Cytochrome P450 2C9 - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot P11712 (CP2C9_HUMAN)

Last modified July 7, 2009. Version 116. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Cytochrome P450 2C9
Alternative name(s):
    (R)-limonene 6-monooxygenase
    EC=1.14.13.80
    (S)-limonene 6-monooxygenase
    EC=1.14.13.48
    (S)-limonene 7-monooxygenase
    EC=1.14.13.49
    CYPIIC9
    P450 PB-1
    P450 MP-4/MP-8
    S-mephenytoin 4-hydroxylase
    P-450MP

Gene names

Name:	CYP2C9
Synonyms:	CYP2C10

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	490 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
Catalytic activity	⁺-(R)-limonene + NADPH + O₂ = (+)-trans-carveol + NADP⁺ + H₂O. ^--(S)-limonene + NADPH + O₂ = (-)-trans-carveol + NADP⁺ + H₂O. ^--(S)-limonene + NADPH + O₂ = (-)-perillyl alcohol + NADP⁺ + H₂O.
Cofactor	Heme group.
Subcellular location	Endoplasmic reticulum membrane; Peripheral membrane protein. Microsome membrane; Peripheral membrane protein.
Induction	By rifampicin.
Sequence similarities	Belongs to the cytochrome P450 family.

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Ontologies

Keywords
Cellular component	Endoplasmic reticulum Membrane Microsome
Coding sequence diversity	Polymorphism
Ligand	Heme Iron Metal-binding NADP
Molecular function	Monooxygenase Oxidoreductase
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	drug metabolic process Inferred from direct assay. Source: UniProtKB oxidation reduction Non-traceable author statement. Source: UniProtKB
Cellular component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell microsome Ref.1 Ref.5 Traceable author statement. Source: UniProtKB
Molecular function	(S)-limonene 6-monooxygenase activity Inferred from electronic annotation. Source: EC (S)-limonene 7-monooxygenase activity Inferred from electronic annotation. Source: EC 4-hydroxyacetophenone monooxygenase activity Inferred from electronic annotation. Source: EC electron carrier activity Inferred from electronic annotation. Source: InterPro heme binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 490

490

Cytochrome P450 2C9

PRO_0000051700

Sites

Metal binding

435

Iron (heme axial ligand)

Natural variations

Natural variant

L → I in allele CYP2C9*7.

VAR_018862

Natural variant

144

R → C in allele CYP2C9*2. dbSNP rs1799853. Ref.3 Ref.15 Ref.16 Ref.20

VAR_008343

Natural variant

150

R → H in allele CYP2C9*8. dbSNP rs7900194. Ref.3 Ref.15 Ref.16 Ref.20

VAR_018863

Natural variant

251

H → R in allele CYP2C9*9. dbSNP rs2256871. Ref.3 Ref.20

VAR_018864

Natural variant

272

E → G in allele CYP2C9*10. dbSNP rs9332130. Ref.3

VAR_018865

Natural variant

335

R → W in allele CYP2C9*11. Ref.20 Ref.19

VAR_018866

Natural variant

358

Y → C: dbSNP rs1057909. Ref.16 Ref.5 Ref.6

VAR_008344

Natural variant

359

I → L in allele CYP2C9*3; responsible for the tolbutamide poor metabolizer phenotype. dbSNP rs1057910. Ref.3 Ref.15 Ref.16 Ref.20 Ref.17

VAR_008345

Natural variant

359

I → T in allele CYP2C9*4. Ref.3 Ref.15 Ref.16 Ref.20 Ref.17

VAR_013515

Natural variant

360

D → E in allele CYP2C9*5; increases the K(m) value for substrates tested. Ref.15 Ref.16 Ref.20 Ref.18

VAR_013516

Natural variant

413

L → P Ref.20

VAR_024717

Natural variant

417

G → D Ref.16 Ref.5 Ref.6

VAR_008346

Natural variant

489

P → S in allele CYP2C9*12. dbSNP rs9332239. Ref.3

VAR_018867

Experimental info

Sequence conflict

L → I Ref.2

Sequence conflict

175

C → Y Ref.1

Sequence conflict

239

F → L Ref.1

Secondary structure

490

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P11712-1 [UniParc].

