CP2A6_HUMAN
ID CP2A6_HUMAN Reviewed; 494 AA.
AC P11509; A7YAE5; B2R7F6; P00190; P10890; Q16803; Q4VAT9; Q4VAU0; Q4VAU1;
AC Q9H1Z7; Q9UCU0; Q9UK48;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 18-SEP-2019, sequence version 4.
DT 03-AUG-2022, entry version 230.
DE RecName: Full=Cytochrome P450 2A6;
DE EC=1.14.14.-;
DE AltName: Full=1,4-cineole 2-exo-monooxygenase;
DE AltName: Full=CYPIIA6;
DE AltName: Full=Coumarin 7-hydroxylase;
DE AltName: Full=Cytochrome P450 IIA3;
DE AltName: Full=Cytochrome P450(I);
GN Name=CYP2A6; Synonyms=CYP2A3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASN-29.
RC TISSUE=Liver;
RX PubMed=2726448; DOI=10.1093/nar/17.8.2907;
RA Miles J.S., Bickmore W., Brook J.D., McLaren A.W., Meehan R., Wolf C.R.;
RT "Close linkage of the human cytochrome P450IIA and P450IIB gene
RT subfamilies: implications for the assignment of substrate specificity.";
RL Nucleic Acids Res. 17:2907-2917(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT HIS-160.
RC TISSUE=Hepatocyte;
RX PubMed=2748347; DOI=10.1093/nar/17.12.4888;
RA Yamano S., Nagata K., Yamazoe Y., Kato R., Gelboin H.V., Gonzalez F.J.;
RT "cDNA and deduced amino acid sequences of human P450 IIA3 (CYP2A3).";
RL Nucleic Acids Res. 17:4888-4888(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], VARIANT HIS-160, AND CHARACTERIZATION OF
RP VARIANT HIS-160.
RC TISSUE=Hepatocyte;
RX 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 liver
RT microsomes.";
RL Biochemistry 29:1322-1329(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT VAL-479.
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].
RC TISSUE=Mammary gland;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT PHE-392.
RG NIEHS SNPs program;
RL Submitted (SEP-2007) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS HIS-160 AND 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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP PROTEIN SEQUENCE OF 1-20, FUNCTION, SUBCELLULAR LOCATION, INDUCTION, AND
RP TISSUE SPECIFICITY.
RX PubMed=1889415; DOI=10.1111/j.1432-1033.1991.tb16212.x;
RA Maurice M., Emiliani S., Dalet-Beluche I., Derancourt J., Lange R.;
RT "Isolation and characterization of a cytochrome P450 of the IIA subfamily
RT from human liver microsomes.";
RL Eur. J. Biochem. 200:511-517(1991).
RN [11]
RP PROTEIN SEQUENCE OF 1-13, FUNCTION, SUBCELLULAR LOCATION, INDUCTION, AND
RP TISSUE SPECIFICITY.
RX PubMed=1944238;
RA Yun C.H., Shimada T., Guengerich F.P.;
RT "Purification and characterization of human liver microsomal cytochrome P-
RT 450 2A6.";
RL Mol. Pharmacol. 40:679-685(1991).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 116-164, AND VARIANT CYP2A6*6 GLN-128.
RX 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 amino
RT acid substitution (R128Q) that inactivates enzymatic activity.";
RL J. Biol. Chem. 276:17830-17835(2001).
RN [13]
RP PRELIMINARY NUCLEOTIDE SEQUENCE [MRNA] OF 163-494.
