ID   CPA6_HUMAN     STANDARD;      PRT;   494 AA.
AC   P11509; P00190; P10890; Q16803; Q9H1Z7; Q9UK48;
DT   21-JUL-1986 (Rel. 01, Created)
DT   01-OCT-1989 (Rel. 12, Last sequence update)
DT   05-JUL-2004 (Rel. 44, Last annotation update)
DE   Cytochrome P450 2A6 (EC 1.14.14.1) (CYPIIA6) (Coumarin 7-hydroxylase)
DE   (IIA3) (CYP2A3) (P450(I)).
GN   Name=CYP2A6;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Primates; Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE.
RC   TISSUE=Liver;
RX   MEDLINE=90212623; PubMed=2322567;
RA   Yamano S., Tatsuno J., Gonzalez F.J.;
RT   "The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human
RT   liver microsomes.";
RL   Biochemistry 29:1322-1329(1990).
RN   [2]
RP   NUCLEOTIDE SEQUENCE.
RA   Landsman D.;
RL   Submitted (JAN-1989) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE, AND VARIANT ASN-29.
RC   TISSUE=Liver;
RX   MEDLINE=89263705; PubMed=2726448;
RA   Miles J.S., Bickmore W., Brook J.D., McLaren A.W., Meehan R.,
RA   Wolf C.R.;
RT   "Close linkage of the human cytochrome P450IIA and P450IIB gene
RT   subfamilies: implications for the assignment of substrate
RT   specificity.";
RL   Nucleic Acids Res. 17:2907-2917(1989).
RN   [4]
RP   NUCLEOTIDE SEQUENCE.
RC   TISSUE=Liver;
RA   Zhuge J., Qian Y., Xie H., Yu Y.;
RT   "Sequence of a new human cytochrome P450-2A6 cDNA.";
RL   Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE OF 47-494.
RC   TISSUE=Liver;
RX   MEDLINE=89315238; PubMed=2748347;
RA   Yamano S., Nagata K., Yamazoe Y., Kato R., Gelboin H.V.,
RA   Gonzalez F.J.;
RT   "cDNA and deduced amino acid sequences of human P450 IIA3 (CYP2A3).";
RL   Nucleic Acids Res. 17:4888-4888(1989).
RN   [6]
RP   PRELIMINARY NUCLEOTIDE SEQUENCE OF 163-494.
RX   MEDLINE=85140280; PubMed=3856261;
RA   Phillips I.R., Shephard E.A., Ashworth A., Rabin B.R.;
RT   "Isolation and sequence of a human cytochrome P-450 cDNA clone.";
RL   Proc. Natl. Acad. Sci. U.S.A. 82:983-987(1985).
RN   [7]
RP   PROTEIN SEQUENCE OF 1-20, FUNCTION, SUBCELLULAR LOCATION, INDUCTION,
RP   AND TISSUE SPECIFICITY.
RX   PubMed=1889415;
RA   Maurice M., Emiliani S., Dalet-Beluche I., Derancourt J., Lange R.;
RT   "Isolation and characterization of a cytochrome P450 of the IIA
RT   subfamily from human liver microsomes.";
RL   Eur. J. Biochem. 200:511-517(1991).
RN   [8]
RP   PROTEIN SEQUENCE OF 1-13, FUNCTION, SUBCELLULAR LOCATION, INDUCTION,
RP   AND TISSUE SPECIFICITY.
RX   PubMed=1944238;
RA   Yun C.H., Shimada T., Guengerich F.P.;
RT   "Purification and characterization of human liver microsomal
RT   cytochrome P-450 2A6.";
RL   Mol. Pharmacol. 40:679-685(1991).
RN   [9]
RP   CHARACTERIZATION OF VARIANT CYP2A6*2.
RX   MEDLINE=98072289; PubMed=9409631; DOI=10.1016/S0278-6915(97)00066-5;
RA   Hadidi H., Zahlsen K., Idle J.R., Cholerton S.;
RT   "A single amino acid substitution (Leu160His) in cytochrome P450
RT   CYP2A6 causes switching from 7-hydroxylation to 3-hydroxylation of
RT   coumarin.";
RL   Food Chem. Toxicol. 35:903-907(1997).
