>Glutathione Reductase - chemistry</subject><subject>Humans</subject><subject>letter</subject><subject>Life Sciences</subject><subject>Membrane Biology</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Molecular Sequence Data</subject><subject>Nitric Oxide - chemistry</subject><subject>Nitric Oxide - pharmacology</subject><subject>Nitroso Compounds - chemistry</subject><subject>Nitroso Compounds - pharmacology</subject><subject>Protein Conformation</subject><subject>Protein Structure</subject><subject>S-Nitrosoglutathione</subject><subject>Software</subject><issn>1072-8368</issn><issn>2331-365X</issn><issn>1545-9985</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1LwzAYh4Moc05PnoV68aLVpGmT9ChjfuBwFwVvJU3frpEumUkr1r_eSsvw4imH5-GB9xeETgm-JpiKG-NzHKcijBjfQ9OIUhJSlrztoynBPAoFZeIQHXn_jjGJY5xO0CRNYhaRZIqeFua720CgjVSN_pSNtiZoKmfbdRX4ti6rrnBdHdgvXQww74Jt1Xlta7vWKnhehUo6p8H5Y3RQytrDyfjO0Ovd4mX-EC5X94_z22WoaMybkCqRR5JwgRnwCGiexjlRArgoCsFYImLANElKmctCMslyRUkqC66AMyggoTN0MXS3zn604Jtso72CupYGbOsznnIhUp724uUgKme9d1BmW6c30nUZwdnvdNk4XdZP19tnY7bNN1Ds3HGrnl8N3PfErMFl77Z1pr_0n9z5oBvZtA52uT-_RX8ApumFmQ</recordid><startdate>19980401</startdate><enddate>19980401</enddate><creator>Becker, Katja</creator><creator>Savvides, Savvas N</creator><creator>Keese, Michael</creator><creator>Schirmer, R. Heiner</creator><creator>Karplus, P. Andrew</creator><general>Nature Publishing Group US</general><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>7X8</scope></search><sort><creationdate>19980401</creationdate><title>Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers</title><author>Becker, Katja ; Savvides, Savvas N ; Keese, Michael ; Schirmer, R. Heiner ; Karplus, P. Andrew</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c347t-3c8b2a17806e72e3b94b1c8e78dd866584e0355fabada6a6bc319ad7ce76ede53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Amino Acid Sequence</topic><topic>Biochemistry</topic><topic>Biological Microscopy</topic><topic>Biomedical and Life Sciences</topic><topic>Computer Simulation</topic><topic>Crystallography, X-Ray</topic><topic>Cysteine</topic><topic>Dithiothreitol - pharmacology</topic><topic>Glutathione - analogs & derivatives</topic><topic>Glutathione - chemistry</topic><topic>Glutathione - pharmacology</topic><topic>Glutathione Reductase - antagonists & inhibitors</topic><topic>Glutathione Reductase - chemistry</topic><topic>Humans</topic><topic>letter</topic><topic>Life Sciences</topic><topic>Membrane Biology</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Molecular Sequence Data</topic><topic>Nitric Oxide - chemistry</topic><topic>Nitric Oxide - pharmacology</topic><topic>Nitroso Compounds - chemistry</topic><topic>Nitroso Compounds - pharmacology</topic><topic>Protein Conformation</topic><topic>Protein Structure</topic><topic>S-Nitrosoglutathione</topic><topic>Software</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Becker, Katja</creatorcontrib><creatorcontrib>Savvides, Savvas N</creatorcontrib><creatorcontrib>Keese, Michael</creatorcontrib><creatorcontrib>Schirmer, R. Heiner</creatorcontrib><creatorcontrib>Karplus, P. Andrew</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Nature Structural Biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Becker, Katja</au><au>Savvides, Savvas N</au><au>Keese, Michael</au><au>Schirmer, R. Heiner</au><au>Karplus, P. Andrew</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers</atitle><jtitle>Nature Structural Biology</jtitle><stitle>Nat Struct Mol Biol</stitle><addtitle>Nat Struct Biol</addtitle><date>1998-04-01</date><risdate>1998</risdate><volume>5</volume><issue>4</issue><spage>267</spage><epage>271</epage><pages>267-271</pages><issn>1072-8368</issn><eissn>2331-365X</eissn><eissn>1545-9985</eissn><abstract>Nitric oxide (NO) is a pluripotent regulatory molecule, yet the molecular mechanisms by which it exerts its effects are largely unknown. Few physiologic target molecules of NO have been identified, and even for these, the modifications caused by NO remain uncharacterized. Human glutathione reductase (hGR), a central enzyme of cellular antioxidant defense, is inhibited by S-nitrosoglutathione (GSNO) and by diglutathionyl-dinitroso-iron (DNIC-[GSH]
2
), two
in vivo
transport forms of NO. Here, crystal structures of hGR inactivated by GSNO and DNIC-[GSH]
2
at 1.7 Å resolution provide the first picture of enzyme inactivation by NO-carriers: in GSNO-modified hGR, the active site residue Cys 63 is oxidized to an unusually stable cysteine sulfenic acid (R-SOH), whereas modification with DNIC-[GSH]
2
oxidizes Cys 63 to a cysteine sulfinic acid (R-SO
2
H). Our results illustrate that various forms of NO can mediate distinct chemistry, and that sulfhydryl oxidation must be considered as a major mechanism of NO action.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>9546215</pmid><doi>10.1038/nsb0498-267</doi><tpages>5</tpages></addata></record> |
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| subjects | Amino Acid Sequence Biochemistry Biological Microscopy Biomedical and Life Sciences Computer Simulation Crystallography, X-Ray Cysteine Dithiothreitol - pharmacology Glutathione - analogs & derivatives Glutathione - chemistry Glutathione - pharmacology Glutathione Reductase - antagonists & inhibitors Glutathione Reductase - chemistry Humans letter Life Sciences Membrane Biology Models, Molecular Molecular Conformation Molecular Sequence Data Nitric Oxide - chemistry Nitric Oxide - pharmacology Nitroso Compounds - chemistry Nitroso Compounds - pharmacology Protein Conformation Protein Structure S-Nitrosoglutathione Software |
| title | Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers |
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