Reviewed, UniProtKB/Swiss-Prot P33261 (CP2CJ_HUMAN)

Names and origin

Protein names

Recommended name:
    Cytochrome P450 2C19
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
    CYPIIC19
    P450-11A
    Mephenytoin 4-hydroxylase
    CYPIIC17
    P450-254C

Gene names

Name:

CYP2C19

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

Protein attributes

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

General annotation (Comments)

Function	Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
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 By similarity.
Subcellular location	Endoplasmic reticulum membrane; Peripheral membrane protein. Microsome membrane; Peripheral membrane protein.
Induction	P450 can be induced to high levels in liver and other tissues by various foreign compounds, including drugs, pesticides, and carcinogens.
Polymorphism	Genetic variation in CYP2C19 is responsible for poor drug metabolism [MIM:609535]. Individuals can be characterized as either extensive metabolizers (EM) or poor metabolizers (PM). The PM phenotype is inherited in an autosomal recessive manner, with the EM phenotype comprising both homozygous dominant and heteroyzgote genotypes. There are marked interracial differences in the frequency of this polymorphism. Poor metabolizers represent 2-5% of Caucasians, 13-23% of Asian populations, and as many as 38-79% of individuals of some of the islands of Polynesia and Micronesia. Different alleles of CYP2C19 are known: CYP2C19*1A CYP2C19*1B, CYP2C19*1C, CYP2C19*2A (CYP2C19m1 or CYP2C19m1A), CYP2C19*2B (CYP2C19m1B), CYP2C19*2C (CYP2C19*21), CYP2C19*3A (CYP2C19m2), CYP2C19*3B (CYP2C19*20), CYP2C19*4 (CYP2C19m3), CYP2C19*5A (CYP2C19m4), CYP2C19*5B, CYP2C19*6, CYP2C19*7, CYP2C19*8, CYP2C19*9, CYP2C19*10, CYP2C19*11 CYP2C19*12, CYP2C19*13, CYP2C19*14 CYP2C19*15, CYP2C19*16, CYP2C19*18, CYP2C19*19. Defective CYP2C19*2 and CYP2C19*3 alleles are characterized by a splice mutation and a stop codon, respectively, and account for most of the PM alleles. The sequence shown is that of allele CYP2C19*1B.
Sequence similarities	Belongs to the cytochrome P450 family.
Caution	P450-254C was originally listed as a separate gene (CYP2C17). Resequencing demonstrated that it is not a separate gene, but a chimera. The 5'-portion corresponds to a partial 2C18 clone, and the 3'-portion corresponds to a partial 2C19 clone.

Ontologies

Keywords
Cellular component	Endoplasmic reticulum Membrane Microsome
Coding sequence diversity	Polymorphism
Ligand	Heme Iron Metal-binding NADP
Molecular function	Monooxygenase Oxidoreductase
Technical term	Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	drug metabolic process Inferred from direct assay. Source: UniProtKB oxidation reduction Inferred from direct assay. Source: UniProtKB
Cellular component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell microsome Traceable author statement. Source: ProtInc
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 oxygen binding Traceable author statement. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 490	490	Cytochrome P450 2C19		PRO_0000051708
Sites
	Metal binding	435	1	Iron (heme axial ligand) By similarity
Natural variations
	Natural variant	17	1	L → P in allele CYP2C19*14. Ref.14		VAR_021268
	Natural variant	19	1	I → L in allele CYP2C19*15. Ref.14 Ref.3		VAR_021269
	Natural variant	51	1	S → G in allele CYP2C19*19. Ref.17		VAR_024083
	Natural variant	74	1	M → T Ref.16		VAR_024718
	Natural variant	92	1	E → D: dbSNP rs17878459.		VAR_021270
	Natural variant	120	1	W → R in allele CYP2C19*8; loss of activity. Ref.13		VAR_008357
	Natural variant	122	1	E → A Ref.3		VAR_021271
	Natural variant	132	1	R → Q in allele CYP2C19*6; loss of activity. Ref.11		VAR_008358
	Natural variant	144	1	R → H in allele CYP2C19*9. Ref.14 Ref.3 Ref.16		VAR_021272
	Natural variant	150	1	R → H in allele CYP2C19*11. Ref.14		VAR_021273
	Natural variant	161	1	A → P Ref.17		VAR_024084
	Natural variant	168	1	F → L Ref.16		VAR_024719
	Natural variant	227	1	P → L in allele CYP2C19*10. dbSNP rs6413438. Ref.14		VAR_020123
	Natural variant	329	1	R → H in allele CYP2C19*18. Ref.17		VAR_024085
	Natural variant	331	1	V → I in allele CYP2C19*1A, allele CYP2C19*5A, allele CYP2C19*8 and allele CYP2C19*16. dbSNP rs3758581. Ref.3 Ref.17 Ref.16 Ref.5		VAR_001255
	Natural variant	410	1	R → C in allele CYP2C19*13. Ref.14 Ref.3		VAR_021274
	Natural variant	433	1	R → W in allele CYP2C19*5A and allele CYP2C19*5B; loss of activity. Ref.10 Ref.12		VAR_008359
	Natural variant	442	1	R → C in allele CYP2C19*16; lowered catalytic activity. Ref.15		VAR_021275

