ID CP2C9_HUMAN Reviewed; 490 AA. AC P11712; P11713; Q16756; Q16872; DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot. DT 30-MAY-2000, sequence version 3. DT 01-JUL-2008, entry version 104. DE Cytochrome P450 2C9 (EC 1.14.13.80) ((R)-limonene 6-monooxygenase) DE (EC 1.14.13.48) ((S)-limonene 6-monooxygenase) (EC 1.14.13.49) ((S)- DE limonene 7-monooxygenase) (CYPIIC9) (P450 PB-1) (P450 MP-4/MP-8) (S- DE mephenytoin 4-hydroxylase) (P-450MP). GN Name=CYP2C9; Synonyms=CYP2C10; 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. RX MEDLINE=88103561; PubMed=2827463; RA Meehan R.R., Gosden J.R., Rout D., Hastie N.D., Friedberg T., RA Adesnik M., Buckland R., van Heyningen V., Fletcher J.M., Spurr N.K., RA Sweeney J., Wolf C.R.; RT "Human cytochrome P-450 PB-1: a multigene family involved in RT mephenytoin and steroid oxidations that maps to chromosome 10."; RL Am. J. Hum. Genet. 42:26-37(1988). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX MEDLINE=88096500; PubMed=3697070; DOI=10.1093/nar/15.23.10053; RA Kimura S., Pastewka J., Gelboin H.V., Gonzalez F.J.; RT "cDNA and amino acid sequences of two members of the human P450IIC RT gene subfamily."; RL Nucleic Acids Res. 15:10053-10054(1987). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS CYS-144; HIS-150; RP ARG-251; GLY-272; LEU-359 AND SER-489. RA Rieder M.J., Livingston R.J., Daniels M.R., Chung M.-W., RA Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., RA Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A.; RT "NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department RT of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)."; RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-490. RC TISSUE=Liver; RX MEDLINE=88139258; PubMed=2963808; RA Yasumori T., Kawano S., Nagata K., Shimada M., Yamazoe Y., Kato R.; RT "Nucleotide sequence of a human liver cytochrome P-450 related to the RT rat male specific form."; RL J. Biochem. 102:1075-1082(1987). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 6-490, AND VARIANTS CYS-358 AND ASP-417. RC TISSUE=Liver; RX MEDLINE=87185403; PubMed=3032244; DOI=10.1021/bi00378a016; RA Umbenhauer D.R., Martin M.V., Lloyd R.S., Guengerich F.P.; RT "Cloning and sequence determination of a complementary DNA related to RT human liver microsomal cytochrome P-450 S-mephenytoin 4-hydroxylase."; RL Biochemistry 26:1094-1099(1987). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 6-490, AND VARIANTS CYS-358 AND ASP-417. RX MEDLINE=89062423; PubMed=3196692; DOI=10.1021/bi00418a039; RA Ged C., Umbenhauer D.R., Bellew T.M., Bork R.W., Srivastava P.K., RA Shinriki N., Lloyd R.S., Guengerich F.P.; RT "Characterization of cDNAs, mRNAs, and proteins related to human liver RT microsomal cytochrome P-450 (S)-mephenytoin 4'-hydroxylase."; RL Biochemistry 27:6929-6940(1988). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 14-490. RX MEDLINE=93075249; PubMed=1445376; RA Ohgiya S., Komori M., Ohi H., Shiramatsu K., Shinriki N., Kamataki T.; RT "Six-base deletion occurring in messages of human cytochrome P-450 in RT the CYP2C subfamily results in reduction of tolbutamide hydroxylase RT activity."; RL Biochem. Int. 27:1073-1081(1992). RN [8] RP PROTEIN SEQUENCE OF 1-29, AND CHARACTERIZATION. RX MEDLINE=86085934; PubMed=3079764; RA Shimada T., Misono K.S., Guengerich F.P.; RT "Human liver microsomal cytochrome P-450 mephenytoin 4-hydroxylase, a RT prototype of genetic polymorphism in oxidative drug metabolism. RT Purification and characterization of two similar forms involved in the RT reaction."; RL J. Biol. Chem. 261:909-921(1986). RN [9] RP PROTEIN SEQUENCE OF 1-25. RX MEDLINE=89214010; PubMed=3243766; RA Komori M., Hashizume T., Ohi H., Miura T., Kitada M., Nagashima K., RA Kamataki T.; RT "Cytochrome P-450 in human liver microsomes: high-performance liquid RT chromatographic isolation of three forms and their characterization."; RL J. Biochem. 104:912-916(1988). RN [10] RP PARTIAL PROTEIN SEQUENCE. RX MEDLINE=91312325; PubMed=1857342; RA Srivastava P.K., Yun C.H., Beaune P.H., Ged C., Guengerich F.P.; RT "Separation of human liver microsomal tolbutamide hydroxylase and (S)- RT mephenytoin 4'-hydroxylase cytochrome P-450 enzymes."; RL Mol. Pharmacol. 40:69-79(1991). RN [11] RP PROTEIN SEQUENCE OF 1-9; 21-157; 169-249; 264-424; 426-476 AND RP 484-487. RX MEDLINE=96404946; PubMed=8809086; DOI=10.1006/abbi.1996.0414; RA Haining R.L., Hunter A.P., Veronese M.E., Trager W.F., Rettie A.E.; RT "Allelic variants of human cytochrome P450 2C9: baculovirus-mediated RT expression, purification, structural characterization, substrate RT stereoselectivity, and prochiral selectivity of the wild-type and RT I359L mutant forms."; RL Arch. Biochem. Biophys. 333:447-458(1996). RN [12] RP PROTEIN SEQUENCE OF 1-20. RX MEDLINE=94029017; PubMed=8215449; DOI=10.1006/abbi.1993.1536; RA Sandhu P., Baba T., Guengerich F.P.; RT "Expression of modified cytochrome P450 2C10 (2C9) in Escherichia RT coli, purification, and reconstitution of catalytic activity."; RL Arch. Biochem. Biophys. 306:443-450(1993). RN [13] RP CHARACTERIZATION. RX MEDLINE=21947688; PubMed=11950794; DOI=10.1124/dmd.30.5.602; RA Miyazawa M., Shindo M., Shimada T.; RT "Metabolism of (+)- and (-)-limonenes to respective carveols and RT perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes."; RL Drug Metab. Dispos. 30:602-607(2002). RN [14] RP X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) OF 30-490. RX MEDLINE=22761295; PubMed=12861225; DOI=10.1038/nature01862; RA Williams P.A., Cosme J., Ward A., Angove H.C., Matak-Vinkovic D., RA Jhoti H.; RT "Crystal structure of human cytochrome P450 2C9 with bound warfarin."; RL Nature 424:464-468(2003). RN [15] RP VARIANTS CYP2C9*2 CYS-144 AND CYP2C9*3 LEU-359. RX MEDLINE=97101957; PubMed=8946475; RA Stubbins M.J., Harries L.W., Smith G., Tarbit M.H., Wolf C.R.; RT "Genetic analysis of the human cytochrome P450 CYP2C9 locus."; RL Pharmacogenetics 6:429-439(1996). RN [16] RP VARIANTS CYP2C9*2 