ID   CP2E1_HUMAN             Reviewed;         493 AA.
AC   P05181; Q5VZD5; Q9UK47;
DT   13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT   01-APR-1988, sequence version 1.
DT   05-SEP-2012, entry version 141.
DE   RecName: Full=Cytochrome P450 2E1;
DE            EC=1.14.13.-;
DE   AltName: Full=4-nitrophenol 2-hydroxylase;
DE            EC=1.14.13.n7;
DE   AltName: Full=CYPIIE1;
DE   AltName: Full=Cytochrome P450-J;
GN   Name=CYP2E1; Synonyms=CYP2E;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   MEDLINE=87057367; PubMed=3782137;
RA   Song B.-J., Gelboin H.V., Park S.-S., Yang C.S., Gonzalez F.J.;
RT   "Complementary DNA and protein sequences of ethanol-inducible rat and
RT   human cytochrome P-450s. Transcriptional and post-transcriptional
RT   regulation of the rat enzyme.";
RL   J. Biol. Chem. 261:16689-16697(1986).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   MEDLINE=89166510; PubMed=3233219; DOI=10.1021/bi00425a019;
RA   Umeno M., McBride O.W., Yang C.S., Gelboin H.V., Gonzalez F.J.;
RT   "Human ethanol-inducible P450IIE1: complete gene sequence, promoter
RT   characterization, chromosome mapping, and cDNA-directed expression.";
RL   Biochemistry 27:9006-9013(1988).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Liver;
RA   Zhuge J., Qian Y., Xie H., Yu Y.;
RT   "Sequence of a new human cytochrome P450-2E1 cDNA and establishing the
RT   transgenic cell line.";
RL   Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ASP-219; CYS-366 AND
RP   LEU-457.
RG   NIEHS SNPs program;
RL   Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15164054; DOI=10.1038/nature02462;
RA   Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA   Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA   Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA   Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA   Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA   Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA   Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA   Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA   Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA   Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA   Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA   Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA   Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA   Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA   Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA   Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA   Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA   Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA   Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA   Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA   Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA   Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA   Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA   Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA   Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT   "The DNA sequence and comparative analysis of human chromosome 10.";
RL   Nature 429:375-381(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA   Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA   Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA   Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA   Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA   Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA   Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA   Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 32-493.
RC   TISSUE=Brain;
RA   Yoo M., Shin S.W.;
RT   "Partial sequence of human brain cytochrome P450 2E1.";
RL   Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 387-432.
RA   Iwahashi K., Okuyama E., Nakamura K., Furukawa A., Ichikawa Y.;
RT   "Rapid detection of a novel mutation in the human CYP2EI exon VIII by
RT   the PCR method.";
RL   Submitted (APR-1995) to the EMBL/GenBank/DDBJ databases.
RN   [9]
RP   PROTEIN SEQUENCE OF 1-20.
RC   TISSUE=Liver;
RX   MEDLINE=88049662; PubMed=3675576; DOI=10.1016/0006-291X(87)91100-4;
RA   Lasker J.M., Raucy J., Kubota S., Bloswick B.P., Black M.,
RA   Lieber C.S.;
RT   "Purification and characterization of human liver cytochrome P-450-
RT   ALC.";
RL   Biochem. Biophys. Res. Commun. 148:232-238(1987).
RN   [10]
RP   PROTEIN SEQUENCE OF 3-20.
RX   MEDLINE=90068606; PubMed=2587619;
RA   Robinson R.C., Shorr R.G., Varrichio A., Park S.S., Gelboin H.V.,
RA   Miller H., Friedman F.K.;
RT   "Human liver cytochrome P-450 related to a rat acetone-inducible,
RT   nitrosamine-metabolizing cytochrome P-450: identification and
RT   isolation.";
RL   Pharmacology 39:137-144(1989).
RN   [11]
RP   PROTEIN SEQUENCE OF 23-42.
RX   MEDLINE=94304233; PubMed=8031147; DOI=10.1006/abbi.1994.1280;
RA   Gillam E.M., Guo Z., Guengerich F.P.;
RT   "Expression of modified human cytochrome P450 2E1 in Escherichia coli,
RT   purification, and spectral and catalytic properties.";
RL   Arch. Biochem. Biophys. 312:59-66(1994).
RN   [12]
RP   CATALYTIC ACTIVITY.
RX   PubMed=9348445; DOI=10.1021/tx970048z;
RA   Zerilli A., Ratanasavanh D., Lucas D., Goasduff T., Dreano Y.,
RA   Menard C., Picart D., Berthou F.;
RT   "Both cytochromes P450 2E1 and 3A are involved in the O-hydroxylation
RT   of p-nitrophenol, a catalytic activity known to be specific for P450
RT   2E1.";
RL   Chem. Res. Toxicol. 10:1205-1212(1997).
