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Protein

Phylloquinone omega-hydroxylase CYP4F2

Gene

CYP4F2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Omega-hydroxylase that oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids and xenobiotics. Plays a key role in vitamin K catabolism by mediating omega-hydroxylation of vitamin K1 (phylloquinone), and menaquinone-4 (MK-4), a form of vitamin K2. Hydroxylation of phylloquinone and MK-4 probably regulates blood coagulation (PubMed:19297519, PubMed:24138531). Also shows arachidonic acid omega-hydroxylase activity in kidney, by mediating conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), possibly influencing blood pressure control (PubMed:10660572, PubMed:17341693, PubMed:18574070). Also acts as a leukotriene-B4 omega-hydroxylase by mediating conversion of leukotriene-B4 (LTB4) to its omega-hydroxylated metabolite 20-hydroxyleukotriene-B4 (20-OH LTB4) (PubMed:8026587, PubMed:9799565).7 Publications

Catalytic activityi

(6Z,8E,10E,14Z)-(5S,12R)-5,12-dihydroxyicosa-6,8,10,14-tetraenoate + NADPH + O2 = (6Z,8E,10E,14Z)-(5S,12R)-5,12,20-trihydroxyicosa-6,8,10,14-tetraenoate + NADP+ + H2O.2 Publications
Phylloquinone + [reduced NADPH--hemoprotein reductase] + O2 = omega-hydroxyphylloquinone + [oxidized NADPH--hemoprotein reductase] + H2O.1 Publication
(5Z,8Z,11Z,14Z)-icosatetraenoate + [reduced NADPH--hemoprotein reductase] + O2 = (5Z,8Z,11Z,14Z)-20-hydroxyicosa-5,8,11,14-tetraenoate + [oxidized NADPH--hemoprotein reductase] + H2O.1 Publication

Cofactori

hemeBy similarity

Kineticsi

kcat is 0.067 min(-1) with menaquinone-4 (MK-4) as substrate.1 Publication
  1. KM=74.8 µM for leukotriene-B41 Publication
  2. KM=1.7 µM for menaquinone-4 (MK-4)1 Publication
  1. Vmax=2.42 nmol/min/mg enzyme1 Publication

Pathwayi: phylloquinone degradation

This protein is involved in the pathway phylloquinone degradation, which is part of Cofactor degradation.1 Publication
View all proteins of this organism that are known to be involved in the pathway phylloquinone degradation and in Cofactor degradation.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei328Heme (covalent; via 1 link)By similarity1
Metal bindingi468Iron (heme axial ligand)By similarity1

GO - Molecular functioni

GO - Biological processi

  • arachidonic acid metabolic process Source: UniProtKB
  • blood coagulation Source: UniProtKB
  • drug metabolic process Source: UniProtKB
  • epoxygenase P450 pathway Source: UniProtKB
  • icosanoid metabolic process Source: Reactome
  • leukotriene B4 catabolic process Source: UniProtKB
  • leukotriene metabolic process Source: Reactome
  • long-chain fatty acid metabolic process Source: BHF-UCL
  • menaquinone catabolic process Source: UniProtKB
  • negative regulation of icosanoid secretion Source: UniProtKB
  • omega-hydroxylase P450 pathway Source: Reactome
  • oxidation-reduction process Source: UniProtKB
  • phylloquinone catabolic process Source: UniProtKB
  • positive regulation of icosanoid secretion Source: UniProtKB
  • pressure natriuresis Source: UniProtKB
  • regulation of blood pressure Source: UniProtKB
  • renal water homeostasis Source: UniProtKB
  • sodium ion homeostasis Source: UniProtKB
  • very long-chain fatty acid metabolic process Source: BHF-UCL
  • vitamin E metabolic process Source: UniProtKB
  • vitamin K catabolic process Source: UniProtKB

Keywordsi

Molecular functionMonooxygenase, Oxidoreductase
LigandHeme, Iron, Metal-binding, NADP

Enzyme and pathway databases

BioCyciMetaCyc:HS02675-MONOMER
BRENDAi1.14.13.30 2681
ReactomeiR-HSA-211935 Fatty acids
R-HSA-211958 Miscellaneous substrates
R-HSA-211979 Eicosanoids
R-HSA-2142691 Synthesis of Leukotrienes (LT) and Eoxins (EX)
R-HSA-2142816 Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)
UniPathwayiUPA01054