CYS-144; CYS-358; CYP2C9*3 LEU-359 AND ASP-417. RX MEDLINE=97264536; PubMed=9110362; RA Bhasker C.R., Miners J.O., Coulter S., Birkett D.J.; RT "Allelic and functional variability of cytochrome P4502C9."; RL Pharmacogenetics 7:51-58(1997). RN [17] RP VARIANT CYP2C9*4 THR-359. RX MEDLINE=20201783; PubMed=10739176; RX DOI=10.1097/00008571-200002000-00011; RA Imai J., Ieiri I., Mamiya K., Miyahara S., Furuumi H., Nanba E., RA Yamane M., Fukumaki Y., Ninomiya H., Tashiro N., Otsubo K., RA Higuchi S.; RT "Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese RT epileptic patients: genetic analysis of the CYP2C9 locus."; RL Pharmacogenetics 10:85-89(2000). RN [18] RP VARIANT CYP2C9*5 GLU-360. RX MEDLINE=21348506; PubMed=11455026; RA Dickmann L.J., Rettie A.E., Kneller M.B., Kim R.B., Wood A.J., RA Stein C.M., Wilkinson G.R., Schwarz U.I.; RT "Identification and functional characterization of a new CYP2C9 RT variant (CYP2C9*5) expressed among African Americans."; RL Mol. Pharmacol. 60:382-387(2001). RN [19] RP VARIANT CYP2C9*11 TRP-335. RX MEDLINE=21925104; PubMed=11926893; DOI=10.1001/jama.287.13.1690; RA Higashi M.K., Veenstra D.L., Kondo L.M., Wittkowsky A.K., RA Srinouanprachanh S.L., Farin F.M., Rettie A.E.; RT "Association between CYP2C9 genetic variants and anticoagulation- RT related outcomes during warfarin therapy."; RL JAMA 287:1690-1698(2002). RN [20] RP VARIANTS CYS-144; HIS-150; ARG-251; TRP-335; LEU-359; GLU-360 AND RP PRO-413. 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: Cytochromes P450 are a group of heme-thiolate CC monooxygenases. In liver microsomes, this enzyme is involved in an CC NADPH-dependent electron transport pathway. It oxidizes a variety CC of structurally unrelated compounds, including steroids, fatty CC acids, and xenobiotics. This enzyme contributes to the wide CC pharmacokinetics variability of the metabolism of drugs such as S- CC warfarin, diclofenac, phenytoin, tolbutamide and losartan. CC -!- CATALYTIC ACTIVITY: (+)-(R)-limonene + NADPH + O(2) = (+)-trans- CC carveol + NADP(+) + H(2)O. CC -!- CATALYTIC ACTIVITY: (-)-(S)-limonene + NADPH + O(2) = (-)-trans- CC carveol + NADP(+) + H(2)O. CC -!- CATALYTIC ACTIVITY: (-)-(S)-limonene + NADPH + O(2) = (-)-perillyl CC alcohol + 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 rifampicin. CC -!- SIMILARITY: Belongs to the cytochrome P450 family. CC -!- WEB RESOURCE: Name=Cytochrome P450 Allele Nomenclature Committee; CC Note=CYP2C9 alleles; CC URL="http://www.cypalleles.ki.se/cyp2c9.htm"; 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; M21940; AAA52159.1; -; mRNA. DR EMBL; AY341248; AAP88931.1; -; Genomic_DNA. DR EMBL; AY702706; AAT94065.1; -; Genomic_DNA. DR EMBL; M15331; AAA52157.1; -; mRNA. DR EMBL; D00173; BAA00123.1; -; mRNA. DR EMBL; M21939; AAA52158.1; -; mRNA. DR EMBL; S46963; AAB23864.2; ALT_SEQ; mRNA. DR PIR; B38462; B38462. DR PIR; D28951; D28951. DR RefSeq; NP_000762.2; -. DR UniGene; Hs.282624; -. DR PDB; 1OG2; X-ray; 2.60 A; A/B=30-490. DR PDB; 1OG5; X-ray; 