RN   [13]
RP   X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 32-493 IN COMPLEX WITH THE
RP   INHIBITORS INDAZOLE AND 4-METHYLPYRAZOLE AND HEME.
RX   PubMed=18818195; DOI=10.1074/jbc.M805999200;
RA   Porubsky P.R., Meneely K.M., Scott E.E.;
RT   "Structures of human cytochrome P-450 2E1. Insights into the binding
RT   of inhibitors and both small molecular weight and fatty acid
RT   substrates.";
RL   J. Biol. Chem. 283:33698-33707(2008).
RN   [14]
RP   VARIANTS CYP2E1*2 HIS-76 AND CYP2E1*3 ILE-389.
RX   MEDLINE=97211623; PubMed=9058590;
RA   Hu Y., Oscarson M., Johansson I., Yue Q.Y., Dahl M.L., Tabone M.,
RA   Arinco S., Albano E., Ingelman-Sundberg M.;
RT   "Genetic polymorphism of human CYP2E1: characterization of two variant
RT   alleles.";
RL   Mol. Pharmacol. 51:370-376(1997).
RN   [15]
RP   VARIANT CYP2E1*4 ILE-179.
RX   MEDLINE=99114670; PubMed=9918138;
RA   Fairbrother K.S., Grove J., de Waziers I., Steimel D.T., Day C.P.,
RA   Crespi C.L., Daly A.K.;
RT   "Detection and characterization of novel polymorphisms in the CYP2E1
RT   gene.";
RL   Pharmacogenetics 8:543-552(1998).
RN   [16]
RP   VARIANTS ILE-179 AND LEU-457.
RX   PubMed=15469410; DOI=10.1517/14622416.5.7.895;
RA   Solus J.F., Arietta B.J., Harris J.R., Sexton D.P., Steward J.Q.,
RA   McMunn C., Ihrie P., Mehall J.M., Edwards T.L., Dawson E.P.;
RT   "Genetic variation in eleven phase I drug metabolism genes in an
RT   ethnically diverse population.";
RL   Pharmacogenomics 5:895-931(2004).
CC   -!- FUNCTION: Metabolizes several precarcinogens, drugs, and solvents
CC       to reactive metabolites. Inactivates a number of drugs and
CC       xenobiotics and also bioactivates many xenobiotic substrates to
CC       their hepatotoxic or carcinogenic forms.
CC   -!- CATALYTIC ACTIVITY: 4-nitrophenol + NADPH + O(2) = 4-nitrocatechol
CC       + NADP(+) + H(2)O.
CC   -!- COFACTOR: Heme group.
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral
CC       membrane protein. Microsome membrane; Peripheral membrane protein.
CC   -!- INDUCTION: By ethanol and isoniazid.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family.
CC   -!- WEB RESOURCE: Name=Cytochrome P450 Allele Nomenclature Committee;
CC       Note=CYP2E1 alleles;
CC       URL="http://www.cypalleles.ki.se/cyp2e1.htm";
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=CYP2E1 entry;
CC       URL="http://en.wikipedia.org/wiki/CYP2E1";
CC   -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC       URL="http://egp.gs.washington.edu/data/cyp2e1/";
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DR   EMBL; J02625; AAA35743.1; -; mRNA.
DR   EMBL; J02843; AAA52155.1; -; Genomic_DNA.
DR   EMBL; AF182276; AAF13601.1; -; mRNA.
DR   EMBL; DQ515958; ABF47105.1; -; Genomic_DNA.
DR   EMBL; AL161645; CAH70047.1; -; Genomic_DNA.
DR   EMBL; CH471211; EAW61357.1; -; Genomic_DNA.
DR   EMBL; AF084225; AAD13753.1; -; mRNA.
DR   EMBL; D50111; BAA08796.1; -; Genomic_DNA.
DR   IPI; IPI00007282; -.
DR   PIR; A31949; A31949.
DR   RefSeq; NP_000764.1; NM_000773.3.
DR   UniGene; Hs.12907; -.
DR   PDB; 3E4E; X-ray; 2.60 A; A/B=32-493.
DR   PDB; 3E6I; X-ray; 2.20 A; A/B=32-493.
DR   PDB; 3GPH; X-ray; 2.70 A; A/B=32-493.
DR   PDB; 3KOH; X-ray; 2.90 A; A/B=32-493.
DR   PDB; 3LC4; X-ray; 3.10 A; A/B=32-493.
DR   PDB; 3T3Z; X-ray; 2.35 A; A/B/C/D=32-493.
DR   PDBsum; 3E4E; -.
DR   PDBsum; 3E6I; -.
DR   PDBsum; 3GPH; -.
DR   PDBsum; 3KOH; -.
DR   PDBsum; 3LC4; -.
DR   PDBsum; 3T3Z; -.
DR   ProteinModelPortal; P05181; -.
DR   SMR; P05181; 32-493.
