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Protein

UDP-glucuronosyltransferase 1-4

Gene

UGT1A4

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

Functioni

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1 (By similarity).By similarity

Miscellaneous

The gene is part of the UGT1A complex locus which displays alternative use of promoters, first exons and terminal exons. The locus is defined by 13 first exons, which are alternatively spliced to 3 other common exons and 2 alternative terminal exons 5. From the 27 possible mRNA isoforms, 9 produce functionally active polypeptides (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10) called isoforms 1 (i1). Use of an alternative exon 5 (5b) as terminal exon is leading to 9 additional alternatively spliced products termed isoforms i2 and which lack transferase activity.

Catalytic activityi

UDP-glucuronate + acceptor = UDP + acceptor beta-D-glucuronoside.

GO - Molecular functioni

  • enzyme binding Source: BHF-UCL
  • glucuronosyltransferase activity Source: UniProtKB
  • protein heterodimerization activity Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionGlycosyltransferase, Transferase

Enzyme and pathway databases

BioCyciMetaCyc:HS11970-MONOMER
BRENDAi2.4.1.17 2681
ReactomeiR-HSA-156588 Glucuronidation
R-HSA-189483 Heme degradation
R-HSA-5579016 Defective UGT1A4 causes hyperbilirubinemia
SABIO-RKiP22310
SIGNORiP22310

Protein family/group databases

CAZyiGT1 Glycosyltransferase Family 1

Chemistry databases

SwissLipidsiSLP:000001872

Names & Taxonomyi

Protein namesi
Recommended name:
UDP-glucuronosyltransferase 1-4 (EC:2.4.1.17)
Short name:
UDPGT 1-4
Short name:
UGT1*4
Short name:
UGT1-04
Short name:
UGT1.4
Alternative name(s):
Bilirubin-specific UDPGT isozyme 2
Short name:
hUG-BR2
UDP-glucuronosyltransferase 1-D
Short name:
UGT-1D
Short name:
UGT1D
UDP-glucuronosyltransferase 1A4
Gene namesi
Name:UGT1A4
Synonyms:GNT1, UGT1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

EuPathDBiHostDB:ENSG00000244474.5
HGNCiHGNC:12536 UGT1A4
MIMi191740 gene
606429 gene
neXtProtiNX_P22310

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

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transmembranei492 – 508HelicalSequence analysisAdd BLAST17

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane, Microsome

Pathology & Biotechi

Involvement in diseasei

Gilbert syndrome (GILBS)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionOccurs as a consequence of reduced bilirubin transferase activity and is often detected in young adults with vague non-specific complaints.
See also OMIM:143500
Crigler-Najjar syndrome 1 (CN1)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionPatients have severe hyperbilirubinemia and usually die of kernicterus (bilirubin accumulation in the basal ganglia and brainstem nuclei) within the first year of life. CN1 inheritance is autosomal recessive.
See also OMIM:218800
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_007711376S → F in CN1. 1 PublicationCorresponds to variant dbSNP:rs72551353EnsemblClinVar.1
Crigler-Najjar syndrome 2 (CN2)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionPatients have less severe hyperbilirubinemia and usually survive into adulthood without neurologic damage. Phenobarbital, which induces the partially deficient glucuronyl transferase, can diminish the jaundice. CN2 inheritance is autosomal dominant.
See also OMIM:606785
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_009506132L → P in CN2. 1 PublicationCorresponds to variant dbSNP:rs72551337Ensembl.1
Natural variantiVAR_007710332Q → R in CN2. 1 PublicationCorresponds to variant dbSNP:rs72551348EnsemblClinVar.1
Natural variantiVAR_009507487Y → D in CN2. 1 PublicationCorresponds to variant dbSNP:rs34993780EnsemblClinVar.1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi54657
MalaCardsiUGT1A4
MIMi143500 phenotype
218800 phenotype
606785 phenotype
OpenTargetsiENSG00000244474
PharmGKBiPA37179

Chemistry databases

ChEMBLiCHEMBL3619
DrugBankiDB06216 Asenapine
DB00363 Clozapine
DB04953 Ezogabine
DB00555 Lamotrigine
DB00683 Midazolam
DB00910 Paricalcitol
DB00675 Tamoxifen
DB00831 Trifluoperazine
DB00197 Troglitazone
DB00313 Valproic Acid

Polymorphism and mutation databases

BioMutaiUGT1A4
DMDMi136731

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 28Sequence analysisAdd BLAST28
ChainiPRO_000003600329 – 534UDP-glucuronosyltransferase 1-4Add BLAST506

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi119N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi142N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi296N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi348N-linked (GlcNAc...) asparagine1 Publication1

Keywords - PTMi

Glycoprotein

Proteomic databases

EPDiP22310
PaxDbiP22310
PeptideAtlasiP22310
PRIDEiP22310
ProteomicsDBi53982

PTM databases

iPTMnetiP22310
PhosphoSitePlusiP22310

Expressioni

Tissue specificityi

Isoform 1 and isoform 2 are expressed in liver, kidney, colon and small intestine. Isoform 2 but not isoform 1 is expressed in esophagus. Not expressed in skin.2 Publications

Inductioni

By phenobarbital.