RX PubMed=3856261; DOI=10.1073/pnas.82.4.983;
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 [14]
RP CATALYTIC ACTIVITY, FUNCTION AS 1,4-CINEOLE 2-EXO-MONOOXYGENASE, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=11695850; DOI=10.1080/00498250110065595;
RA Miyazawa M., Shindo M., Shimada T.;
RT "Roles of cytochrome P450 3A enzymes in the 2-hydroxylation of 1,4-cineole,
RT a monoterpene cyclic ether, by rat and human liver microsomes.";
RL Xenobiotica 31:713-723(2001).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 29-494 IN COMPLEX WITH COUMARIN;
RP HEME AND THE INHIBITOR METHOXSALEN, FUNCTION, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=16086027; DOI=10.1038/nsmb971;
RA Yano J.K., Hsu M.H., Griffin K.J., Stout C.D., Johnson E.F.;
RT "Structures of human microsomal cytochrome P450 2A6 complexed with coumarin
RT and methoxsalen.";
RL Nat. Struct. Mol. Biol. 12:822-823(2005).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 29-494 IN COMPLEX WITH PHENACETIN
RP AND HEME, AND FUNCTION.
RX PubMed=17125252; DOI=10.1021/jm060519r;
RA Yano J.K., Denton T.T., Cerny M.A., Zhang X., Johnson E.F., Cashman J.R.;
RT "Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity,
RT difference spectra, mechanism of inhibition, and protein
RT cocrystallization.";
RL J. Med. Chem. 49:6987-7001(2006).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 29-494 IN COMPLEX WITH PHENACETIN
RP AND HEME, FUNCTION, CHARACTERIZATION OF VARIANTS LEU-110 AND MET-365, AND
RP MUTAGENESIS OF ILE-208; SER-213; ILE-300; GLY-301; SER-369 AND ARG-372.
RX PubMed=18779312; DOI=10.1124/dmd.108.023770;
RA DeVore N.M., Smith B.D., Urban M.J., Scott E.E.;
RT "Key residues controlling phenacetin metabolism by human cytochrome P450 2A
RT enzymes.";
RL Drug Metab. Dispos. 36:2582-2590(2008).
RN [19]
RP CHARACTERIZATION OF VARIANT CYP2A6*2 HIS-160.
RX 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 CYP2A6
RT causes switching from 7-hydroxylation to 3-hydroxylation of coumarin.";
RL Food Chem. Toxicol. 35:903-907(1997).
RN [20]
RP VARIANT CYP2A6*5 VAL-479.
RX 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 CYP2A
RT locus: implications for nicotine metabolism.";
RL FEBS Lett. 460:321-327(1999).
RN [21]
RP VARIANTS CYP2A6*7 THR-471 AND CYP2A6*8 LEU-485.
RX PubMed=11237731; DOI=10.1006/bbrc.2001.4422;
RA Ariyoshi N., Sawamura Y., Kamataki T.;
RT "A novel single nucleotide polymorphism altering stability and activity of
RT CYP2a6.";
RL Biochem. Biophys. Res. Commun. 281:810-814(2001).
RN [22]
RP VARIANTS CYP2A6*13 ARG-5; CYP2A6*14 ASN-29; CYP2A6*15 GLU-194 AND CYP2A6*16
RP 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 gene
RT in Japanese and Caucasians.";
RL Drug Metab. Pharmacokinet. 17:482-487(2002).
RN [23]
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, nine
RT esterase genes, and two other genes in the Japanese population.";
RL J. Hum. Genet. 48:249-270(2003).
RN [24]
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 ethnically
RT diverse population.";
RL Pharmacogenomics 5:895-931(2004).
RN [25]
RP VARIANTS LEU-110; LEU-118; LEU-128; ALA-131; ASP-418; ASP-419 AND TYR-438.
RX PubMed=18360915; DOI=10.1002/humu.20698;
RA Mwenifumbo J.C., Al Koudsi N., Ho M.K., Zhou Q., Hoffmann E.B.,
RA Sellers E.M., Tyndale R.F.;
RT "Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in
RT a population of Black African descent.";
RL Hum. Mutat. 29:679-688(2008).
RN [26]
RP VARIANTS CYS-203; SER-203 AND MET-365, AND CHARACTERIZATION OF VARIANT
RP CYS-203.
RX PubMed=18216723; DOI=10.1097/fpc.0b013e3282f3606e;
RA Ho M.K., Mwenifumbo J.C., Zhao B., Gillam E.M., Tyndale R.F.;
RT "A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in
RT vivo and decreases smoking in a population of Black-African descent.";
RL Pharmacogenet. Genomics 18:67-75(2008).
