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| | ==Human Cytochrome P450 2A6 I208S/I300F/G301A/S369G in complex with Pilocarpine== | | ==Human Cytochrome P450 2A6 I208S/I300F/G301A/S369G in complex with Pilocarpine== |
| - | <StructureSection load='3t3q' size='340' side='right' caption='[[3t3q]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='3t3q' size='340' side='right'caption='[[3t3q]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3t3q]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T3Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T3Q FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3t3q]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T3Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T3Q FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9PL:(3S,4R)-3-ETHYL-4-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]DIHYDROFURAN-2(3H)-ONE'>9PL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9PL:(3S,4R)-3-ETHYL-4-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]DIHYDROFURAN-2(3H)-ONE'>9PL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ebs|3ebs]], [[2fdy|2fdy]], [[1z11|1z11]], [[1z10|1z10]], [[2fdu|2fdu]], [[2fdv|2fdv]], [[2pg7|2pg7]], [[2pg6|2pg6]], [[2pg5|2pg5]], [[2fdw|2fdw]], [[3t3r|3t3r]], [[3t3s|3t3s]], [[3t3z|3t3z]]</td></tr> | + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3ebs|3ebs]], [[2fdy|2fdy]], [[1z11|1z11]], [[1z10|1z10]], [[2fdu|2fdu]], [[2fdv|2fdv]], [[2pg7|2pg7]], [[2pg6|2pg6]], [[2pg5|2pg5]], [[2fdw|2fdw]], [[3t3r|3t3r]], [[3t3s|3t3s]], [[3t3z|3t3z]]</div></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP2A3, CYP2A6, CYP2A6 I208S/I300F/G301A/S369G ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP2A3, CYP2A6, CYP2A6 I208S/I300F/G301A/S369G ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </span></td></tr> | + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3t3q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t3q OCA], [http://pdbe.org/3t3q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3t3q RCSB], [http://www.ebi.ac.uk/pdbsum/3t3q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3t3q ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3t3q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t3q OCA], [https://pdbe.org/3t3q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t3q RCSB], [https://www.ebi.ac.uk/pdbsum/3t3q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t3q ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP2A6_HUMAN CP2A6_HUMAN]] Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.<ref>PMID:1889415</ref> <ref>PMID:1944238</ref> <ref>PMID:11695850</ref> <ref>PMID:16086027</ref> <ref>PMID:17125252</ref> <ref>PMID:18779312</ref> | + | [[https://www.uniprot.org/uniprot/CP2A6_HUMAN CP2A6_HUMAN]] Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.<ref>PMID:1889415</ref> <ref>PMID:1944238</ref> <ref>PMID:11695850</ref> <ref>PMID:16086027</ref> <ref>PMID:17125252</ref> <ref>PMID:18779312</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 3t3q" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 3t3q" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Unspecific monooxygenase]] | | [[Category: Unspecific monooxygenase]] |
| | [[Category: DeVore, N M]] | | [[Category: DeVore, N M]] |
| Structural highlights
3t3q is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 3ebs, 2fdy, 1z11, 1z10, 2fdu, 2fdv, 2pg7, 2pg6, 2pg5, 2fdw, 3t3r, 3t3s, 3t3z |
| Gene: | CYP2A3, CYP2A6, CYP2A6 I208S/I300F/G301A/S369G (HUMAN) |
| Activity: | Unspecific monooxygenase, with EC number 1.14.14.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[CP2A6_HUMAN] Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Human xenobiotic-metabolizing cytochrome P450 (CYP) enzymes can each bind and monooxygenate a diverse set of substrates, including drugs, often producing a variety of metabolites. Additionally, a single ligand can interact with multiple CYP enzymes, but often the protein structural similarities and differences that mediate such overlapping selectivity are not well understood. Even though the CYP superfamily has a highly canonical global protein fold, there are large variations in the active site size, topology, and conformational flexibility. We have determined how a related set of three human CYP enzymes bind and interact with a common inhibitor, the muscarinic receptor agonist drug pilocarpine. Pilocarpine binds and inhibits the hepatic CYP2A6 and respiratory CYP2A13 enzymes much more efficiently than the hepatic CYP2E1 enzyme. To elucidate key residues involved in pilocarpine binding, crystal structures of CYP2A6 (2.4 A), CYP2A13 (3.0 A), CYP2E1 (2.35 A), and the CYP2A6 mutant enzyme, CYP2A6 I208S/I300F/G301A/S369G (2.1 A) have been determined with pilocarpine in the active site. In all four structures, pilocarpine coordinates to the heme iron, but comparisons reveal how individual residues lining the active sites of these three distinct human enzymes interact differently with the inhibitor pilocarpine. Database Structural data are available in the Protein Data Bank database under the accession numbers 3T3Q (CYP2A6 I208S/I300F/G301A/S369G with pilocarpine), 3T3R (CYP2A6 with pilocarpine), 3T3S (CYP2A13 with pilocarpine), and 3T3Z (CYP2E1 with pilocarpine).
Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine.,Devore NM, Meneely KM, Bart AG, Stephens ES, Battaile KP, Scott EE FEBS J. 2011 Nov 3. doi: 10.1111/j.1742-4658.2011.08412.x. PMID:22051186[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Maurice M, Emiliani S, Dalet-Beluche I, Derancourt J, Lange R. Isolation and characterization of a cytochrome P450 of the IIA subfamily from human liver microsomes. Eur J Biochem. 1991 Sep 1;200(2):511-7. PMID:1889415
- ↑ Yun CH, Shimada T, Guengerich FP. Purification and characterization of human liver microsomal cytochrome P-450 2A6. Mol Pharmacol. 1991 Nov;40(5):679-85. PMID:1944238
- ↑ Miyazawa M, Shindo M, Shimada T. Roles of cytochrome P450 3A enzymes in the 2-hydroxylation of 1,4-cineole, a monoterpene cyclic ether, by rat and human liver microsomes. Xenobiotica. 2001 Oct;31(10):713-23. PMID:11695850 doi:10.1080/00498250110065595
- ↑ Yano JK, Hsu MH, Griffin KJ, Stout CD, Johnson EF. Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen. Nat Struct Mol Biol. 2005 Sep;12(9):822-3. Epub 2005 Aug 7. PMID:16086027 doi:http://dx.doi.org/10.1038/nsmb971
- ↑ Yano JK, Denton TT, Cerny MA, Zhang X, Johnson EF, Cashman JR. Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization. J Med Chem. 2006 Nov 30;49(24):6987-7001. PMID:17125252 doi:http://dx.doi.org/10.1021/jm060519r
- ↑ DeVore NM, Smith BD, Urban MJ, Scott EE. Key residues controlling phenacetin metabolism by human cytochrome P450 2A enzymes. Drug Metab Dispos. 2008 Dec;36(12):2582-90. Epub 2008 Sep 8. PMID:18779312 doi:10.1124/dmd.108.023770
- ↑ Devore NM, Meneely KM, Bart AG, Stephens ES, Battaile KP, Scott EE. Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine. FEBS J. 2011 Nov 3. doi: 10.1111/j.1742-4658.2011.08412.x. PMID:22051186 doi:10.1111/j.1742-4658.2011.08412.x
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