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3ebs

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Revision as of 03:47, 25 December 2014

Human Cytochrome P450 2A6 I208S/I300F/G301A/S369G in complex with Phenacetin

Structural highlights

3ebs is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	1z11, 2fdy, 1z10, 2fdu, 2fdv, 2fdw, 2pg6, 2pg7, 2pg5, 2p85
Gene:	CYP2A6, CYP2A3 (Homo sapiens)
Activity:	Unspecific monooxygenase, with EC number 1.14.14.1
Resources:	FirstGlance, OCA, RCSB, PDBsum

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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Cytochrome P450s (P450s) metabolize a large number of diverse substrates with specific regio- and stereospecificity. A number of compounds, including nicotine, cotinine, and aflatoxin B(1), are metabolites of the 94% identical CYP2A13 and CYP2A6 enzymes but at different rates. Phenacetin and 4-aminobiphenyl were identified as substrates of human cytochromes P450 1A2 and 2A13 but not of CYP2A6. The purpose of this study was to identify active site amino acids that are responsible for CYP2A substrate specificity using phenacetin as a structural probe. Ten amino acid residues that differ in the CYP2A13 and CYP2A6 active sites were exchanged between the two enzymes. Phenacetin binding revealed that the six substitution, CYP2A13 S208I, A213S, F300I, A301G, M365V, and G369S decreased phenacetin affinity. Although incorporation of individual CYP2A13 residues into CYP2A6 had little effect on this enzyme's very low levels of phenacetin metabolism, the combination of double, triple, and quadruple substitutions at positions 208, 300, 301, and 369 increasingly endowed CYP2A6 with the ability to metabolize phenacetin. Enzyme kinetics revealed that the CYP2A6 I208S/I300F/G301A/S369G mutant protein O-deethylated phenacetin with a K(m) of 10.3 muM and a k(cat) of 2.9 min(-1), which compare very favorably with those of CYP2A13 (K(m) of 10.7 muM and k(cat) of 3.8 min(-1)). A 2.15 A crystal structure of the mutant CYP2A6 I208S/I300F/G301A/S369G protein with phenacetin in the active site provided a structural rationale for the differences in phenacetin metabolism between CYP2A6 and CYP2A13.

Key residues controlling phenacetin metabolism by human cytochrome P450 2A enzymes.,DeVore NM, Smith BD, Urban MJ, Scott EE Drug Metab Dispos. 2008 Dec;36(12):2582-90. Epub 2008 Sep 8. PMID:18779312^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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, 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

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3ebs"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[3ebs]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EBS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EBS FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=N4E:N-(4-ETHOXYPHENYL)ACETAMIDE'>N4E</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=N4E:N-(4-ETHOXYPHENYL)ACETAMIDE'>N4E</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1z11|1z11]], [[2fdy|2fdy]], [[1z10|1z10]], [[2fdu|2fdu]], [[2fdv|2fdv]], [[2fdw|2fdw]], [[2pg6|2pg6]], [[2pg7|2pg7]], [[2pg5|2pg5]], [[2p85|2p85]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1z11|1z11]], [[2fdy|2fdy]], [[1z10|1z10]], [[2fdu|2fdu]], [[2fdv|2fdv]], [[2fdw|2fdw]], [[2pg6|2pg6]], [[2pg7|2pg7]], [[2pg5|2pg5]], [[2p85|2p85]]</td></tr>
-<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP2A6, CYP2A3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP2A6, CYP2A3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
-<tr><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'>[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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ebs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ebs OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ebs RCSB], [http://www.ebi.ac.uk/pdbsum/3ebs PDBsum]</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=3ebs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ebs OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ebs RCSB], [http://www.ebi.ac.uk/pdbsum/3ebs PDBsum]</span></td></tr>
-<table>
+</table>
+== 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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 36: / Line 38: @@
 [[Category: Homo sapiens]]
 [[Category: Unspecific monooxygenase]]
-[[Category: DeVore, N M.]]
+[[Category: DeVore, N M]]
-[[Category: Scott, E E.]]
+[[Category: Scott, E E]]
 [[Category: Cyp2a13]]
 [[Category: Cyp2a6]]

3ebs

From Proteopedia

Revision as of 03:47, 25 December 2014

Human Cytochrome P450 2A6 I208S/I300F/G301A/S369G in complex with Phenacetin

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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