2.55 A; A/B=30-490. DR PDB; 1R9O; X-ray; 2.00 A; A=23-489. DR PDBsum; 1OG2; -. DR PDBsum; 1OG5; -. DR PDBsum; 1R9O; -. DR SMR; P11712; 44-490. DR Ensembl; ENSG00000138109; Homo sapiens. DR GeneID; 1559; -. DR KEGG; hsa:1559; -. DR H-InvDB; HIX0035375; -. DR HGNC; HGNC:2623; CYP2C9. DR MIM; 601130; gene. DR PharmGKB; PA126; -. DR HOGENOM; P11712; -. DR HOVERGEN; P11712; -. DR DrugBank; DB01418; Acenocoumarol. DR DrugBank; DB00969; Alosetron. DR DrugBank; DB01118; Amiodarone. DR DrugBank; DB00025; Antihemophilic Factor. DR DrugBank; DB00673; Aprepitant. DR DrugBank; DB00559; Bosentan. DR DrugBank; DB00821; Carprofen. DR DrugBank; DB01136; Carvedilol. DR DrugBank; DB00482; Celecoxib. DR DrugBank; DB01242; Clomipramine. DR DrugBank; DB00250; Dapsone. DR DrugBank; DB00705; Delavirdine. DR DrugBank; DB00967; Desloratadine. DR DrugBank; DB00304; Desogestrel. DR DrugBank; DB00586; Diclofenac. DR DrugBank; DB00736; Esomeprazole. DR DrugBank; DB00749; Etodolac. DR DrugBank; DB00196; Fluconazole. DR DrugBank; DB00472; Fluoxetine. DR DrugBank; DB00712; Flurbiprofen. DR DrugBank; DB01095; Fluvastatin. DR DrugBank; DB00176; Fluvoxamine. DR DrugBank; DB00983; Formoterol. DR DrugBank; DB01241; Gemfibrozil. DR DrugBank; DB01381; Ginkgo biloba. DR DrugBank; DB01016; Glibenclamide. DR DrugBank; DB00222; Glimepiride. DR DrugBank; DB01067; Glipizide. DR DrugBank; DB01018; Guanfacine. DR DrugBank; DB00327; Hydromorphone. DR DrugBank; DB01050; Ibuprofen. DR DrugBank; DB00458; Imipramine. DR DrugBank; DB01029; Irbesartan. DR DrugBank; DB01026; Ketoconazole. DR DrugBank; DB00448; Lansoprazole. DR DrugBank; DB00678; Losartan. DR DrugBank; DB01283; Lumiracoxib. DR DrugBank; DB00470; Marinol. DR DrugBank; DB00784; Mefenamic acid. DR DrugBank; DB00814; Meloxicam. DR DrugBank; DB00532; Mephenytoin. DR DrugBank; DB00916; Metronidazole. DR DrugBank; DB01110; Miconazole. DR DrugBank; DB00683; Midazolam. DR DrugBank; DB00471; Montelukast. DR DrugBank; DB00731; Nateglinide. DR DrugBank; DB00220; Nelfinavir. DR DrugBank; DB00622; Nicardipine. DR DrugBank; DB01192; Oxymorphone. DR DrugBank; DB00213; Pantoprazole. DR DrugBank; DB00617; Paramethadione. DR DrugBank; DB00946; Phenprocoumon. DR DrugBank; DB00252; Phenytoin. DR DrugBank; DB00175; Pravastatin. DR DrugBank; DB00908; Quinidine. DR DrugBank; DB00503; Ritonavir. DR DrugBank; DB00412; Rosiglitazone. DR DrugBank; DB01104; Sertraline. DR DrugBank; DB00203; Sildenafil. DR DrugBank; DB01015; Sulfamethoxazole. DR DrugBank; DB00870; Suprofen. DR DrugBank; DB00675; Tamoxifen. DR DrugBank; DB00469; Tenoxicam. DR DrugBank; DB00342; Terfenadine. DR DrugBank; DB01124; Tolbutamide. DR DrugBank; DB00214; Torasemide. DR DrugBank; DB01361; Troleandomycin. DR DrugBank; DB00580; Valdecoxib. DR DrugBank; DB00177; Valsartan. DR DrugBank; DB00582; Voriconazole. DR DrugBank; DB00682; Warfarin. DR DrugBank; DB00549; Zafirlukast. DR DrugBank; DB00744; Zileuton. DR LinkHub; P11712; -. DR ArrayExpress; P11712; -. DR CleanEx; HS_CYP2C9; -. DR