Molecular modelling of cytochrome P4502D6 (CYP2D6) based on an alignment with CYP102 : structural studies on specific CYP2D6 substrate metabolism
1. A molecular model of CYP2D6 has been constructed from the bacterial form CYP102 via a homology alignment between the CYP2D subfamily and CYP102 protein sequences. 2. A number of typical CYP2D6 substrates are shown to fit the putative active site of the enzyme, as can the specific inhibitor quinid...
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| Veröffentlicht in: | Xenobiotica 1997-04, Vol.27 (4), p.319-339 |
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| container_title | Xenobiotica |
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| creator | LEWIS, D. F. V EDDERSHAW, P. J GOLDFARB, P. S TARBIT, M. H |
| description | 1. A molecular model of CYP2D6 has been constructed from the bacterial form CYP102 via a homology alignment between the CYP2D subfamily and CYP102 protein sequences. 2. A number of typical CYP2D6 substrates are shown to fit the putative active site of the enzyme, as can the specific inhibitor quinidine. 3. Some of the allelic variants in CYP2D6, which give rise to genetic polymorphisms in 2D6-mediated metabolism, can be rationalized in terms of their position within the active site region. 4. The results of site-directed mutagenesis experiments are consistent with the CYP2D6 model generated from the CYP102 crystal structure. 5. The possibility of an alternative orientation within the active site may explain the CYP2D6-mediated metabolism of relatively large-sized substrates. |
| doi_str_mv | 10.1080/004982597240497 |
| format | Article |
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The possibility of an alternative orientation within the active site may explain the CYP2D6-mediated metabolism of relatively large-sized substrates.</description><identifier>ISSN: 0049-8254</identifier><identifier>EISSN: 1366-5928</identifier><identifier>DOI: 10.1080/004982597240497</identifier><identifier>PMID: 9149373</identifier><identifier>CODEN: XENOBH</identifier><language>eng</language><publisher>London: Taylor & Francis</publisher><subject>Alleles ; Amino Acid Sequence ; Analytical, structural and metabolic biochemistry ; Bacterial Proteins ; Biological and medical sciences ; Cytochrome P-450 CYP2D6 - chemistry ; Cytochrome P-450 CYP2D6 - genetics ; Cytochrome P-450 CYP2D6 - metabolism ; Cytochrome P-450 Enzyme System - chemistry ; Cytochrome P-450 Enzyme System - genetics ; Cytochrome P-450 Enzyme System - metabolism ; Enzymes and enzyme inhibitors ; Fundamental and applied biological sciences. Psychology ; Isoenzymes - chemistry ; Isoenzymes - genetics ; Isoenzymes - metabolism ; Mixed Function Oxygenases - chemistry ; Mixed Function Oxygenases - genetics ; Mixed Function Oxygenases - metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; NADPH-Ferrihemoprotein Reductase ; Ondansetron - metabolism ; Oxidoreductases ; Polymorphism, Genetic ; Sequence Homology, Amino Acid ; Serotonin Antagonists - metabolism</subject><ispartof>Xenobiotica, 1997-04, Vol.27 (4), p.319-339</ispartof><rights>1997 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2656067$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9149373$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LEWIS, D. F. V</creatorcontrib><creatorcontrib>EDDERSHAW, P. J</creatorcontrib><creatorcontrib>GOLDFARB, P. S</creatorcontrib><creatorcontrib>TARBIT, M. H</creatorcontrib><title>Molecular modelling of cytochrome P4502D6 (CYP2D6) based on an alignment with CYP102 : structural studies on specific CYP2D6 substrate metabolism</title><title>Xenobiotica</title><addtitle>Xenobiotica</addtitle><description>1. A molecular model of CYP2D6 has been constructed from the bacterial form CYP102 via a homology alignment between the CYP2D subfamily and CYP102 protein sequences. 2. A number of typical CYP2D6 substrates are shown to fit the putative active site of the enzyme, as can the specific inhibitor quinidine. 3. Some of the allelic variants in CYP2D6, which give rise to genetic polymorphisms in 2D6-mediated metabolism, can be rationalized in terms of their position within the active site region. 4. The results of site-directed mutagenesis experiments are consistent with the CYP2D6 model generated from the CYP102 crystal structure. 5. The possibility of an alternative orientation within the active site may explain the CYP2D6-mediated metabolism of relatively large-sized substrates.</description><subject>Alleles</subject><subject>Amino Acid Sequence</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Bacterial Proteins</subject><subject>Biological and medical sciences</subject><subject>Cytochrome P-450 CYP2D6 - chemistry</subject><subject>Cytochrome P-450 CYP2D6 - genetics</subject><subject>Cytochrome P-450 CYP2D6 - metabolism</subject><subject>Cytochrome P-450 Enzyme System - chemistry</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Isoenzymes - chemistry</subject><subject>Isoenzymes - genetics</subject><subject>Isoenzymes - metabolism</subject><subject>Mixed Function Oxygenases - chemistry</subject><subject>Mixed Function Oxygenases - genetics</subject><subject>Mixed Function Oxygenases - metabolism</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Mutagenesis, Site-Directed</subject><subject>NADPH-Ferrihemoprotein