ID CP2A6_HUMAN Reviewed; 494 AA. AC P11509; P00190; P10890; Q16803; Q4VAT9; Q4VAU0; Q4VAU1; Q9H1Z7; AC Q9UK48; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 10-JUL-2007, sequence version 2. DT 11-SEP-2007, entry version 100. DE Cytochrome P450 2A6 (EC 1.14.14.1) (CYPIIA6) (Coumarin 7-hydroxylase) DE (P450 IIA3) (CYP2A3) (P450(I)). GN Name=CYP2A6; Synonyms=CYP2A3; 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], AND VARIANT ASN-29. RC TISSUE=Liver; RX MEDLINE=89263705; PubMed=2726448; DOI=10.1093/nar/17.8.2907; 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 [2] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANT HIS-160, AND CHARACTERIZATION OF RP VARIANT HIS-160. RC TISSUE=Hepatocyte; RX MEDLINE=90212623; PubMed=2322567; DOI=10.1021/bi00457a031; 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 [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT HIS-160. RC TISSUE=Hepatocyte; RA Landsman D.; RL Submitted (JAN-1989) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA]. 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 [LARGE SCALE MRNA], AND VARIANTS HIS-160 AND RP ARG-476. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] 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 [7] RP PROTEIN SEQUENCE OF 1-13, FUNCTION, SUBCELLULAR LOCATION, INDUCTION, RP AND TISSUE SPECIFICITY. RX MEDLINE=92049260; 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 [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 47-494. RC TISSUE=Hepatocyte; RX MEDLINE=89315238; PubMed=2748347; DOI=10.1093/nar/17.12.4888; 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 [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 116-164, AND VARIANT CYP2A6*6 RP 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 [10] RP PRELIMINARY NUCLEOTIDE SEQUENCE [MRNA] 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 [11] RP CHARACTERIZATION OF VARIANT CYP2A6*2 HIS-160. 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 [12] 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 [13] 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 [14] RP VARIANTS CYP2A6*13 ARG-5; CYP2A6*14 ASN-29; CYP2A6*15 GLU-194 AND RP CYP2A6*16 SER-203. RX PubMed=15618701; DOI=10.2133/dmpk.17.482; 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 [15] RP VARIANTS ASP-419 AND THR-471. RX MEDLINE=22652616; 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). RN [16] RP VARIANTS ARG-5; ASN-29; LEU-118; GLN-128; PRO-224; MET-365; ASP-418; RP ASP-419; THR-471; ARG-476 AND LEU-485. 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: 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: Endoplasmic reticulum membrane; Peripheral CC membrane protein. CC -!- TISSUE SPECIFICITY: Liver. CC -!- INDUCTION: By phenobarbital and dexamethasone. CC -!- SIMILARITY: Belongs to the cytochrome P450 family. CC -!- WEB RESOURCE: Name=Cytochrome P450 Allele Nomenclature Committee; CC Note=CYP2A6 alleles; URL="http://www.cypalleles.ki.se/cyp2a6.htm"; CC -!