Gene expression databases

BgeeiENSG00000244474 Expressed in 29 organ(s), highest expression level in right lobe of liver
GenevisibleiP22310 HS

Interactioni

Subunit structurei

Isoform 1 interacts with isoform 2/i2 suggesting that oligomerization is involved in negative regulation of transferase activity by isoform 2. Isoform 1 also interacts with respective i2 isoforms of UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10.1 Publication

GO - Molecular functioni

Protein-protein interaction databases

BioGridi120086, 3 interactors
IntActiP22310, 9 interactors
STRINGi9606.ENSP00000362508

Chemistry databases

BindingDBiP22310

Structurei

3D structure databases

ProteinModelPortaliP22310
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the UDP-glycosyltransferase family.Curated

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1192 Eukaryota
COG1819 LUCA
GeneTreeiENSGT00760000118949
HOGENOMiHOG000220832
HOVERGENiHBG004033
InParanoidiP22310
KOiK00699
OMAiDGVMGNI
OrthoDBiEOG091G06JC
PhylomeDBiP22310
TreeFamiTF315472

Family and domain databases

InterProiView protein in InterPro
IPR002213 UDP_glucos_trans
IPR035595 UDP_glycos_trans_CS
PfamiView protein in Pfam
PF00201 UDPGT, 1 hit
PROSITEiView protein in PROSITE
PS00375 UDPGT, 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: P22310-1) [UniParc]FASTAAdd to basket
Also known as: i1

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
MARGLQVPLP RLATGLLLLL SVQPWAESGK VLVVPTDGSP WLSMREALRE
60 70 80 90 100
LHARGHQAVV LTPEVNMHIK EEKFFTLTAY AVPWTQKEFD RVTLGYTQGF
110 120 130 140 150
FETEHLLKRY SRSMAIMNNV SLALHRCCVE LLHNEALIRH LNATSFDVVL
160 170 180 190 200
TDPVNLCGAV LAKYLSIPAV FFWRYIPCDL DFKGTQCPNP SSYIPKLLTT
210 220 230 240 250
NSDHMTFLQR VKNMLYPLAL SYICHTFSAP YASLASELFQ REVSVVDLVS
260 270 280 290 300
YASVWLFRGD FVMDYPRPIM PNMVFIGGIN CANGKPLSQE FEAYINASGE
310 320 330 340 350
HGIVVFSLGS MVSEIPEKKA MAIADALGKI PQTVLWRYTG TRPSNLANNT
360 370 380 390 400
ILVKWLPQND LLGHPMTRAF ITHAGSHGVY ESICNGVPMV MMPLFGDQMD
410 420 430 440 450
NAKRMETKGA GVTLNVLEMT SEDLENALKA VINDKSYKEN IMRLSSLHKD
460 470 480 490 500
RPVEPLDLAV FWVEFVMRHK GAPHLRPAAH DLTWYQYHSL DVIGFLLAVV
510 520 530
LTVAFITFKC CAYGYRKCLG KKGRVKKAHK SKTH
Length:534
Mass (Da):60,025
Last modified:August 1, 1991 - v1
Checksum:iAB745D46F57538BE
GO
Isoform 2 (identifier: P22310-2) [UniParc]FASTAAdd to basket
Also known as: i2, UGT1A4s

The sequence of this isoform differs from the canonical sequence as follows:
     436-534: SYKENIMRLS...VKKAHKSKTH → RKKQQSGRQM

Show »
Length:445
Mass (Da):49,802
Checksum:iBB72EF2CDE4C0482
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05984411R → W. Corresponds to variant dbSNP:rs3892221Ensembl.1
Natural variantiVAR_02468424P → T1 PublicationCorresponds to variant dbSNP:rs6755571Ensembl.1
Natural variantiVAR_05858448L → V2 PublicationsCorresponds to variant dbSNP:rs2011425EnsemblClinVar.1
Natural variantiVAR_06187068H → Y. Corresponds to variant dbSNP:rs45621441Ensembl.1
Natural variantiVAR_009506132L → P in CN2. 1 PublicationCorresponds to variant dbSNP:rs72551337Ensembl.1
Natural variantiVAR_052454176I → F. Corresponds to variant dbSNP:rs45540231Ensembl.1
Natural variantiVAR_007710332Q → R in CN2. 1 PublicationCorresponds to variant dbSNP:rs72551348EnsemblClinVar.1
Natural variantiVAR_007711376S → F in CN1. 1 PublicationCorresponds to variant dbSNP:rs72551353EnsemblClinVar.1
Natural variantiVAR_009507487Y → D in CN2. 1 PublicationCorresponds to variant dbSNP:rs34993780EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_053960436 – 534SYKEN…KSKTH → RKKQQSGRQM in isoform 2. 2 PublicationsAdd BLAST99

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M84128 Genomic DNA Translation: AAA61249.1
M84124, M84122, M84123 Genomic DNA Translation: AAA61247.1 Sequence problems.
M57951 mRNA Translation: AAA63196.1
AF297093 Genomic DNA Translation: AAG30422.1
AY435139 mRNA Translation: AAR95640.1
AK313623 mRNA Translation: BAG36384.1
DQ364249 mRNA Translation: ABC96773.1
AC006985 Genomic DNA No translation available.
AC114812 Genomic DNA No translation available.
CH471063 Genomic DNA Translation: EAW71061.1
BC139784 mRNA Translation: AAI39785.1
CCDSiCCDS33405.1 [P22310-1]
RefSeqiNP_009051.1, NM_007120.2 [P22310-1]
UniGeneiHs.554822

Genome annotation databases

EnsembliENST00000373409; ENSP00000362508; ENSG00000244474 [P22310-1]
ENST00000450233; ENSP00000408608; ENSG00000244474 [P22310-2]
GeneIDi54657
KEGGihsa:54657
UCSCiuc002vux.4 human [P22310-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiUD14_HUMAN
AccessioniPrimary (citable) accession number: P22310
Secondary accession number(s): B2R937, B8K288, Q5DT00
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1991
Last sequence update: August 1, 1991
Last modified: September 12, 2018
This is version 187 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, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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