Sequences

	Sequence		Length	Mass (Da)
	P33261-1 [UniParc]. Last modified March 1, 2005. Version 3. Checksum: 17DB04C50A132C53	FASTA	490	55,931
	10 20 30 40 50 60 MDPFVVLVLC LSCLLLLSIW RQSSGRGKLP PGPTPLPVIG NILQIDIKDV SKSLTNLSKI 70 80 90 100 110 120 YGPVFTLYFG LERMVVLHGY EVVKEALIDL GEEFSGRGHF PLAERANRGF GIVFSNGKRW 130 140 150 160 170 180 KEIRRFSLMT LRNFGMGKRS IEDRVQEEAR CLVEELRKTK ASPCDPTFIL GCAPCNVICS 190 200 210 220 230 240 IIFQKRFDYK DQQFLNLMEK LNENIRIVST PWIQICNNFP TIIDYFPGTH NKLLKNLAFM 250 260 270 280 290 300 ESDILEKVKE HQESMDINNP RDFIDCFLIK MEKEKQNQQS EFTIENLVIT AADLLGAGTE 310 320 330 340 350 360 TTSTTLRYAL LLLLKHPEVT AKVQEEIERV VGRNRSPCMQ DRGHMPYTDA VVHEVQRYID 370 380 390 400 410 420 LIPTSLPHAV TCDVKFRNYL IPKGTTILTS LTSVLHDNKE FPNPEMFDPR HFLDEGGNFK 430 440 450 460 470 480 KSNYFMPFSA GKRICVGEGL ARMELFLFLT FILQNFNLKS LIDPKDLDTT PVVNGFASVP 490 PFYQLCFIPV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily." Romkes M., Faletto M.B., Blaisdell J.A., Raucy J.L., Goldstein J.A. Biochemistry 30:3247-3255(1991) [PubMed: 2009263] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ALLELE CYP2C19*1A). Tissue: Liver.
[2]	Erratum Romkes M., Faletto M.B., Blaisdell J.A., Raucy J.L., Goldstein J.A. Biochemistry 32:1390-1390(1993) [PubMed: 8095407] [Abstract] Cited for: SEQUENCE REVISION.
[3]	NIEHS SNPs program Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS LEU-19; ASP-92; ALA-122; HIS-144; ILE-331 AND CYS-410.
[4]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed: 15164054] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Gene structure, upstream region and allelic variants of cyp2c19, the s-mephenytoin hydroxylase." de Morais S.M.F., Blaisdell J.A. Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-160 AND 274-490, VARIANT ILE-331.
[6]	"Isolation and characterization of human liver cytochrome P450 2C19: correlation between 2C19 and S-mephenytoin 4'-hydroxylation." Wrighton S.A., Stevens J.C., Becker G.W., VandenBranden M. Arch. Biochem. Biophys. 306:240-245(1993) [PubMed: 8215410] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-16. Tissue: Liver.
[7]	"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.
[8]	"The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans." de Morais S.M.F., Wilkinson G.R., Blaisdell J., Nakamura K., Meyer U.A., Goldstein J.A. J. Biol. Chem. 269:15419-15422(1994) [PubMed: 8195181] [Abstract] Cited for: INVOLVEMENT IN POOR DRUG METABOLISM, IDENTIFICATION OF ALLELE CYP2C19*2A.