Last modified May 30, 2000. Version 3.
Checksum: 4FDFC395303A4E3E
Show »

FASTA

490

55,628

        10         20         30         40         50         60 
MDSLVVLVLC LSCLLLLSLW RQSSGRGKLP PGPTPLPVIG NILQIGIKDI SKSLTNLSKV 

        70         80         90        100        110        120 
YGPVFTLYFG LKPIVVLHGY EAVKEALIDL GEEFSGRGIF PLAERANRGF GIVFSNGKKW 

       130        140        150        160        170        180 
KEIRRFSLMT LRNFGMGKRS IEDRVQEEAR CLVEELRKTK ASPCDPTFIL GCAPCNVICS 

       190        200        210        220        230        240 
IIFHKRFDYK DQQFLNLMEK LNENIKILSS PWIQICNNFS PIIDYFPGTH NKLLKNVAFM 

       250        260        270        280        290        300 
KSYILEKVKE HQESMDMNNP QDFIDCFLMK MEKEKHNQPS EFTIESLENT AVDLFGAGTE 

       310        320        330        340        350        360 
TTSTTLRYAL LLLLKHPEVT AKVQEEIERV IGRNRSPCMQ DRSHMPYTDA VVHEVQRYID 

       370        380        390        400        410        420 
LLPTSLPHAV TCDIKFRNYL IPKGTTILIS LTSVLHDNKE FPNPEMFDPH HFLDEGGNFK 

       430        440        450        460        470        480 
KSKYFMPFSA GKRICVGEAL AGMELFLFLT SILQNFNLKS LVDPKNLDTT PVVNGFASVP 