RN   [10]
RP   VARIANT CYP2A6*5 VAL-479.
RX   MEDLINE=20012952; PubMed=10544257; DOI=10.1016/S0014-5793(99)01364-2;
RA   Oscarson M., McLellan R.A., Gullsten H., Agundez J.A., Benitez J.,
RA   Rautio A., Raunio H., Pelkonen O., Ingelman-Sundberg M.;
RT   "Identification and characterisation of novel polymorphisms in the
RT   CYP2A locus: implications for nicotine metabolism.";
RL   FEBS Lett. 460:321-327(1999).
RN   [11]
RP   VARIANTS CYP2A6*7 THR-471 AND CYP2A6*8 LEU-485.
RX   MEDLINE=21134319; PubMed=11237731; DOI=10.1006/bbrc.2001.4422;
RA   Ariyoshi N., Sawamura Y., Kamataki T.;
RT   "A novel single nucleotide polymorphism altering stability and
RT   activity of CYP2a6.";
RL   Biochem. Biophys. Res. Commun. 281:810-814(2001).
RN   [12]
RP   VARIANT CYP2A6*6 GLN-128.
RX   MEDLINE=21264563; PubMed=11278503; DOI=10.1074/jbc.M009432200;
RA   Kitagawa K., Kunugita N., Kitagawa M., Kawamoto T.;
RT   "CYP2A6*6, a novel polymorphism in cytochrome p450 2A6, has a single
RT   amino acid substitution (R128Q) that inactivates enzymatic activity.";
RL   J. Biol. Chem. 276:17830-17835(2001).
RN   [13]
RP   VARIANTS CYP2A6*13 ARG-5; CYP2A6*14 ASN-29; CYP2A6*15 GLU-194 AND
RP   CYP2A6*16 SER-203.
RA   Kiyotani K., Fujieda M., Yamazaki H., Shimada T., Guengerich F.P.,
RA   Parkinson A., Nakagawa K., Ishizaki T., Kamataki T.;
RT   "Twenty one novel single nucleotide polymorphisms (SNPs) of the CYP2A6
RT   Gene in Japanese and Caucasians.";
RL   Drug Metab. Pharmacokinet. 17:482-487(2002).
RN   [14]
RP   VARIANTS ASP-419 AND THR-471.
RX   PubMed=12721789; DOI=10.1007/s10038-003-0021-7;
RA   Saito S., Iida A., Sekine A., Kawauchi S., Higuchi S., Ogawa C.,
RA   Nakamura Y.;
RT   "Catalog of 680 variations among eight cytochrome p450 (CYP) genes,
RT   nine esterase genes, and two other genes in the Japanese population.";
RL   J. Hum. Genet. 48:249-270(2003).
CC   -!- FUNCTION: Exhibits a high coumarin 7-hydroxylase activity. Can act
CC       in the hydroxylation of the anti-cancer drugs cyclophosphamide and
CC       ifosphamide. Competent in the metabolic activation of aflatoxin
CC       B1. Constitutes the major nicotine C-oxidase.
CC   -!- CATALYTIC ACTIVITY: RH + reduced flavoprotein + O(2) = ROH +
CC       oxidized flavoprotein + H(2)O.
CC   -!- SUBCELLULAR LOCATION: Membrane-bound. Endoplasmic reticulum.
CC   -!- TISSUE SPECIFICITY: Liver.
CC   -!- INDUCTION: By phenobarbital and dexamethasone.
CC   -!- POLYMORPHISM: The CYP2A6*2 allele causes switching from 7-
CC       hydroxylation to 3-hydroxylation of coumarin.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family.
CC   -!- DATABASE: NAME=Cytochrome P450 Allele Nomenclature Committee;
CC       NOTE=CYP2A6 alleles;
CC       WWW="http://www.imm.ki.se/CYPalleles/cyp2a6.htm".
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DR   EMBL; M33318; AAA52067.1; -.
DR   EMBL; X13930; CAA32118.1; -.
DR   EMBL; X13897; CAA32097.1; -.
DR   EMBL; AF182275; AAF13600.1; -.
DR   EMBL; X13929; CAA32117.1; -.