[9]	"Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese." De Morais S.M.F., Wilkinson G.R., Blaisdell J., Meyer U.A., Nakamura K., Goldstein J.A. Mol. Pharmacol. 46:594-598(1994) [PubMed: 7969038] [Abstract] Cited for: INVOLVEMENT IN POOR DRUG METABOLISM, IDENTIFICATION OF ALLELE CYP2C19*3A.
[10]	"Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele." Xiao Z.S., Goldstein J.A., Xie H.G., Blaisdell J., Wang W., Jiang C.H., Yan F.X., He N., Huang S.L., Xu Z.H., Zhou H.H. J. Pharmacol. Exp. Ther. 281:604-609(1997) [PubMed: 9103550] [Abstract] Cited for: VARIANT TRP-433.
[11]	"Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin." Ibeanu G.C., Goldstein J.A., Meyer U.A., Benhamou S., Bouchardy C., Dayer P., Ghanayem B.I., Blaisdell J. J. Pharmacol. Exp. Ther. 286:1490-1495(1998) [PubMed: 9732415] [Abstract] Cited for: VARIANTS ASP-92 AND GLN-132.
[12]	"An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians." Ibeanu G.C., Blaisdell J., Ghanayem B.I., Beyeler C., Benhamou S., Bouchardy C., Wilkinson G.R., Dayer P., Daly A.K., Goldstein J.A. Pharmacogenetics 8:129-135(1998) [PubMed: 10022751] [Abstract] Cited for: VARIANT TRP-433.
[13]	"A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin." Ibeanu G.C., Blaisdell J., Ferguson R.J., Ghanayem B.I., Brosen K., Benhamou S., Bouchardy C., Wilkinson G.R., Dayer P., Goldstein J.A. J. Pharmacol. Exp. Ther. 290:635-640(1999) [PubMed: 10411572] [Abstract] Cited for: VARIANT ARG-120.
[14]	"Identification and functional characterization of new potentially defective alleles of human CYP2C19." Blaisdell J., Mohrenweiser H., Jackson J., Ferguson S., Coulter S., Chanas B., Xi T., Ghanayem B., Goldstein J.A. Pharmacogenetics 12:703-711(2002) [PubMed: 12464799] [Abstract] Cited for: VARIANTS PRO-17; LEU-19; HIS-144; HIS-150; LEU-227 AND CYS-410.
[15]	"A novel single nucleotide polymorphism (SNP) of the CYP2C19 gene in a Japanese subject with lowered capacity of mephobarbital 4'-hydroxylation." Morita J., Kobayashi K., Wanibuchi A., Kimura M., Irie S., Ishizaki T., Chiba K. Drug Metab. Pharmacokinet. 19:236-238(2004) [PubMed: 15499191] [Abstract] Cited for: VARIANT CYS-442.
[16]	"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 THR-74; HIS-144; LEU-168 AND ILE-331.
[17]	"Genetic variations and haplotypes of CYP2C19 in a Japanese population." Fukushima-Uesaka H., Saito Y., Maekawa K., Ozawa S., Hasegawa R., Kajio H., Kuzuya N., Yasuda K., Kawamoto M., Kamatani N., Suzuki K., Yanagawa T., Tohkin M., Sawada J. Drug Metab. Pharmacokinet. 20:300-307(2005) [PubMed: 16141610] [Abstract] Cited for: VARIANTS GLY-51; PRO-161; HIS-329 AND ILE-331.
+	Additional computationally mapped references.