Chemistry databases

SwissLipidsiSLP:000000421

Names & Taxonomyi

Protein namesi
Recommended name:
Phylloquinone omega-hydroxylase CYP4F2Curated (EC:1.14.14.781 Publication)
Alternative name(s):
20-hydroxyeicosatetraenoic acid synthase1 Publication (EC:1.14.14.-1 Publication)
Short name:
20-HETE synthase1 Publication
Arachidonic acid omega-hydroxylase1 Publication
CYPIVF2
Cytochrome P450 4F2
Cytochrome P450-LTB-omega
Leukotriene-B(4) 20-monooxygenase 1
Leukotriene-B(4) omega-hydroxylase 1Curated (EC:1.14.13.302 Publications)
Gene namesi
Name:CYP4F2Imported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

EuPathDBiHostDB:ENSG00000186115.12
HGNCiHGNC:2645 CYP4F2
MIMi604426 gene
neXtProtiNX_P78329

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane, Microsome

Pathology & Biotechi

Involvement in diseasei

Coumarin resistance (CMRES)7 Publications
Disease susceptibility may be associated with variations affecting the gene represented in this entry. The variant Met-433 is associated with coumarin (the brand name of warfarin) resistance by increasing coumarin maintenance dose in patients on this anti-coagulant therapy. This is probably due to decreased activity of the phylloquinone omega-hydroxylase activity, leading to an increase in hepatic vitamin K levels that warfarin must antagonize (PubMed:24138531).1 Publication
Disease descriptionA condition characterized by partial or complete resistance to warfarin or other 4-hydroxycoumarin derivatives. These drugs are used as anti-coagulants for the prevention of thromboembolic diseases in subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement.
See also OMIM:122700

Organism-specific databases

DisGeNETi8529
MalaCardsiCYP4F2
MIMi122700 phenotype
OpenTargetsiENSG00000186115
Orphaneti413674 Vitamin K antagonists toxicity or dose selection
PharmGKBiPA27121

Chemistry databases

ChEMBLiCHEMBL3379
DrugBankiDB08868 Fingolimod
DB09148 Florbetaben (18F)
GuidetoPHARMACOLOGYi1344

Polymorphism and mutation databases

BioMutaiCYP4F2
DMDMi6166044

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
PropeptideiPRO_00004305811 – 41 Publication4
ChainiPRO_00000518505 – 520Phylloquinone omega-hydroxylase CYP4F2Add BLAST516

Proteomic databases

MaxQBiP78329
PaxDbiP78329
PeptideAtlasiP78329
PRIDEiP78329
ProteomicsDBi57568

PTM databases

iPTMnetiP78329
PhosphoSitePlusiP78329

Expressioni

Tissue specificityi

Liver. Also present in kidney: specifically expressed in the S2 and S3 segments of proximal tubules in cortex and outer medulla (PubMed:10660572).2 Publications

Gene expression databases

BgeeiENSG00000186115
CleanExiHS_CYP4F2
ExpressionAtlasiP78329 baseline and differential
GenevisibleiP78329 HS

Organism-specific databases

HPAiHPA014048
HPA058960

Interactioni

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi114099, 2 interactors
IntActiP78329, 33 interactors
STRINGi9606.ENSP00000221700

Chemistry databases

BindingDBiP78329

Structurei

3D structure databases

ProteinModelPortaliP78329
SMRiP78329
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the cytochrome P450 family.Curated

Phylogenomic databases

eggNOGiKOG0157 Eukaryota
COG2124 LUCA
GeneTreeiENSGT00900000140829
HOVERGENiHBG000182
InParanoidiP78329
KOiK17726
OMAiAYNHEPN
PhylomeDBiP78329
TreeFamiTF105088

Family and domain databases

Gene3Di1.10.630.10, 1 hit
InterProiView protein in InterPro
IPR001128 Cyt_P450
IPR017972 Cyt_P450_CS
IPR002401 Cyt_P450_E_grp-I
IPR036396 Cyt_P450_sf
PfamiView protein in Pfam
PF00067 p450, 1 hit
PRINTSiPR00463 EP450I
PR00385 P450
SUPFAMiSSF48264 SSF48264, 1 hit
PROSITEiView protein in PROSITE
PS00086 CYTOCHROME_P450, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P78329-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSQLSLSWLG LWPVAASPWL LLLLVGASWL LAHVLAWTYA FYDNCRRLRC
60 70 80 90 100
FPQPPRRNWF WGHQGMVNPT EEGMRVLTQL VATYPQGFKV WMGPISPLLS
110 120 130 140 150
LCHPDIIRSV INASAAIAPK DKFFYSFLEP WLGDGLLLSA GDKWSRHRRM
160 170 180 190 200
LTPAFHFNIL KPYMKIFNES VNIMHAKWQL LASEGSACLD MFEHISLMTL
210 220 230 240 250
DSLQKCVFSF DSHCQEKPSE YIAAILELSA LVSKRHHEIL LHIDFLYYLT
260 270 280 290 300
PDGQRFRRAC RLVHDFTDAV IQERRRTLPS QGVDDFLQAK AKSKTLDFID
310 320 330 340 350
VLLLSKDEDG KKLSDEDIRA EADTFMFEGH DTTASGLSWV LYHLAKHPEY
360 370 380 390 400
QERCRQEVQE LLKDREPKEI EWDDLAHLPF LTMCMKESLR LHPPVPVISR
410 420 430 440 450
HVTQDIVLPD GRVIPKGIIC LISVFGTHHN PAVWPDPEVY DPFRFDPENI
460 470 480 490 500
KERSPLAFIP FSAGPRNCIG QTFAMAEMKV VLALTLLRFR VLPDHTEPRR
510 520
KPELVLRAEG GLWLRVEPLS
Length:520
Mass (Da):59,853
Last modified:May 1, 1997 - v1
Checksum:i1791F9E6EECB59B5
GO
Isoform 2 (identifier: P78329-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-149: Missing.
     307-339: DEDGKKLSDEDIRAEADTFMFEGHDTTASGLSW → AMTPRPVVSPGSCTTLQSTQNTRSAAGRRCKNF
     340-520: Missing.