- WEB RESOURCE: Name=Wikipedia; Note=CYP2A6 entry; CC URL="http://en.wikipedia.org/wiki/CYP2A6"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X13897; CAA32097.1; -; mRNA. DR EMBL; M33318; AAA52067.1; -; mRNA. DR EMBL; X13929; CAA32117.1; -; mRNA. DR EMBL; X13930; CAA32118.1; -; mRNA. DR EMBL; AF182275; AAF13600.1; -; mRNA. DR EMBL; BC096253; AAH96253.3; -; mRNA. DR EMBL; BC096254; AAH96254.1; -; mRNA. DR EMBL; BC096255; AAH96255.1; -; mRNA. DR EMBL; BC096256; AAH96256.1; -; mRNA. DR EMBL; AF326721; AAG45229.1; -; Genomic_DNA. DR EMBL; K03192; AAA52147.1; ALT_SEQ; mRNA. DR PIR; A00190; O4HUPB. DR PIR; S04698; O4HUA6. DR UniGene; Hs.439056; -. DR PDB; 1Z10; X-ray; A/B/C/D=29-494. DR PDB; 1Z11; X-ray; A/B/C/D=29-494. DR Ensembl; ENSG00000198077; Homo sapiens. DR KEGG; hsa:1548; -. DR HGNC; HGNC:2610; CYP2A6. DR MIM; 122720; gene+phenotype. DR PharmGKB; PA121; -. DR BioCyc; MetaCyc:ENSG00000171563-MONOMER; -. DR Reactome; REACT_2063.3; Xenobiotic metabolism. DR LinkHub; P11509; -. DR ArrayExpress; P11509; -. DR GermOnline; ENSG00000198077; Homo sapiens. DR GO; GO:0005792; C:microsome; TAS:ProtInc. DR GO; GO:0008389; F:coumarin 7-hydroxylase activity; TAS:ProtInc. DR GO; GO:0019825; F:oxygen binding; TAS:ProtInc. DR InterPro; IPR001128; Cyt_P450. DR InterPro; IPR002401; Cyt_P450_E_grp-I. DR InterPro; IPR008067; Cyt_P450_E_grp-I_CYP2A-like. DR Gene3D; G3DSA:1.10.630.10; Cyt_P450; 1. DR PANTHER; PTHR19383; Cyt_P450; 1. DR Pfam; PF00067; p450; 1. DR PRINTS; PR00463; EP450I. DR PRINTS; PR01684; EP450ICYP2A. DR PRINTS; PR00385; P450. DR PROSITE; PS00086; CYTOCHROME_P450; 1. PE 1: Evidence at protein level; KW 3D-structure; Direct protein sequencing; Endoplasmic reticulum; Heme; KW Iron; Membrane; Metal-binding; Microsome; Monooxygenase; KW Oxidoreductase; Polymorphism. FT CHAIN 1 494 Cytochrome P450 2A6. FT /FTId=PRO_0000051668. 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 118 118 F -> L. FT /FTId=VAR_024711. FT VARIANT 128 128 R -> Q (in allele CYP2A6*6; loss of FT activity). FT /FTId=VAR_011577. FT VARIANT 160 160 L -> H (in allele CYP2A6*2; unable to FT catalyze 7-hydroxylation of coumarin; FT causes switching from coumarin 7- FT hydroxylation to 3-hydroxylation; FT dbSNP:rs1801272). 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 224 224 S -> P. FT /FTId=VAR_024712. FT VARIANT 365 365 V -> M. FT /FTId=VAR_024713. FT VARIANT 418 418 N -> D. FT /FTId=VAR_024714. 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 476 476 K -> R. FT /FTId=VAR_024715. 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. 1). FT CONFLICT 255 255 N -> K (in Ref. 1). FT CONFLICT 326 326 K -> Q (in Ref. 1). FT TURN 41 43 FT HELIX 46 48 FT HELIX 51 53 FT HELIX 54 65 FT STRAND 67 73 FT STRAND 76 81 FT HELIX 84 91 FT TURN 92 98 FT HELIX 105 111 FT STRAND 115 118 FT HELIX 121 137 FT TURN 138 141 FT HELIX 143 162 FT TURN 163 165 FT HELIX 171 187 FT HELIX 196 213 FT HELIX 215 227 FT HELIX 233 256 FT HELIX 267 277 FT TURN 278 280 FT HELIX 288 301 FT HELIX 304 319 FT HELIX 321 334 FT STRAND 337 339 FT HELIX 343 348 FT HELIX 350 363 FT STRAND 390 393 FT HELIX 395 399 FT TURN 402 404 FT HELIX 413 416 FT HELIX 442 459 FT STRAND 460 466 FT HELIX 468 470 FT STRAND 474 484 FT STRAND 489 493 SQ SEQUENCE 494 AA; 56517 MW; 562D697ADE558B04 CRC64; MLASGMLLVA LLVCLTVMVL MSVWQQRKSK GKLPPGPTPL PFIGNYLQLN TEQMYNSLMK ISERYGPVFT IHLGPRRVVV LCGHDAVREA LVDQAEEFSG RGEQATFDWV FKGYGVVFSN GERAKQLRRF SIATLRDFGV GKRGIEERIQ EEAGFLIDAL 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 //