CC -!- FUNCTION: Exhibits a high coumarin 7-hydroxylase activity. Can act in
CC the hydroxylation of the anti-cancer drugs cyclophosphamide and
CC ifosphamide. Competent in the metabolic activation of aflatoxin B1.
CC Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-
CC monooxygenase. Possesses low phenacetin O-deethylation activity.
CC {ECO:0000269|PubMed:11695850, ECO:0000269|PubMed:16086027,
CC ECO:0000269|PubMed:17125252, ECO:0000269|PubMed:18779312,
CC ECO:0000269|PubMed:1889415, ECO:0000269|PubMed:1944238}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,4-cineole + O2 + reduced [NADPH--hemoprotein reductase] = 2-
CC exo-hydroxy-1,4-cineole + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:49160, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:80788,
CC ChEBI:CHEBI:90956; Evidence={ECO:0000269|PubMed:11695850};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.23 uM for coumarin {ECO:0000269|PubMed:16086027};
CC KM=530 uM for 1,4-cineole {ECO:0000269|PubMed:11695850};
CC Vmax=3.5 nmol/min/nmol enzyme toward 1,4-cineole
CC {ECO:0000269|PubMed:11695850};
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral
CC membrane protein. Microsome membrane; Peripheral membrane protein.
CC -!- TISSUE SPECIFICITY: Liver. {ECO:0000269|PubMed:1889415,
CC ECO:0000269|PubMed:1944238}.
CC -!- INDUCTION: By phenobarbital and dexamethasone.
CC {ECO:0000269|PubMed:1889415, ECO:0000269|PubMed:1944238}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA52147.1; Type=Miscellaneous discrepancy; Note=Numerous conflicts and frameshifts.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=PharmVar Pharmacogen Variation Consortium;
CC Note=CYP2A6 alleles;
CC URL="https://www.pharmvar.org/gene/CYP2A6";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/cyp2a6/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=CYP2A6 entry;
CC URL="https://en.wikipedia.org/wiki/CYP2A6";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CYP2A6ID40240ch19q13.html";
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DR EMBL; X13897; CAA32097.1; -; mRNA.
DR EMBL; X13929; CAA32117.1; -; mRNA.
DR EMBL; X13930; CAA32118.1; -; mRNA.
DR EMBL; M33318; AAA52067.1; -; mRNA.
DR EMBL; AF182275; AAF13600.1; -; mRNA.
DR EMBL; AK312964; BAG35803.1; -; mRNA.
DR EMBL; EU135979; ABV02584.1; -; Genomic_DNA.
DR EMBL; FJ440681; ACK44068.1; -; Genomic_DNA.
DR EMBL; AC008537; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471126; EAW57012.1; -; Genomic_DNA.
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 CCDS; CCDS12568.1; -.
DR PIR; A00190; O4HUPB.
DR PIR; S04698; O4HUA6.
DR RefSeq; NP_000753.3; NM_000762.5.
DR PDB; 1Z10; X-ray; 1.90 A; A/B/C/D=29-494.
DR PDB; 1Z11; X-ray; 2.05 A; A/B/C/D=29-494.
DR PDB; 2FDU; X-ray; 1.85 A; A/B/C/D=29-494.
DR PDB; 2FDV; X-ray; 1.65 A; A/B/C/D=29-494.
DR PDB; 2FDW; X-ray; 2.05 A; A/B/C/D=29-494.
DR PDB; 2FDY; X-ray; 1.95 A; A/B/C/D=29-494.
DR PDB; 3EBS; X-ray; 2.15 A; A/B/C/D=29-494.
DR PDB; 3T3Q; X-ray; 2.10 A; A/B/C/D=29-494.
DR PDB; 3T3R; X-ray; 2.40 A; A/B/C/D=29-494.
DR PDB; 4EJJ; X-ray; 2.30 A; A/B/C/D=29-494.