GermOnline; ENSG00000138109; Homo sapiens. DR GO; GO:0005783; C:endoplasmic reticulum; NAS:UniProtKB. DR GO; GO:0005792; C:microsome; TAS:UniProtKB. DR GO; GO:0004497; F:monooxygenase activity; NAS:UniProtKB. DR GO; GO:0055114; P:oxidation reduction; NAS:UniProtKB. DR InterPro; IPR001128; Cyt_P450. DR InterPro; IPR002401; Cyt_P450_E_grp-I. DR InterPro; IPR008068; Cyt_P450_E_grp-I_CYP2B-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; PR01685; EP450ICYP2B. 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; NADP; KW Oxidoreductase; Polymorphism. FT CHAIN 1 490 Cytochrome P450 2C9. FT /FTId=PRO_0000051700. FT METAL 435 435 Iron (heme axial ligand). FT VARIANT 19 19 L -> I (in allele CYP2C9*7). FT /FTId=VAR_018862. FT VARIANT 144 144 R -> C (in allele CYP2C9*2; FT dbSNP:rs1799853). FT /FTId=VAR_008343. FT VARIANT 150 150 R -> H (in allele CYP2C9*8; FT dbSNP:rs7900194). FT /FTId=VAR_018863. FT VARIANT 251 251 H -> R (in allele CYP2C9*9; FT dbSNP:rs2256871). FT /FTId=VAR_018864. FT VARIANT 272 272 E -> G (in allele CYP2C9*10; FT dbSNP:rs9332130). FT /FTId=VAR_018865. FT VARIANT 335 335 R -> W (in allele CYP2C9*11). FT /FTId=VAR_018866. FT VARIANT 358 358 Y -> C (in dbSNP:rs1057909). FT /FTId=VAR_008344. FT VARIANT 359 359 I -> L (in allele CYP2C9*3; responsible FT for the tolbutamide poor metabolizer FT phenotype; dbSNP:rs1057910). FT /FTId=VAR_008345. FT VARIANT 359 359 I -> T (in allele CYP2C9*4). FT /FTId=VAR_013515. FT VARIANT 360 360 D -> E (in allele CYP2C9*5; increases the FT K(m) value for substrates tested). FT /FTId=VAR_013516. FT VARIANT 413 413 L -> P. FT /FTId=VAR_024717. FT VARIANT 417 417 G -> D. FT /FTId=VAR_008346. FT VARIANT 489 489 P -> S (in allele CYP2C9*12; FT dbSNP:rs9332239). FT /FTId=VAR_018867. FT CONFLICT 4 4 L -> I (in Ref. 2). FT CONFLICT 175 175 C -> Y (in Ref. 1). FT CONFLICT 239 239 F -> L (in Ref. 1). FT STRAND 33 35 FT HELIX 47 61 FT STRAND 63 71 FT STRAND 73 77 FT HELIX 80 87 FT TURN 88 94 FT TURN 105 107 FT HELIX 117 131 FT STRAND 134 136 FT HELIX 141 157 FT TURN 158 161 FT HELIX 167 183 FT HELIX 192 208 FT HELIX 230 253 FT HELIX 263 274 FT HELIX 284 315 FT HELIX 317 330 FT STRAND 333 335 FT HELIX 339 344 FT HELIX 346 359 FT STRAND 374 376 FT STRAND 379 381 FT STRAND 386 389 FT HELIX 392 395 FT TURN 398 400 FT STRAND 401 403 FT HELIX 409 412 FT HELIX 431 433 FT HELIX 438 455 FT STRAND 456 462 FT HELIX 464 466 FT STRAND 475 477 FT STRAND 485 489 SQ SEQUENCE 490 AA; 55628 MW; 4FDFC395303A4E3E CRC64; MDSLVVLVLC LSCLLLLSLW RQSSGRGKLP PGPTPLPVIG NILQIGIKDI SKSLTNLSKV YGPVFTLYFG LKPIVVLHGY EAVKEALIDL GEEFSGRGIF PLAERANRGF GIVFSNGKKW KEIRRFSLMT LRNFGMGKRS IEDRVQEEAR CLVEELRKTK ASPCDPTFIL GCAPCNVICS IIFHKRFDYK DQQFLNLMEK LNENIKILSS PWIQICNNFS PIIDYFPGTH NKLLKNVAFM KSYILEKVKE HQESMDMNNP QDFIDCFLMK MEKEKHNQPS EFTIESLENT AVDLFGAGTE TTSTTLRYAL LLLLKHPEVT AKVQEEIERV IGRNRSPCMQ DRSHMPYTDA VVHEVQRYID LLPTSLPHAV TCDIKFRNYL IPKGTTILIS LTSVLHDNKE FPNPEMFDPH HFLDEGGNFK KSKYFMPFSA GKRICVGEAL AGMELFLFLT SILQNFNLKS LVDPKNLDTT PVVNGFASVP PFYQLCFIPV //