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MGP005314

UniProt Annotations

Entry Information
Gene NameUDP glucuronosyltransferase 1 family, polypeptide A1
Protein EntryUD11_HUMAN
UniProt IDP22309
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; Synonyms=i1; IsoId=P22309-1; Sequence=Displayed; Name=2; Synonyms=i2, UGT1A1s; IsoId=P22309-2; Sequence=VSP_053958;
Biophysicochemical PropertiesKinetic parameters: KM=0.26 uM for bilirubin {ECO:0000269|PubMed:18004206}; Vmax=1080 pmol/min/mg enzyme with bilirubin as substrate {ECO:0000269|PubMed:18004206};
Catalytic ActivityUDP-glucuronate + acceptor = UDP + acceptor beta-D-glucuronoside. {ECO:0000269|PubMed:18004206, ECO:0000269|PubMed:18004212}.
DiseaseCrigler-Najjar syndrome 1 (CN1) [MIM:218800]: Patients 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. {ECO:0000269|PubMed:11013440, ECO:0000269|PubMed:15712364, ECO:0000269|PubMed:1634050, ECO:0000269|PubMed:17229650, ECO:0000269|PubMed:19830808, ECO:0000269|PubMed:23992562, ECO:0000269|PubMed:7906695, ECO:0000269|PubMed:7989045, ECO:0000269|PubMed:7989595, ECO:0000269|PubMed:8226884}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseCrigler-Najjar syndrome 2 (CN2) [MIM:606785]: Patients 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. {ECO:0000269|PubMed:11013440, ECO:0000269|PubMed:11370628, ECO:0000269|PubMed:12402338, ECO:0000269|PubMed:15712364, ECO:0000269|PubMed:17229650, ECO:0000269|PubMed:19830808, ECO:0000269|PubMed:23099197, ECO:0000269|PubMed:23992562, ECO:0000269|PubMed:7989595, ECO:0000269|PubMed:8276413, ECO:0000269|PubMed:8280139, ECO:0000269|PubMed:8706880, ECO:0000269|PubMed:9621515, ECO:0000269|PubMed:9639672}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseGilbert syndrome (GILBS) [MIM:143500]: Occurs as a consequence of reduced bilirubin transferase activity and is often detected in young adults with vague non-specific complaints. {ECO:0000269|PubMed:11013440, ECO:0000269|PubMed:12139570, ECO:0000269|PubMed:7715297, ECO:0000269|PubMed:9627603}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseTransient familial neonatal hyperbilirubinemia (HBLRTFN) [MIM:237900]: A condition characterized by excessive concentration of bilirubin in the blood, which may lead to jaundice. Breast milk jaundice is a common problem in nursing infants. {ECO:0000269|PubMed:11061796}. Note=The disease may be caused by mutations affecting the gene represented in this entry. The defect has been ascribed to various breast milk substances, but the component or combination of components that is responsible remains unclear. Defects of UGT1A1 are an underlying cause of the prolonged unconjugated hyperbilirubinemia associated with breast milk. One or more components in the milk may trigger the jaundice in infants who have such mutations. Mutations are identical to those detected in patients with Gilbert syndrome, a risk factor of neonatal non-physiologic hyperbilirubinemia and a genetic factor in fasting hyperbilirubinemia.
FunctionUDPGT 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. Is also able to catalyze the glucuronidation of 17beta-estradiol, 17alpha-ethinylestradiol, 1-hydroxypyrene, 4- methylumbelliferone, 1-naphthol, paranitrophenol, scopoletin, and umbelliferone. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1. {ECO:0000269|PubMed:18004206, ECO:0000269|PubMed:19545173, ECO:0000269|PubMed:19830808}.
MiscellaneousThe 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.
PolymorphismGenetic variation in UGT1A1 defines the bilirubin serum levels quantitative trait locus 1 (BILIQTL1) [MIM:601816]. Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism.
Sequence CautionSequence=AAA61247.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; Sequence=AAF03522.2; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
SimilarityBelongs to the UDP-glycosyltransferase family. {ECO:0000305}.
Subcellular LocationIsoform 1: Microsome. Endoplasmic reticulum membrane {ECO:0000305}; Single-pass membrane protein {ECO:0000305}.
Subcellular LocationIsoform 2: Endoplasmic reticulum.
SubunitIsoform 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 UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10. Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGT1A1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX. {ECO:0000269|PubMed:17187418, ECO:0000269|PubMed:20610558}.
Tissue SpecificityIsoform 1 and isoform 2 are expressed in liver, colon and small intestine. Isoform 2 but not isoform 1 is expressed in kidney. Isoform 1 and isoform 2 are not expressed in esophagus. Not expressed in skin. {ECO:0000269|PubMed:1339448, ECO:0000269|PubMed:17187418, ECO:0000269|PubMed:18004212}.
Web ResourceName=Wikipedia; Note=Glucuronosyltransferase entry; URL="http://en.wikipedia.org/wiki/Glucuronosyltransferase";
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