DR PDB; 4RUI; X-ray; 2.61 A; A/B/C/D/E/F=29-494.
DR PDBsum; 1Z10; -.
DR PDBsum; 1Z11; -.
DR PDBsum; 2FDU; -.
DR PDBsum; 2FDV; -.
DR PDBsum; 2FDW; -.
DR PDBsum; 2FDY; -.
DR PDBsum; 3EBS; -.
DR PDBsum; 3T3Q; -.
DR PDBsum; 3T3R; -.
DR PDBsum; 4EJJ; -.
DR PDBsum; 4RUI; -.
DR AlphaFoldDB; P11509; -.
DR SMR; P11509; -.
DR BioGRID; 107927; 5.
DR IntAct; P11509; 2.
DR STRING; 9606.ENSP00000301141; -.
DR BindingDB; P11509; -.
DR ChEMBL; CHEMBL5282; -.
DR DrugBank; DB07621; (5-(PYRIDIN-3-YL)FURAN-2-YL)METHANAMINE.
DR DrugBank; DB07623; 4,4'-DIPYRIDYL DISULFIDE.
DR DrugBank; DB00316; Acetaminophen.
DR DrugBank; DB01118; Amiodarone.
DR DrugBank; DB00182; Amphetamine.
DR DrugBank; DB01435; Antipyrine.
DR DrugBank; DB05676; Apremilast.
DR DrugBank; DB01274; Arformoterol.
DR DrugBank; DB09274; Artesunate.
DR DrugBank; DB11586; Asunaprevir.
DR DrugBank; DB00972; Azelastine.
DR DrugBank; DB00443; Betamethasone.
DR DrugBank; DB01222; Budesonide.
DR DrugBank; DB06119; Cenobamate.
DR DrugBank; DB00356; Chlorzoxazone.
DR DrugBank; DB00568; Cinnarizine.
DR DrugBank; DB00604; Cisapride.
DR DrugBank; DB06470; Clomethiazole.
DR DrugBank; DB00257; Clotrimazole.
DR DrugBank; DB00363; Clozapine.
DR DrugBank; DB04665; Coumarin.
DR DrugBank; DB00531; Cyclophosphamide.
DR DrugBank; DB06292; Dapagliflozin.
DR DrugBank; DB01234; Dexamethasone.
DR DrugBank; DB14649; Dexamethasone acetate.
DR DrugBank; DB00216; Eletriptan.
DR DrugBank; DB00330; Ethambutol.
DR DrugBank; DB01039; Fenofibrate.
DR DrugBank; DB04841; Flunarizine.
DR DrugBank; DB01544; Flunitrazepam.
DR DrugBank; DB00544; Fluorouracil.
DR DrugBank; DB00690; Flurazepam.
DR DrugBank; DB01213; Fomepizole.
DR DrugBank; DB00983; Formoterol.
DR DrugBank; DB01159; Halothane.
DR DrugBank; DB00741; Hydrocortisone.
DR DrugBank; DB01181; Ifosfamide.
DR DrugBank; DB00951; Isoniazid.
DR DrugBank; DB01026; Ketoconazole.
DR DrugBank; DB01006; Letrozole.
DR DrugBank; DB00281; Lidocaine.
DR DrugBank; DB06448; Lonafarnib.
DR DrugBank; DB04871; Lorcaserin.
DR DrugBank; DB01043; Memantine.
DR DrugBank; DB00170; Menadione.
DR DrugBank; DB00763; Methimazole.
DR DrugBank; DB00553; Methoxsalen.
DR DrugBank; DB01028; Methoxyflurane.
DR DrugBank; DB00959; Methylprednisolone.
DR DrugBank; DB00916; Metronidazole.
DR DrugBank; DB01011; Metyrapone.
DR DrugBank; DB01110; Miconazole.
DR DrugBank; DB00471; Montelukast.
DR DrugBank; DB07609; N,N-DIMETHYL(5-(PYRIDIN-3-YL)FURAN-2-YL)METHANAMINE.
DR DrugBank; DB07617; N-METHYL(5-(PYRIDIN-3-YL)FURAN-2-YL)METHANAMINE.
DR DrugBank; DB00238; Nevirapine.
DR DrugBank; DB00184; Nicotine.
DR DrugBank; DB01115; Nifedipine.
DR DrugBank; DB06712; Nilvadipine.
DR DrugBank; DB00717; Norethisterone.
DR DrugBank; DB00312; Pentobarbital.
DR DrugBank; DB03783; Phenacetin.
DR DrugBank; DB01174; Phenobarbital.
DR DrugBank; DB00252; Phenytoin.
DR DrugBank; DB01085; Pilocarpine.
DR DrugBank; DB04977; Plitidepsin.
DR DrugBank; DB14631; Prednisolone phosphate.
DR DrugBank; DB00635; Prednisone.
DR DrugBank; DB00396; Progesterone.
DR DrugBank; DB01045; Rifampicin.
DR DrugBank; DB15119; Ropeginterferon alfa-2b.
DR DrugBank; DB01037; Selegiline.
DR DrugBank; DB06739; Seratrodast.
DR DrugBank; DB01236; Sevoflurane.
DR DrugBank; DB00675; Tamoxifen.
DR DrugBank; DB09256; Tegafur.
DR DrugBank; DB09327; Tegafur-uracil.
DR DrugBank; DB00752; Tranylcypromine.
DR DrugBank; DB00755; Tretinoin.
DR DrugBank; DB12245; Triclabendazole.
DR DrugBank; DB00313; Valproic acid.
DR DrugBank; DB09068; Vortioxetine.
DR DrugBank; DB00495; Zidovudine.
DR DrugCentral; P11509; -.
DR GuidetoPHARMACOLOGY; 1321; -.
DR iPTMnet; P11509; -.
DR PhosphoSitePlus; P11509; -.
DR BioMuta; CYP2A6; -.
DR DMDM; 308153612; -.
DR MassIVE; P11509; -.
DR PaxDb; P11509; -.
DR PeptideAtlas; P11509; -.
DR PRIDE; P11509; -.
DR ProteomicsDB; 52786; -.
DR Antibodypedia; 55503; 505 antibodies from 32 providers.
DR DNASU; 1548; -.
DR Ensembl; ENST00000301141.10; ENSP00000301141.4; ENSG00000255974.8.
DR GeneID; 1548; -.
DR KEGG; hsa:1548; -.
DR MANE-Select; ENST00000301141.10; ENSP00000301141.4; NM_000762.6; NP_000753.3.
DR UCSC; uc002opl.4; human.
DR CTD; 1548; -.
DR DisGeNET; 1548; -.
DR GeneCards; CYP2A6; -.
DR HGNC; HGNC:2610; CYP2A6.
DR HPA; ENSG00000255974; Tissue enriched (liver).
DR MalaCards; CYP2A6; -.
DR MIM; 122720; gene+phenotype.
DR neXtProt; NX_P11509; -.
DR OpenTargets; ENSG00000255974; -.
DR Orphanet; 529831; Letrozole toxicity.
DR PharmGKB; PA121; -.
DR VEuPathDB; HostDB:ENSG00000255974; -.
DR eggNOG; KOG0156; Eukaryota.
DR GeneTree; ENSGT00940000154117; -.
DR InParanoid; P11509; -.
DR OMA; FGWIFEN; -.
DR OrthoDB; 702827at2759; -.
DR PhylomeDB; P11509; -.
DR TreeFam; TF352043; -.
DR BioCyc; MetaCyc:HS10343-MON; -.
DR BRENDA; 1.14.14.1; 2681.
DR PathwayCommons; P11509; -.
DR Reactome; R-HSA-211981; Xenobiotics.
DR Reactome; R-HSA-211999; CYP2E1 reactions.
DR SABIO-RK; P11509; -.
DR SignaLink; P11509; -.
DR BioGRID-ORCS; 1548; 7 hits in 999 CRISPR screens.
DR ChiTaRS; CYP2A6; human.
DR EvolutionaryTrace; P11509; -.