DR   EMBL; K03192; AAA52147.1; ALT_SEQ.
DR   EMBL; AF326721; AAG45229.1; -.
DR   PIR; S04698; O4HUA6.
DR   HSSP; P00179; 1DT6.
DR   Ensembl; ENSG00000198470; Homo sapiens.
DR   Genew; HGNC:2610; CYP2A6.
DR   MIM; 122720; -.
DR   GO; GO:0005792; C:microsome; TAS.
DR   GO; GO:0008389; F:coumarin 7-hydroxylase activity; TAS.
DR   GO; GO:0019825; F:oxygen binding; TAS.
DR   InterPro; IPR001128; Cytochrome_P450.
DR   InterPro; IPR008067; EP450_CYP2A.
DR   InterPro; IPR002401; EP450I.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00463; EP450I.
DR   PRINTS; PR01684; EP450ICYP2A.
DR   PRINTS; PR00385; P450.
DR   PROSITE; PS00086; CYTOCHROME_P450; 1.
KW   Direct protein sequencing; Electron transport; Endoplasmic reticulum;
KW   Heme; Membrane; Microsome; Monooxygenase; Oxidoreductase;
KW   Polymorphism.
FT   METAL       439    439       Iron (heme axial ligand).
FT   VARIANT       5      5       G -> R (in allele CYP2A6*13).
FT                                /FTId=VAR_018330.
FT   VARIANT      29     29       S -> N (in allele CYP2A6*14).
FT                                /FTId=VAR_018331.
FT   VARIANT     128    128       R -> Q (in allele CYP2A6*6; loss of
FT                                activity).
FT                                /FTId=VAR_011577.
FT   VARIANT     160    160       H -> L (in allele CYP2A6*2;
FT                                dbSNP:1801272).
FT                                /FTId=VAR_001249.
FT   VARIANT     194    194       K -> E (in allele CYP2A6*15).
FT                                /FTId=VAR_018332.
FT   VARIANT     203    203       R -> S (in allele CYP2A6*16).
FT                                /FTId=VAR_018333.
FT   VARIANT     419    419       E -> D.
FT                                /FTId=VAR_018375.
FT   VARIANT     471    471       I -> T (in allele CYP2A6*7).
FT                                /FTId=VAR_011578.
FT   VARIANT     479    479       G -> V (in allele CYP2A6*5; loss of
FT                                activity).
FT                                /FTId=VAR_008356.
FT   VARIANT     485    485       R -> L (in allele CYP2A6*8).
FT                                /FTId=VAR_011579.
FT   CONFLICT      3      7       Missing (in Ref. 3).
FT   CONFLICT    255    255       N -> K (in Ref. 3).
FT   CONFLICT    326    326       K -> Q (in Ref. 3).
SQ   SEQUENCE   494 AA;  56541 MW;  93866A3F1D12A4F8 CRC64;
     MLASGMLLVA LLVCLTVMVL MSVWQQRKSK GKLPPGPTPL PFIGNYLQLN TEQMYNSLMK
     ISERYGPVFT IHLGPRRVVV LCGHDAVREA LVDQAEEFSG RGEQATFDWV FKGYGVVFSN
     GERAKQLRRF SIATLRDFGV GKRGIEERIQ EEAGFLIDAH RGTGGANIDP TFFLSRTVSN
     VISSIVFGDR FDYKDKEFLS LLRMMLGIFQ FTSTSTGQLY EMFSSVMKHL PGPQQQAFQL
     LQGLEDFIAK KVEHNQRTLD PNSPRDFIDS FLIRMQEEEK NPNTEFYLKN LVMTTLNLFI
     GGTETVSTTL RYGFLLLMKH PEVEAKVHEE IDRVIGKNRQ PKFEDRAKMP YMEAVIHEIQ
     RFGDVIPMSL ARRVKKDTKF RDFFLPKGTE VYPMLGSVLR DPSFFSNPQD FNPQHFLNEK
     GQFKKSDAFV PFSIGKRNCF GEGLARMELF LFFTTVMQNF RLKSSQSPKD IDVSPKHVGF
     ATIPRNYTMS FLPR
//