Web resources

Cytochrome P450 Allele Nomenclature Committee

CYP2C19 alleles

NIEHS-SNPs

Cross-references

Sequence databases
EMBLGenBankDDBJ	M61854 mRNA. Translation: AAB59426.1. M61858 mRNA. Translation: AAA52145.1. Sequence problems. L07093 mRNA. Translation: AAA36660.1. Sequence problems. AY796203 Genomic DNA. Translation: AAV41877.1. AL583836, AL133513 Genomic DNA. Translation: CAH74068.1. AL133513, AL583836 Genomic DNA. Translation: CAH73444.1. L39098, L39097 Genomic DNA. Translation: AAL31347.1. L39102 , L39099, L39100, L39101 Genomic DNA. Translation: AAL31348.1. L31506 Genomic DNA. No translation available. L31507 Genomic DNA. No translation available. L32982 Genomic DNA. No translation available. L32983 Genomic DNA. No translation available.
IPI	IPI00013323.
PIR	F38462. G38462. I52418.
RefSeq	NP_000760.1.
UniGene	Hs.282409
3D structure databases
HSSP	HSSP built from PDB template 1OG2 based on UniProtKB P11712.
SMR	P33261. Positions 44-490.
ModBase	Search...
PTM databases
PhosphoSite	P33261.
Proteomic databases
PRIDE	P33261.
Genome annotation databases
Ensembl	ENSG00000165841. Homo sapiens. [Contig view]
GeneID	1557.
KEGG	hsa:1557.
NMPDR	fig|9606.3.peg.4383.
UCSC	uc001kjx.1. human.
Organism-specific databases
GeneCards	GC10P096512.
HGNC	HGNC:2621. CYP2C19.
HPA	HPA015066.
MIM	124020. gene. 609535. phenotype.
PharmGKB	PA124.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P33261.
HOVERGEN	P33261.
OMA	P33261. ESMDINN.
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	P33261.
Bgee	P33261.
CleanEx	HS_CYP2C19.
GermOnline	ENSG00000165841. 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	DB00546. Adinazolam. DB01424. Aminophenazone. DB00321. Amitriptyline. DB01060. Amoxicillin. DB01274. Arformoterol. DB00188. Bortezomib. DB00395. Carisoprodol. DB00356. Chlorzoxazone. DB01166. Cilostazol. DB00215. Citalopram. DB01211. Clarithromycin. DB00349. Clobazam. DB01151. Desipramine. DB00967. Desloratadine. DB00586. Diclofenac. DB00343. Diltiazem. DB00625. Efavirenz. DB00736. Esomeprazole. DB00927. Famotidine. DB00949. Felbamate. DB01216. Finasteride. DB01544. Flunitrazepam. DB00176. Fluvoxamine. DB00983. Formoterol. DB01320. Fosphenytoin. DB01018. Guanfacine. DB00458. Imipramine. DB00328. Indomethacin. DB01026. Ketoconazole. DB00448. Lansoprazole. DB01259. Lapatinib. DB00455. Loratadine. DB01065. Melatonin. DB00532. Mephenytoin. DB00333. Methadone. DB00849. Methylphenobarbital. DB01171. Moclobemide. DB00745. Modafinil. DB00220. Nelfinavir. DB00622. Nicardipine. DB00665. Nilutamide. DB00506. Norgestrel. DB00338. Omeprazole. DB00776. Oxcarbazepine. DB00213. Pantoprazole. DB00738. Pentamidine. DB01174. Phenobarbital. DB00252. Phenytoin. DB00794. Primidone. DB00396. Progesterone. DB01131. Proguanil. DB00420. Promazine. DB00908. Quinidine. DB01129. Rabeprazole. DB00863. Ranitidine. DB00503. Ritonavir. DB01037. Selegiline. DB01104. Sertraline. DB00231. Temazepam. DB00444. Teniposide. DB00342. Terfenadine. DB01041. Thalidomide. DB00679. Thioridazine. DB00208. Ticlopidine. DB01124. Tolbutamide. DB00273. Topiramate. DB00752. Tranylcypromine. DB00197. Troglitazone. DB01361. Troleandomycin. DB00582. Voriconazole.
NextBio	6430.
SOURCE	Search...

Entry information

Entry name

CP2CJ_HUMAN

Accession

Primary (citable) accession number: P33261
Secondary accession number(s): P33259 , Q8WZB1, Q8WZB2, Q9UCD4

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1994
Last sequence update:	March 1, 2005
Last modified:	July 7, 2009
This is version 92 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)