UDP glucuronosyltransferase 1 family, polypeptide A1

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UDP glucuronosyltransferase 1 family, polypeptide A1
Identifiers
Symbols UGT1A1 ; BILIQTL1; GNT1; HUG-BR1; UDPGT; UDPGT 1-1; UGT1; UGT1A
External IDs OMIM191740 MGI98898 HomoloGene128034 ChEMBL: 1287617 GeneCards: UGT1A1 Gene
EC number 2.4.1.17
Orthologs
Species Human Mouse
Entrez 54658 394436
Ensembl ENSG00000241635 ENSMUSG00000089960
UniProt P22309 Q63886
RefSeq (mRNA) NM_000463 NM_201645
RefSeq (protein) NP_000454 NP_964007
Location (UCSC) Chr 2:
234.67 – 234.68 Mb
Chr 1:
88.21 – 88.22 Mb
PubMed search [1] [2]

UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the UGT1A1 gene.[1][2]

UGT-1A is a uridine diphosphate glucuronyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites.[3]

Gene[edit]

The UGT1A1 gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter.[3]

Clinical significance[edit]

Mutations in this gene cause serious problems for bilirubin metabolism; each syndrome can be caused by one or many mutations, so they are differentiated mostly by symptoms and not particular mutations:[4]

  • Gilbert syndrome (GS) in many populations, other than southeast and east Asians and Pacific Islanders, is most commonly associated with a homozygous 2-bp insertion (TA) mutation of the TATA box promoter region of the UGT1A1 gene, a polymorphism found in 40% of the alleles of many populations. About 10-15% of these populations are homozygous, but fewer (about 5%) actually develop UGT1A1-associated hyperbilirubinemia, so it appears that this mutation alone may be a necessary but not sufficient factor in GS, perhaps acting in combination with other UGT1A1 mutation(s) to increase the chances of developing GS. In the populations mentioned, since the TATA box mutation is much less common (about 3% of alleles), Gilbert's syndrome is more often due to missense mutations of the actual encoding region of the gene. A special phenobarbital-responsive enhancer module NR3 region (gtPBREM NR3) helps to increase UDPGT enzyme production, which would make it conceptually possible to medically control the bilirubin level, although this is rarely necessary, particularly in adults (usually the level of total serum bilirubin in Gilbert syndrome patients vary from 1 to 6 mg/dL).[4][5]
  • Crigler-Najjar syndrome, type I is associated with mutation(s) that result in a complete absence of normal UDPGT enzyme, which causes a severe hyperbilirubinemia with levels of total serum bilirubin from 20 to 45 mg/dL. Phenobarbital treatment does not help to lower bilirubin level, because it only increases the amount of mutated UDPGT enzyme, which is still unable to catalyze the glucuronidation of bilirubin, which on the other hand makes phenobarbital treatment diagnostically relevant.[4][6]
  • Crigler-Najjar syndrome, type II is associated with other mutation(s) that lead to a reduced activity of the mutated UDPGT enzyme, which causes a hyperbilirubinemia with levels of total serum bilirubin from 6 to 20 mg/dL. In this case phenobarbital treatment helps to lower bilirubin lever by more than 30%.[4][7]
  • Hyperbilirubinemia, familial transient neonatal (also called breastfeeding jaundice) is associated with mutation(s) that alone do not lead to bilirubin level increase in female patients, but their children when breastfed develop from mild to severe hyperbilirubinemia by receiving steroidal substances (with milk) inhibiting glucuronidation of unconjugated bilirubin that may lead to jaundice and even kernicterus.[4][8]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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IrinotecanPathway_WP46359 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article Go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article Go to article go to article
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Irinotecan Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP46359". 

See also[edit]

References[edit]

  1. ^ Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Bélanger A, Fournel-Gigleux S, Green M, Hum DW, Iyanagi T, Lancet D, Louisot P, Magdalou J, Chowdhury JR, Ritter JK, Schachter H, Tephly TR, Tipton KF, Nebert DW (August 1997). "The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence". Pharmacogenetics 7 (4): 255–69. doi:10.1097/00008571-199708000-00001. PMID 9295054. 
  2. ^ Strassburg CP, Manns MP, Tukey RH (April 1998). "Expression of the UDP-glucuronosyltransferase 1A locus in human colon. