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 02-DEC-2020, entry version 223. DE RecName: Full=Cytochrome P450 2A6; DE EC=1.14.13.-; 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=Cytochrome P450 Allele Nomenclature Committee; CC Note=CYP2A6 alleles; CC URL="http://www.cypalleles.ki.se/cyp2a6.htm"; 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"; 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; 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 SMR; P11509; -. DR BioGRID; 107927; 4. 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; 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; 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; DB00412; Rosiglitazone. 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; 468 antibodies. DR DNASU; 1548; -. DR Ensembl; ENST00000301141; ENSP00000301141; ENSG00000255974. DR GeneID; 1548; -. DR KEGG; hsa:1548; -. DR UCSC; uc002opl.4; human. DR CTD; 1548; -. DR DisGeNET; 1548; -. DR EuPathDB; HostDB:ENSG00000255974.6; -. 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 eggNOG; KOG0156; Eukaryota. DR GeneTree; ENSGT00940000154117; -. DR InParanoid; P11509; -. DR OMA; AFNADDY; -. DR OrthoDB; 702827at2759; -. DR PhylomeDB; P11509; -. DR TreeFam; TF352043; -. DR BioCyc; MetaCyc:HS10343-MONOMER; -. 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 BioGRID-ORCS; 1548; 2 hits in 818 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 175 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:0017144; P:drug metabolic process; IDA:BHF-UCL. DR GO; GO:0019373; P:epoxygenase P450 pathway; IBA:GO_Central. DR GO; GO:0042738; P:exogenous drug catabolic process; IDA:BHF-UCL. DR GO; GO:0006082; P:organic acid metabolic process; IBA:GO_Central. DR GO; GO:0055114; P:oxidation-reduction process; IBA:GO_Central. DR GO; GO:0008202; P:steroid metabolic process; IMP:BHF-UCL. DR GO; GO:0006805; P:xenobiotic metabolic process; IBA:GO_Central. 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 Membrane; Metal-binding; Microsome; Monooxygenase; NADP; Oxidoreductase; KW Polymorphism; Reference proteome. FT CHAIN 1..494 FT /note="Cytochrome P450 2A6" FT /id="PRO_0000051668" FT METAL 439 FT /note="Iron (heme axial ligand)" FT BINDING 107 FT /note="Substrate" FT /evidence="ECO:0000305" FT BINDING 297 FT /note="Substrate" 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:0000244|PDB:2FDV" FT HELIX 46..48 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 51..53 FT /evidence="ECO:0000244|PDB:2FDU" FT HELIX 54..65 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 67..73 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 76..81 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 84..91 FT /evidence="ECO:0000244|PDB:2FDV" FT TURN 92..98 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 105..111 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 115..118 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 121..137 FT /evidence="ECO:0000244|PDB:2FDV" FT TURN 138..141 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 143..162 FT /evidence="ECO:0000244|PDB:2FDV" FT TURN 163..165 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 171..187 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 196..212 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 215..227 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 230..232 FT /evidence="ECO:0000244|PDB:2FDY" FT HELIX 233..256 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 267..277 FT /evidence="ECO:0000244|PDB:2FDV" FT TURN 278..280 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 288..319 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 321..334 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 337..339 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 343..348 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 350..363 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 378..380 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 383..385 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 390..393 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 395..399 FT /evidence="ECO:0000244|PDB:2FDV" FT TURN 402..404 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 405..407 FT /evidence="ECO:0000244|PDB:4RUI" FT HELIX 413..416 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 419..421 FT /evidence="ECO:0000244|PDB:3T3Q" FT HELIX 442..459 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 460..466 FT /evidence="ECO:0000244|PDB:2FDV" FT HELIX 468..470 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 476..483 FT /evidence="ECO:0000244|PDB:2FDV" FT STRAND 489..493 FT /evidence="ECO:0000244|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 //