Note: No experimental confirmation available.
Show »
Length:190
Mass (Da):21,709
Checksum:iE137B6FDB0B39573
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti12 – 13WP → CR in AAC50052 (Ref. 3) Curated2
Sequence conflicti12 – 13WP → CR in AAF86378 (PubMed:10860554).Curated2
Sequence conflicti25V → A in AAH67437 (PubMed:15489334).Curated1
Sequence conflicti169E → D in AAH67440 (PubMed:15489334).Curated1
Sequence conflicti336G → V in AAC50052 (Ref. 3) Curated1
Sequence conflicti391L → V in AAC50052 (Ref. 3) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0131167S → Y1 PublicationCorresponds to variant dbSNP:rs3093104Ensembl.1
Natural variantiVAR_01311712W → G3 PublicationsCorresponds to variant dbSNP:rs3093105Ensembl.1
Natural variantiVAR_013118185G → V2 PublicationsCorresponds to variant dbSNP:rs3093153Ensembl.1
Natural variantiVAR_020125269A → D. Corresponds to variant dbSNP:rs1805040Ensembl.1
Natural variantiVAR_013119433V → M Polymorphism probably associated with CMRES; increases warfarin maintenance dose in patients on warfarin anti-coagulant therapy, possibly due to increased hepatic vitamin K levels that warfarin must antagonize. Decreased phylloquinone omega-hydroxylase activity. Decreased production of 20-hydroxyeicosatetraenoic acid (20-HETE). 10 PublicationsCorresponds to variant dbSNP:rs2108622EnsemblClinVar.1
Natural variantiVAR_013120519L → M1 PublicationCorresponds to variant dbSNP:rs3093200Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0555781 – 149Missing in isoform 2. 1 PublicationAdd BLAST149
Alternative sequenceiVSP_055579307 – 339DEDGK…SGLSW → AMTPRPVVSPGSCTTLQSTQ NTRSAAGRRCKNF in isoform 2. 1 PublicationAdd BLAST33
Alternative sequenceiVSP_055580340 – 520Missing in isoform 2. 1 PublicationAdd BLAST181

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D26480 mRNA Translation: BAA05490.1
AB015306 Genomic DNA Translation: BAA75823.1
U02388 mRNA Translation: AAC50052.2
AK290790 mRNA Translation: BAF83479.1
AK300961 mRNA Translation: BAG62587.1
AF467894 Genomic DNA Translation: AAL67578.1
AC005336 Genomic DNA Translation: AAC27730.1
AC004791 Genomic DNA No translation available.
CH471106 Genomic DNA Translation: EAW84509.1
CH471106 Genomic DNA Translation: EAW84510.1
BC067437 mRNA Translation: AAH67437.1
BC067439 mRNA Translation: AAH67439.1
BC067440 mRNA Translation: AAH67440.1
AF221943 Genomic DNA Translation: AAF86378.1
CCDSiCCDS12336.1 [P78329-1]
PIRiS45702
RefSeqiNP_001073.3, NM_001082.4 [P78329-1]
UniGeneiHs.558423

Genome annotation databases

EnsembliENST00000221700; ENSP00000221700; ENSG00000186115 [P78329-1]
GeneIDi8529
KEGGihsa:8529
UCSCiuc002nbs.2 human [P78329-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCP4F2_HUMAN
AccessioniPrimary (citable) accession number: P78329
Secondary accession number(s): A0A024R7K3
, A8K425, B4DV75, Q16677, Q6NWT4, Q6NWT6, Q9NNZ0, Q9UIU8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: May 1, 1997
Last modified: July 18, 2018
This is version 172 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. SIMILARITY comments
    Index of protein domains and families

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