Reductase</subject><subject>Ondansetron - metabolism</subject><subject>Oxidoreductases</subject><subject>Polymorphism, Genetic</subject><subject>Sequence Homology, Amino Acid</subject><subject>Serotonin Antagonists - metabolism</subject><issn>0049-8254</issn><issn>1366-5928</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kM1LHTEUxUOx6NO67krIQopdTHvzPeNOnvYDFF24cfVIMnc0kpk8JxmKf0b_40Z8FC6cA-d3z-IQ8pnBNwYtfAeQXctVZ7isznwgKya0blTH2z2yekubGssDcpjzMwBoxvk-2e-Y7IQRK_L3JkX0S7QzHVOPMYbpkaaB-teS_NOcRqR3UgG_1PRs_XBX9St1NmNP00RtvRgepxGnQv-E8kQrwoDTc5rLvPiyzDZWu_QB89tD3qIPQ_D0vYrmxVXQFqQjFutSDHn8RD4ONmY83ukRuf9xdb_-1Vzf_vy9vrhutlzr0hgwTiiFAIxjrzvbO2-wRyWM5zBIyZVx3Gs2dC1yydvBeQmdAS-8Vk4ckS_vtds5vSyYy2YM2dcB7IRpyRumGROg2gqe7MDFjdhvtnMY7fy62U1Y89NdbrO3cZjt5EP-j3GtNGgj_gE97H5c</recordid><startdate>19970401</startdate><enddate>19970401</enddate><creator>LEWIS, D. 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H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p266t-707b355e0012ed69adbc7ede537c20f44257b2c61f98e2428fbc40970c3c65b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Alleles</topic><topic>Amino Acid Sequence</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Bacterial Proteins</topic><topic>Biological and medical sciences</topic><topic>Cytochrome P-450 CYP2D6 - chemistry</topic><topic>Cytochrome P-450 CYP2D6 - genetics</topic><topic>Cytochrome P-450 CYP2D6 - metabolism</topic><topic>Cytochrome P-450 Enzyme System - chemistry</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Isoenzymes - chemistry</topic><topic>Isoenzymes - genetics</topic><topic>Isoenzymes - metabolism</topic><topic>Mixed Function Oxygenases - chemistry</topic><topic>Mixed Function Oxygenases - genetics</topic><topic>Mixed Function Oxygenases - metabolism</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Mutagenesis, Site-Directed</topic><topic>NADPH-Ferrihemoprotein Reductase</topic><topic>Ondansetron - metabolism</topic><topic>Oxidoreductases</topic><topic>Polymorphism, Genetic</topic><topic>Sequence Homology, Amino Acid</topic><topic>Serotonin Antagonists - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LEWIS, D. F. V</creatorcontrib><creatorcontrib>EDDERSHAW, P. J</creatorcontrib><creatorcontrib>GOLDFARB, P. S</creatorcontrib><creatorcontrib>TARBIT, M. H</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Xenobiotica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>LEWIS, D. F. V</au><au>EDDERSHAW, P. J</au><au>GOLDFARB, P. S</au><au>TARBIT, M. H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular modelling of cytochrome P4502D6 (CYP2D6) based on an alignment with CYP102 : structural studies on specific CYP2D6 substrate metabolism</atitle><jtitle>Xenobiotica</jtitle><addtitle>Xenobiotica</addtitle><date>1997-04-01</date><risdate>1997</risdate><volume>27</volume><issue>4</issue><spage>319</spage><epage>339</epage><pages>319-339</pages><issn>0049-8254</issn><eissn>1366-5928</eissn><coden>XENOBH</coden><abstract>1. A molecular model of CYP2D6 has been constructed from the bacterial form CYP102 via a homology alignment between the CYP2D subfamily and CYP102 protein sequences. 2. A number of typical CYP2D6 substrates are shown to fit the putative active site of the enzyme, as can the specific inhibitor quinidine. 3. Some of the allelic variants in CYP2D6, which give rise to genetic polymorphisms in 2D6-mediated metabolism, can be rationalized in terms of their position within the active site region. 4. The results of site-directed mutagenesis experiments are consistent with the CYP2D6 model generated from the CYP102 crystal structure. 5. The possibility of an alternative orientation within the active site may explain the CYP2D6-mediated metabolism of relatively large-sized substrates.</abstract><cop>London</cop><pub>Taylor & Francis</pub><pmid>9149373</pmid><doi>10.1080/004982597240497</doi><tpages>21</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0049-8254 |
| ispartof | Xenobiotica, 1997-04, Vol.27 (4), p.319-339 |
| issn | 0049-8254 1366-5928 |
| language | eng |
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| source | MEDLINE; Taylor & Francis Medical Library - CRKN; Taylor & Francis Journals Complete |
| subjects | Alleles Amino Acid Sequence Analytical, structural and metabolic biochemistry Bacterial Proteins Biological and medical sciences Cytochrome P-450 CYP2D6 - chemistry Cytochrome P-450 CYP2D6 - genetics Cytochrome P-450 CYP2D6 - metabolism Cytochrome P-450 Enzyme System - chemistry Cytochrome P-450 Enzyme System - genetics Cytochrome P-450 Enzyme System - metabolism Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Isoenzymes - chemistry Isoenzymes - genetics Isoenzymes - metabolism Mixed Function Oxygenases - chemistry Mixed Function Oxygenases - genetics Mixed Function Oxygenases - metabolism Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed NADPH-Ferrihemoprotein Reductase Ondansetron - metabolism Oxidoreductases Polymorphism, Genetic Sequence Homology, Amino Acid Serotonin Antagonists - metabolism |
| title | Molecular modelling of cytochrome P4502D6 (CYP2D6) based on an alignment with CYP102 : structural studies on specific CYP2D6 substrate metabolism |
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