DR   IntAct; P05181; 10.
DR   STRING; P05181; -.
DR   PhosphoSite; P05181; -.
DR   DMDM; 117250; -.
DR   PeptideAtlas; P05181; -.
DR   PRIDE; P05181; -.
DR   Ensembl; ENST00000252945; ENSP00000252945; ENSG00000130649.
DR   Ensembl; ENST00000463117; ENSP00000440689; ENSG00000130649.
DR   GeneID; 1571; -.
DR   KEGG; hsa:1571; -.
DR   UCSC; uc001lnj.1; human.
DR   CTD; 1571; -.
DR   GeneCards; GC10P135352; -.
DR   HGNC; HGNC:2631; CYP2E1.
DR   HPA; HPA009128; -.
DR   HPA; HPA029564; -.
DR   MIM; 124040; gene.
DR   neXtProt; NX_P05181; -.
DR   PharmGKB; PA129; -.
DR   eggNOG; COG2124; -.
DR   GeneTree; ENSGT00670000097505; -.
DR   HOGENOM; HOG000036992; -.
DR   HOVERGEN; HBG015789; -.
DR   InParanoid; P05181; -.
DR   KO; K07415; -.
DR   OMA; RNYGMGK; -.
DR   OrthoDB; EOG48WC22; -.
DR   PhylomeDB; P05181; -.
DR   BioCyc; MetaCyc:ENSG00000130649-MONOMER; -.
DR   Reactome; REACT_111217; Metabolism.
DR   DrugBank; DB00316; Acetaminophen.
DR   DrugBank; DB00356; Chlorzoxazone.
DR   DrugBank; DB00568; Cinnarizine.
DR   DrugBank; DB00636; Clofibrate.
DR   DrugBank; DB00851; Dacarbazine.
DR   DrugBank; DB00250; Dapsone.
DR   DrugBank; DB00228; Enflurane.
DR   DrugBank; DB00402; Eszopiclone.
DR   DrugBank; DB00898; Ethanol.
DR   DrugBank; DB00593; Ethosuximide.
DR   DrugBank; DB01213; Fomepizole.
DR   DrugBank; DB00143; Glutathione.
DR   DrugBank; DB01159; Halothane.
DR   DrugBank; DB01355; Hexobarbital.
DR   DrugBank; DB00753; Isoflurane.
DR   DrugBank; DB00951; Isoniazid.
DR   DrugBank; DB00170; Menadione.
DR   DrugBank; DB00532; Mephenytoin.
DR   DrugBank; DB01028; Methoxyflurane.
DR   DrugBank; DB00683; Midazolam.
DR   DrugBank; DB01204; Mitoxantrone.
DR   DrugBank; DB00184; Nicotine.
DR   DrugBank; DB01115; Nifedipine.
DR   DrugBank; DB00698; Nitrofurantoin.
DR   DrugBank; DB01173; Orphenadrine.
DR   DrugBank; DB00780; Phenelzine.
DR   DrugBank; DB00908; Quinidine.
DR   DrugBank; DB00118; S-Adenosylmethionine.
DR   DrugBank; DB01236; Sevoflurane.
DR   DrugBank; DB00277; Theophylline.
DR   DrugBank; DB01124; Tolbutamide.
DR   EvolutionaryTrace; P05181; -.
DR   GenomeRNAi; 1571; -.
DR   NextBio; 6461; -.
DR   ArrayExpress; P05181; -.
DR   Bgee; P05181; -.
DR   CleanEx; HS_CYP2E1; -.
DR   Genevestigator; P05181; -.
DR   GermOnline; ENSG00000130649; Homo sapiens.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR   GO; GO:0005792; C:microsome; IDA:BHF-UCL.
DR   GO; GO:0009055; F:electron carrier activity; IEA:InterPro.
DR   GO; GO:0020037; F:heme binding; IDA:UniProtKB.
DR   GO; GO:0016709; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NADH or NADPH as one donor, and incorporation of one atom of oxygen; TAS:UniProtKB.
DR   GO; GO:0016712; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen; IEA:InterPro.
DR   GO; GO:0019825; F:oxygen binding; TAS:ProtInc.
DR   GO; GO:0017144; P:drug metabolic process; IDA:BHF-UCL.
DR   GO; GO:0046483; P:heterocycle metabolic process; IDA:BHF-UCL.
DR   GO; GO:0016098; P:monoterpenoid metabolic process; IDA:BHF-UCL.
DR   GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR   GO; GO:0008202; P:steroid metabolic process; IMP:BHF-UCL.
DR   GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome.
DR   Gene3D; G3DSA:1.10.630.10; Cyt_P450; 1.
DR   InterPro; IPR001128; Cyt_P450.
DR   InterPro; IPR017972; Cyt_P450_CS.
DR   InterPro; IPR002401; Cyt_P450_E_grp-I.