DR GeneWiki; CYP2A6; -.
DR GenomeRNAi; 1548; -.
DR Pharos; P11509; Tchem.
DR PRO; PR:P11509; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; P11509; protein.
DR Bgee; ENSG00000255974; Expressed in right lobe of liver and 148 other tissues.
DR ExpressionAtlas; P11509; baseline and differential.
DR Genevisible; P11509; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005881; C:cytoplasmic microtubule; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0008392; F:arachidonic acid epoxygenase activity; IBA:GO_Central.
DR GO; GO:0008389; F:coumarin 7-hydroxylase activity; IDA:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; IPI:BHF-UCL.
DR GO; GO:0020037; F:heme binding; IDA:UniProtKB.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
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; IBA:GO_Central.
DR GO; GO:0008395; F:steroid hydroxylase activity; IBA:GO_Central.
DR GO; GO:0046226; P:coumarin catabolic process; IDA:BHF-UCL.
DR GO; GO:0009804; P:coumarin metabolic process; IDA:BHF-UCL.
DR GO; GO:0019373; P:epoxygenase P450 pathway; IBA:GO_Central.
DR GO; GO:0006082; P:organic acid metabolic process; IBA:GO_Central.
DR GO; GO:0008202; P:steroid metabolic process; IMP:BHF-UCL.
DR GO; GO:0042178; P:xenobiotic catabolic process; IDA:BHF-UCL.
DR GO; GO:0006805; P:xenobiotic metabolic process; IDA:BHF-UCL.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR008067; Cyt_P450_E_grp-I_CYP2A-like.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR01684; EP450ICYP2A.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Endoplasmic reticulum; Heme; Iron;
KW Lipid metabolism; Membrane; Metal-binding; Microsome; Monooxygenase; NADP;
KW Oxidoreductase; Reference proteome.
FT CHAIN 1..494
FT /note="Cytochrome P450 2A6"
FT /id="PRO_0000051668"
FT BINDING 107
FT /ligand="substrate"
FT /evidence="ECO:0000305"
FT BINDING 297
FT /ligand="substrate"
FT BINDING 439
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT VARIANT 5
FT /note="G -> R (in allele CYP2A6*13; dbSNP:rs28399434)"
FT /evidence="ECO:0000269|PubMed:15469410,
FT ECO:0000269|PubMed:15618701"
FT /id="VAR_018330"
FT VARIANT 29
FT /note="S -> N (in allele CYP2A6*14; dbSNP:rs28399435)"
FT /evidence="ECO:0000269|PubMed:15469410,
FT ECO:0000269|PubMed:15618701, ECO:0000269|PubMed:2726448"
FT /id="VAR_018331"
FT VARIANT 110
FT /note="V -> L (in allele CYP2A6*24; increases phenacetin O-
FT deethylation activity 4 fold; dbSNP:rs72549435)"
FT /evidence="ECO:0000269|PubMed:18360915,
FT ECO:0000269|PubMed:18779312"
FT /id="VAR_055035"
FT VARIANT 118
FT /note="F -> L (in allele CYP2A6*25 and allele CYP2A6*26;
FT dbSNP:rs28399440)"
FT /evidence="ECO:0000269|PubMed:15469410,
FT ECO:0000269|PubMed:18360915"
FT /id="VAR_024711"
FT VARIANT 128
FT /note="R -> L (in allele CYP2A6*26; dbSNP:rs4986891)"
FT /evidence="ECO:0000269|PubMed:18360915"
FT /id="VAR_055036"
FT VARIANT 128
FT /note="R -> Q (in allele CYP2A6*6; loss of activity;
FT dbSNP:rs4986891)"
FT /evidence="ECO:0000269|PubMed:11278503,
FT ECO:0000269|PubMed:15469410"
FT /id="VAR_011577"
