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Protein

Phylloquinone omega-hydroxylase CYP4F2

Gene

CYP4F2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 + NADPH + O2 = omega-hydroxyphylloquinone + NADP+ + H2O.1 Publication
(5Z,8Z,11Z,14Z)-icosatetraenoate + NADPH + O2 = (5Z,8Z,11Z,14Z)-20-hydroxyicosa-5,8,11,14-tetraenoate + NADP+ + H2O.1 Publication

Cofactori

hemeBy similarity

Kineticsi

kcat is 0.067 min(-1) with menaquinone-4 (MK-4) as substrate.1 Publication

Manual assertion based on experiment ini

  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
Complete GO annotation...

Keywords - Molecular functioni

Monooxygenase, Oxidoreductase

Keywords - Ligandi

Heme, Iron, Metal-binding, NADP

Enzyme and pathway databases

BioCyciMetaCyc:HS02675-MONOMER.
ZFISH: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:1.14.13.1941 Publication)
Alternative name(s):
20-hydroxyeicosatetraenoic acid synthase1 Publication (EC:1.14.13.-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

HGNCiHGNC:2645. CYP4F2.

Subcellular locationi

GO - Cellular componenti

  • apical plasma membrane Source: UniProtKB
  • cytoplasm Source: UniProtKB
  • endoplasmic reticulum membrane Source: UniProtKB
  • intracellular membrane-bounded organelle Source: UniProtKB
  • organelle membrane Source: UniProtKB-SubCell
Complete GO annotation...

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
Feature keyPosition(s)DescriptionActionsGraphical viewLength
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 rs2108622dbSNPEnsembl.1

Organism-specific databases

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

Chemistry databases

ChEMBLiCHEMBL3379.
DrugBankiDB08868. Fingolimod.
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.

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

WithEntry#Exp.IntActNotes
NCK1P163332EBI-1752413,EBI-389883

Protein-protein interaction databases

BioGridi114099. 2 interactors.
IntActiP78329. 5 interactors.
STRINGi9606.ENSP00000221700.

Chemistry databases

BindingDBiP78329.

Structurei

3D structure databases

ProteinModelPortaliP78329.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the cytochrome P450 family.Curated

Phylogenomic databases

eggNOGiKOG0157. Eukaryota.
COG2124. LUCA.
GeneTreeiENSGT00760000118816.
HOVERGENiHBG000182.
InParanoidiP78329.
KOiK17726.
OMAiHPENIKE.
PhylomeDBiP78329.
TreeFamiTF105088.

Family and domain databases

Gene3Di1.10.630.10. 1 hit.
InterProiIPR001128. Cyt_P450.
IPR017972. Cyt_P450_CS.
IPR002401. Cyt_P450_E_grp-I.
[Graphical view]
PfamiPF00067. p450. 1 hit.
[Graphical view]
PRINTSiPR00463. EP450I.
PR00385. P450.
SUPFAMiSSF48264. SSF48264. 1 hit.
PROSITEiPS00086. CYTOCHROME_P450. 1 hit.
[Graphical view]

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 → Y.1 PublicationCorresponds to variant rs3093104dbSNPEnsembl.1
Natural variantiVAR_01311712W → G.3 PublicationsCorresponds to variant rs3093105dbSNPEnsembl.1
Natural variantiVAR_013118185G → V.2 PublicationsCorresponds to variant rs3093153dbSNPEnsembl.1
Natural variantiVAR_020125269A → D.Corresponds to variant rs1805040dbSNPEnsembl.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 rs2108622dbSNPEnsembl.1
Natural variantiVAR_013120519L → M.1 PublicationCorresponds to variant rs3093200dbSNPEnsembl.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

Cross-referencesi

Web resourcesi

SeattleSNPs

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.

3D structure databases

ProteinModelPortaliP78329.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114099. 2 interactors.
IntActiP78329. 5 interactors.
STRINGi9606.ENSP00000221700.

Chemistry databases

BindingDBiP78329.
ChEMBLiCHEMBL3379.
DrugBankiDB08868. Fingolimod.
GuidetoPHARMACOLOGYi1344.
SwissLipidsiSLP:000000421.

PTM databases

iPTMnetiP78329.
PhosphoSitePlusiP78329.

Polymorphism and mutation databases

BioMutaiCYP4F2.
DMDMi6166044.

Proteomic databases

MaxQBiP78329.
PaxDbiP78329.
PeptideAtlasiP78329.
PRIDEiP78329.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi8529.
DisGeNETi8529.
GeneCardsiCYP4F2.
HGNCiHGNC:2645. CYP4F2.
HPAiHPA014048.
HPA058960.
MalaCardsiCYP4F2.
MIMi122700. phenotype.
604426. gene.
neXtProtiNX_P78329.
OpenTargetsiENSG00000186115.
Orphaneti413674. Vitamin K antagonists toxicity or dose selection.
PharmGKBiPA27121.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0157. Eukaryota.
COG2124. LUCA.
GeneTreeiENSGT00760000118816.
HOVERGENiHBG000182.
InParanoidiP78329.
KOiK17726.
OMAiHPENIKE.
PhylomeDBiP78329.
TreeFamiTF105088.

Enzyme and pathway databases

UniPathwayiUPA01054.
BioCyciMetaCyc:HS02675-MONOMER.
ZFISH: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).

Miscellaneous databases

GeneWikiiCYP4F2.
GenomeRNAii8529.
PROiP78329.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000186115.
CleanExiHS_CYP4F2.
ExpressionAtlasiP78329. baseline and differential.
GenevisibleiP78329. HS.

Family and domain databases

Gene3Di1.10.630.10. 1 hit.
InterProiIPR001128. Cyt_P450.
IPR017972. Cyt_P450_CS.
IPR002401. Cyt_P450_E_grp-I.
[Graphical view]
PfamiPF00067. p450. 1 hit.
[Graphical view]
PRINTSiPR00463. EP450I.
PR00385. P450.
SUPFAMiSSF48264. SSF48264. 1 hit.
PROSITEiPS00086. CYTOCHROME_P450. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCP4F2_HUMAN
AccessioniPrimary (citable) accession number: P78329
Secondary accession number(s): A0A024R7K3
, A8K425, B4DV75, Q16677, Q6NWT4, Q6NWT6, Q9NNZ0, Q9UIU8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: May 1, 1997
Last modified: November 2, 2016
This is version 163 of the entry and version 1 of the sequence. [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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.