       490 
PFYQLCFIPV

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References

[1]	"Human cytochrome P-450 PB-1: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10." Meehan R.R., Gosden J.R., Rout D., Hastie N.D., Friedberg T., Adesnik M., Buckland R., van Heyningen V., Fletcher J.M., Spurr N.K., Sweeney J., Wolf C.R. Am. J. Hum. Genet. 42:26-37(1988) [PubMed: 2827463] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"cDNA and amino acid sequences of two members of the human P450IIC gene subfamily." Kimura S., Pastewka J., Gelboin H.V., Gonzalez F.J. Nucleic Acids Res. 15:10053-10054(1987) [PubMed: 3697070] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	NIEHS SNPs program Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS CYS-144; HIS-150; ARG-251; GLY-272; LEU-359 AND SER-489.
[4]	"Nucleotide sequence of a human liver cytochrome P-450 related to the rat male specific form." Yasumori T., Kawano S., Nagata K., Shimada M., Yamazoe Y., Kato R. J. Biochem. 102:1075-1082(1987) [PubMed: 2963808] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 4-490. Tissue: Liver.
[5]	"Cloning and sequence determination of a complementary DNA related to human liver microsomal cytochrome P-450 S-mephenytoin 4-hydroxylase." Umbenhauer D.R., Martin M.V., Lloyd R.S., Guengerich F.P. Biochemistry 26:1094-1099(1987) [PubMed: 3032244] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 6-490, VARIANTS CYS-358 AND ASP-417. Tissue: Liver.
[6]	"Characterization of cDNAs, mRNAs, and proteins related to human liver microsomal cytochrome P-450 (S)-mephenytoin 4'-hydroxylase." Ged C., Umbenhauer D.R., Bellew T.M., Bork R.W., Srivastava P.K., Shinriki N., Lloyd R.S., Guengerich F.P. Biochemistry 27:6929-6940(1988) [PubMed: 3196692] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 6-490, VARIANTS CYS-358 AND ASP-417.
[7]	"Six-base deletion occurring in messages of human cytochrome P-450 in the CYP2C subfamily results in reduction of tolbutamide hydroxylase activity." Ohgiya S., Komori M., Ohi H., Shiramatsu K., Shinriki N., Kamataki T. Biochem. Int. 27:1073-1081(1992) [PubMed: 1445376] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 14-490.
[8]	"Human liver microsomal cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism. Purification and characterization of two similar forms involved in the reaction." Shimada T., Misono K.S., Guengerich F.P. J. Biol. Chem. 261:909-921(1986) [PubMed: 3079764] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-29, CHARACTERIZATION.
[9]	"Cytochrome P-450 in human liver microsomes: high-performance liquid chromatographic isolation of three forms and their characterization." Komori M., Hashizume T., Ohi H., Miura T., Kitada M., Nagashima K., Kamataki T. J. Biochem. 104:912-916(1988) [PubMed: 3243766] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-25.
[10]	"Separation of human liver microsomal tolbutamide hydroxylase and (S)-mephenytoin 4'-hydroxylase cytochrome P-450 enzymes." Srivastava P.K., Yun C.H., Beaune P.H., Ged C., Guengerich F.P. Mol. Pharmacol. 40:69-79(1991) [PubMed: 1857342] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE.
[11]	"Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms." Haining R.L., Hunter A.P., Veronese M.E., Trager W.F., Rettie A.E. Arch. Biochem. Biophys. 333:447-458(1996) [PubMed: 8809086] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-9; 21-157; 169-249; 264-424; 426-476 AND 484-487.
[12]	"Expression of modified cytochrome P450 2C10 (2C9) in Escherichia coli, purification, and reconstitution of catalytic activity." Sandhu P., Baba T., Guengerich F.P. Arch. Biochem. Biophys. 306:443-450(1993) [PubMed: 8215449] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-20.
[13]	"Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes." Miyazawa M., Shindo M., Shimada T. Drug Metab. Dispos. 30:602-607(2002) [PubMed: 11950794] [Abstract] Cited for: CHARACTERIZATION.
[14]	"Crystal structure of human cytochrome P450 2C9 with bound warfarin." Williams P.A., Cosme J., Ward A., Angove H.C., Matak-Vinkovic D., Jhoti H. Nature 424:464-468(2003) [PubMed: 12861225] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) OF 30-490.
[15]	"Genetic analysis of the human cytochrome P450 CYP2C9 locus." Stubbins M.J., Harries L.W., Smith G., Tarbit M.H., Wolf C.R. Pharmacogenetics 6:429-439(1996) [PubMed: 8946475] [Abstract] Cited for: VARIANTS CYP2C92 CYS-144 AND CYP2C93 LEU-359.
[16]	"Allelic and functional variability of cytochrome P4502C9." Bhasker C.R., Miners J.O., Coulter S., Birkett D.J. Pharmacogenetics 7:51-58(1997) [PubMed: 9110362] [Abstract] Cited for: VARIANTS CYP2C92 CYS-144; CYS-358; CYP2C93 LEU-359 AND ASP-417.
[17]	"Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus." Imai J., Ieiri I., Mamiya K., Miyahara S., Furuumi H., Nanba E., Yamane M., Fukumaki Y., Ninomiya H., Tashiro N., Otsubo K., Higuchi S. Pharmacogenetics 10:85-89(2000) [PubMed: 10739176] [Abstract] Cited for: VARIANT CYP2C9*4 THR-359.
[18]	*"Identification and functional characterization of a new CYP2C9 variant (CYP2C95) expressed among African Americans."** Dickmann L.J., Rettie A.E., Kneller M.B., Kim R.B., Wood A.J., Stein C.M., Wilkinson G.R., Schwarz U.I. Mol. Pharmacol. 60:382-387(2001) [PubMed: 11455026] [Abstract] Cited for: VARIANT CYP2C9*5 GLU-360.
[19]	"Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy." Higashi M.K., Veenstra D.L., Kondo L.M., Wittkowsky A.K., Srinouanprachanh S.L., Farin F.M., Rettie A.E. JAMA 287:1690-1698(2002) [PubMed: 11926893] [Abstract] Cited for: VARIANT CYP2C9*11 TRP-335.
[20]	"Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population." Solus J.F., Arietta B.J., Harris J.R., Sexton D.P., Steward J.Q., McMunn C., Ihrie P., Mehall J.M., Edwards T.L., Dawson E.P. Pharmacogenomics 5:895-931(2004) [PubMed: 15469410] [Abstract] Cited for: VARIANTS CYS-144; HIS-150; ARG-251; TRP-335; LEU-359; GLU-360 AND PRO-413.
+	Additional computationally mapped references.

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Web resources

Cytochrome P450 Allele Nomenclature Committee

CYP2C9 alleles

NIEHS-SNPs

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Cross-references

Sequence databases

M21940 mRNA. Translation: AAA52159.1.
AY341248 Genomic DNA. Translation: AAP88931.1.
AY702706 Genomic DNA. Translation: AAT94065.1.
M15331 mRNA. Translation: AAA52157.1.
D00173 mRNA. Translation: BAA00123.1.
M21939 mRNA. Translation: AAA52158.1.
S46963 mRNA. Translation: AAB23864.2. Sequence problems.

IPI

IPI00007219.

PIR

B38462.
D28951.

RefSeq

NP_000762.2.

UniGene

Hs.282624

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1OG2	X-ray	2.60	A/B	30-490	[»]
1OG5	X-ray	2.55	A/B	30-490	[»]
1R9O	X-ray	2.00	A	23-489	[»]

SMR

P11712. Positions 44-490.

ModBase

Search...

PTM databases

PhosphoSite

P11712.

Proteomic databases

PRIDE

P11712.

Genome annotation databases

Ensembl

ENSG00000138109. Homo sapiens. [Contig view]

GeneID

1559.

KEGG

hsa:1559.

UCSC

uc001kka.2. human.

Organism-specific databases

GeneCards

GC10P096688.

H-InvDB

HIX0035375.

HGNC

HGNC:2623. CYP2C9.

HPA

CAB016123.
HPA015066.

MIM

601130. gene.

PharmGKB

PA126.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P11712.

HOVERGEN

P11712.

OMA

P11712. QPSEFTI.

Enzyme and pathway databases

BRENDA

1.14.13.48. 247.
1.14.13.49. 247.
1.14.13.80. 247.

Reactome

REACT_13433. Biological oxidations.

Gene expression databases

ArrayExpress

P11712.

Bgee

P11712.

CleanEx

HS_CYP2C9.

GermOnline

ENSG00000138109. Homo sapiens.

Family and domain databases

InterPro

IPR001128. Cyt_P450.
IPR017973. Cyt_P450_C.
IPR017972. Cyt_P450_CS.
IPR002401. Cyt_P450_E_grp-I.
[Graphical view]

Gene3D

G3DSA:1.10.630.10. Cyt_P450. 1 hit.

PANTHER

PTHR19383. Cyt_P450. 1 hit.

Pfam

PF00067. p450. 1 hit.
[Graphical view]

PRINTS

PR00463. EP450I.
PR00385. P450.

PROSITE

PS00086. CYTOCHROME_P450. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB01418. Acenocoumarol.
DB00969. Alosetron.
DB01118. Amiodarone.
DB00025. Antihemophilic Factor.
DB00673. Aprepitant.
DB00559. Bosentan.
DB00821. Carprofen.
DB01136. Carvedilol.
DB00482. Celecoxib.
DB01242. Clomipramine.
DB00250. Dapsone.
DB00705. Delavirdine.
DB00967. Desloratadine.
DB00304. Desogestrel.
DB00586. Diclofenac.
DB00736. Esomeprazole.
DB00749. Etodolac.
DB00196. Fluconazole.
DB00472. Fluoxetine.
DB00712. Flurbiprofen.
DB01095. Fluvastatin.
DB00176. Fluvoxamine.
DB00983. Formoterol.
DB01241. Gemfibrozil.
DB01381. Ginkgo biloba.
DB01016. Glibenclamide.
DB00222. Glimepiride.
DB01067. Glipizide.
DB01018. Guanfacine.
DB00327. Hydromorphone.
DB01050. Ibuprofen.
DB00458. Imipramine.
DB01029. Irbesartan.
DB01026. Ketoconazole.
DB00448. Lansoprazole.
DB00678. Losartan.
DB01283. Lumiracoxib.
DB00470. Marinol.
DB00784. Mefenamic acid.
DB00814. Meloxicam.
DB00532. Mephenytoin.
DB00916. Metronidazole.
DB01110. Miconazole.
DB00683. Midazolam.
DB00471. Montelukast.
DB00731. Nateglinide.
DB00220. Nelfinavir.
DB00622. Nicardipine.
DB01192. Oxymorphone.
DB00213. Pantoprazole.
DB00617. Paramethadione.
DB00946. Phenprocoumon.
DB00252. Phenytoin.
DB00175. Pravastatin.
DB00908. Quinidine.
DB00503. Ritonavir.
DB00412. Rosiglitazone.
DB01104. Sertraline.
DB00203. Sildenafil.
DB01015. Sulfamethoxazole.
DB00870. Suprofen.
DB00675. Tamoxifen.
DB00469. Tenoxicam.
DB00342. Terfenadine.
DB01124. Tolbutamide.
DB00214. Torasemide.
DB01361. Troleandomycin.
DB00580. Valdecoxib.
DB00177. Valsartan.
DB00582. Voriconazole.
DB00682. Warfarin.
DB00549. Zafirlukast.
DB00744. Zileuton.

NextBio

6438.

SOURCE

Search...

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Entry information

Entry name

CP2C9_HUMAN

Accession

Primary (citable) accession number: P11712
Secondary accession number(s): P11713, Q16756, Q16872

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	May 30, 2000
Last modified:	July 7, 2009
This is version 116 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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