FT VARIANT 131
FT /note="S -> A (in allele CYP2A6*26; dbSNP:rs59552350)"
FT /evidence="ECO:0000269|PubMed:18360915"
FT /id="VAR_055037"
FT VARIANT 160
FT /note="L -> H (in allele CYP2A6*2; unable to catalyze 7-
FT hydroxylation of coumarin; causes switching from coumarin
FT 7-hydroxylation to 3-hydroxylation; dbSNP:rs1801272)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:2322567, ECO:0000269|PubMed:2748347,
FT ECO:0000269|PubMed:9409631"
FT /id="VAR_001249"
FT VARIANT 194
FT /note="K -> E (in allele CYP2A6*15; dbSNP:rs199916117)"
FT /evidence="ECO:0000269|PubMed:15618701"
FT /id="VAR_018332"
FT VARIANT 203
FT /note="R -> C (in allele CYP2A6*23; greatly reduced
FT activity toward nicotine C-oxidation as well as reduced
FT coumarin 7-hydroxylation; dbSNP:rs56256500)"
FT /evidence="ECO:0000269|PubMed:18216723"
FT /id="VAR_055034"
FT VARIANT 203
FT /note="R -> S (in allele CYP2A6*16; dbSNP:rs56256500)"
FT /evidence="ECO:0000269|PubMed:15618701,
FT ECO:0000269|PubMed:18216723"
FT /id="VAR_018333"
FT VARIANT 224
FT /note="S -> P (in dbSNP:rs28399447)"
FT /evidence="ECO:0000269|PubMed:15469410"
FT /id="VAR_024712"
FT VARIANT 292
FT /note="V -> M (in dbSNP:rs2644906)"
FT /id="VAR_059149"
FT VARIANT 294
FT /note="T -> S (in dbSNP:rs4997557)"
FT /id="VAR_048448"
FT VARIANT 365
FT /note="V -> M (in allele CYP2A6*17; increases phenacetin O-
FT deethylation activity 2 fold; dbSNP:rs28399454)"
FT /evidence="ECO:0000269|PubMed:15469410,
FT ECO:0000269|PubMed:18216723, ECO:0000269|PubMed:18779312"
FT /id="VAR_024713"
FT VARIANT 392
FT /note="Y -> F (in dbSNP:rs1809810)"
FT /evidence="ECO:0000269|Ref.6"
FT /id="VAR_055033"
FT VARIANT 418
FT /note="N -> D (in allele CYP2A6*28; dbSNP:rs28399463)"
FT /evidence="ECO:0000269|PubMed:15469410,
FT ECO:0000269|PubMed:18360915"
FT /id="VAR_024714"
FT VARIANT 419
FT /note="E -> D (in allele CYP2A6*28; dbSNP:rs8192730)"
FT /evidence="ECO:0000269|PubMed:12721789,
FT ECO:0000269|PubMed:15469410, ECO:0000269|PubMed:18360915"
FT /id="VAR_018375"
FT VARIANT 438
FT /note="N -> Y (in allele CYP2A6*24; dbSNP:rs143731390)"
FT /evidence="ECO:0000269|PubMed:18360915"
FT /id="VAR_055038"
FT VARIANT 471
FT /note="I -> T (in allele CYP2A6*7; dbSNP:rs5031016)"
FT /evidence="ECO:0000269|PubMed:11237731,
FT ECO:0000269|PubMed:12721789, ECO:0000269|PubMed:15469410"
FT /id="VAR_011578"
FT VARIANT 476
FT /note="K -> R (in dbSNP:rs6413474)"
FT /evidence="ECO:0000269|PubMed:15469410,
FT ECO:0000269|PubMed:15489334"
FT /id="VAR_024715"
FT VARIANT 479
FT /note="G -> V (in allele CYP2A6*5; loss of activity;
FT dbSNP:rs5031017)"
FT /evidence="ECO:0000269|PubMed:10544257, ECO:0000269|Ref.4"
FT /id="VAR_008356"
FT VARIANT 485
FT /note="R -> L (in allele CYP2A6*8; dbSNP:rs28399468)"
FT /evidence="ECO:0000269|PubMed:11237731,
FT ECO:0000269|PubMed:15469410"
FT /id="VAR_011579"
FT MUTAGEN 208
FT /note="I->S: Increases phenacetin O-deethylation activity
FT 10 fold; when associated with F-300 and A-301. Increases
FT phenacetin O-deethylation activity 38 fold; when associated
FT with F-300; A-301 and G-369."