DR   InterPro; IPR008070; Cyt_P450_E_grp-I_CYP2E-like.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00463; EP450I.
DR   PRINTS; PR01687; EP450ICYP2E.
DR   PRINTS; PR00385; P450.
DR   SUPFAM; SSF48264; Cytochrome_P450; 1.
DR   PROSITE; PS00086; CYTOCHROME_P450; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Complete proteome; Direct protein sequencing;
KW   Endoplasmic reticulum; Heme; Iron; Membrane; Metal-binding; Microsome;
KW   Monooxygenase; NADP; Oxidoreductase; Phosphoprotein; Polymorphism;
KW   Reference proteome.
FT   CHAIN         1    493       Cytochrome P450 2E1.
FT                                /FTId=PRO_0000051751.
FT   REGION      298    303       Substrate binding (Probable).
FT   METAL       437    437       Iron (heme axial ligand).
FT   MOD_RES     129    129       Phosphoserine (By similarity).
FT   VARIANT      76     76       R -> H (in allele CYP2E1*2; reduced
FT                                activity).
FT                                /FTId=VAR_008360.
FT   VARIANT     179    179       V -> I (in allele CYP2E1*4;
FT                                dbSNP:rs6413419).
FT                                /FTId=VAR_008361.
FT   VARIANT     219    219       N -> D (in dbSNP:rs41299426).
FT                                /FTId=VAR_055382.
FT   VARIANT     366    366       S -> C (in dbSNP:rs41299434).
FT                                /FTId=VAR_055383.
FT   VARIANT     389    389       V -> I (in allele CYP2E1*3;
FT                                dbSNP:rs55897648).
FT                                /FTId=VAR_008362.
FT   VARIANT     457    457       H -> L (in dbSNP:rs28969387).
FT                                /FTId=VAR_024727.
FT   CONFLICT      2      2       Missing (in Ref. 9; AA sequence).
FT   CONFLICT     23     23       W -> A (in Ref. 11; AA sequence).
FT   CONFLICT     32     32       L -> N (in Ref. 11; AA sequence).
FT   CONFLICT    235    235       V -> A (in Ref. 3; AAF13601).
FT   TURN         40     42
FT   HELIX        45     47
FT   HELIX        50     52
FT   HELIX        53     64
FT   STRAND       66     72
FT   STRAND       75     80
FT   HELIX        83     91
FT   TURN         94     97
FT   HELIX       104    109
FT   STRAND      112    114
FT   HELIX       122    135
FT   HELIX       142    159
FT   TURN        160    163
FT   HELIX       169    172
FT   HELIX       174    185
FT   HELIX       194    209
FT   HELIX       213    220
FT   HELIX       222    225
FT   STRAND      228    230
FT   HELIX       231    255
FT   STRAND      259    261
FT   HELIX       265    274
FT   STRAND      275    278
FT   STRAND      279    281
FT   HELIX       286    317
FT   HELIX       319    332
FT   TURN        333    336
FT   HELIX       341    346
FT   HELIX       348    361
FT   STRAND      376    378
FT   STRAND      381    383
FT   STRAND      388    391
FT   HELIX       394    397
FT   TURN        400    402
FT   STRAND      403    405
FT   HELIX       411    414
FT   STRAND      419    421
FT   HELIX       433    435
FT   HELIX       440    457
FT   STRAND      458    464
FT   TURN        466    468
FT   STRAND      474    481
FT   STRAND      487    491
SQ   SEQUENCE   493 AA;  56849 MW;  ED0399E32A005644 CRC64;
     MSALGVTVAL LVWAAFLLLV SMWRQVHSSW NLPPGPFPLP IIGNLFQLEL KNIPKSFTRL
     AQRFGPVFTL YVGSQRMVVM HGYKAVKEAL LDYKDEFSGR GDLPAFHAHR DRGIIFNNGP
     TWKDIRRFSL TTLRNYGMGK QGNESRIQRE AHFLLEALRK TQGQPFDPTF LIGCAPCNVI
     ADILFRKHFD YNDEKFLRLM YLFNENFHLL STPWLQLYNN FPSFLHYLPG SHRKVIKNVA
     EVKEYVSERV KEHHQSLDPN CPRDLTDCLL VEMEKEKHSA ERLYTMDGIT VTVADLFFAG
     TETTSTTLRY GLLILMKYPE IEEKLHEEID RVIGPSRIPA IKDRQEMPYM DAVVHEIQRF
     ITLVPSNLPH EATRDTIFRG YLIPKGTVVV PTLDSVLYDN QEFPDPEKFK PEHFLNENGK
     FKYSDYFKPF STGKRVCAGE GLARMELFLL LCAILQHFNL KPLVDPKDID LSPIHIGFGC
     IPPRYKLCVI PRS
//