FT /evidence="ECO:0000269|PubMed:18779312"
FT MUTAGEN 213
FT /note="S->A: No effect on phenacetin O-deethylation
FT activity."
FT /evidence="ECO:0000269|PubMed:18779312"
FT MUTAGEN 300
FT /note="I->F: Increases phenacetin O-deethylation activity 3
FT fold. Increases phenacetin O-deethylation activity 8 fold;
FT when associated with A-301. Increases phenacetin O-
FT deethylation activity 10 fold; when associated with S-208
FT and A-301. Increases phenacetin O-deethylation activity 12
FT fold; when associated with A-301 and G-369. Increases
FT phenacetin O-deethylation activity 38 fold; when associated
FT with S-208; A-301 and G-369."
FT /evidence="ECO:0000269|PubMed:18779312"
FT MUTAGEN 301
FT /note="G->A: Slightly decreases phenacetin O-deethylation
FT activity. Increases phenacetin O-deethylation activity 8
FT fold; when associated with F-300. Increases phenacetin O-
FT deethylation activity 10 fold; when associated with S-208
FT and F-300. Increases phenacetin O-deethylation activity 12
FT fold; when associated with F-300 and G-369. Increases
FT phenacetin O-deethylation activity 38 fold; when associated
FT with S-208; F-300 and G-369."
FT /evidence="ECO:0000269|PubMed:18779312"
FT MUTAGEN 369
FT /note="S->G: Increases phenacetin O-deethylation activity 3
FT fold. Increases phenacetin O-deethylation activity 38 fold;
FT when associated with S-208; F-300 and A-301."
FT /evidence="ECO:0000269|PubMed:18779312"
FT MUTAGEN 372
FT /note="R->H: Increases phenacetin O-deethylation activity 2
FT fold."
FT /evidence="ECO:0000269|PubMed:18779312"
FT CONFLICT 3..7
FT /note="Missing (in Ref. 1; CAA32097)"
FT /evidence="ECO:0000305"
FT CONFLICT 255
FT /note="N -> K (in Ref. 1; CAA32097)"
FT /evidence="ECO:0000305"
FT CONFLICT 326
FT /note="K -> Q (in Ref. 1; CAA32097)"
FT /evidence="ECO:0000305"
FT TURN 41..43
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 46..48
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 51..53
FT /evidence="ECO:0007829|PDB:2FDU"
FT HELIX 54..65
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 67..73
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 76..81
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 84..91
FT /evidence="ECO:0007829|PDB:2FDV"
FT TURN 92..98
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 105..111
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 115..118
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 121..137
FT /evidence="ECO:0007829|PDB:2FDV"
FT TURN 138..141
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 143..162
FT /evidence="ECO:0007829|PDB:2FDV"
FT TURN 163..165
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 171..187
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 196..212
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 215..227
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 230..232
FT /evidence="ECO:0007829|PDB:2FDY"
FT HELIX 233..256
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 267..277
FT /evidence="ECO:0007829|PDB:2FDV"
FT TURN 278..280
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 288..319
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 321..334
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 337..339
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 343..348
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 350..363
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 378..380
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 383..385
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 390..393
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 395..399
FT /evidence="ECO:0007829|PDB:2FDV"
FT TURN 402..404
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 405..407
FT /evidence="ECO:0007829|PDB:4RUI"
FT HELIX 413..416
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 419..421
FT /evidence="ECO:0007829|PDB:3T3Q"
FT HELIX 442..459
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 460..466
FT /evidence="ECO:0007829|PDB:2FDV"
FT HELIX 468..470
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 476..483
FT /evidence="ECO:0007829|PDB:2FDV"
FT STRAND 489..493
FT /evidence="ECO:0007829|PDB:2FDV"
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
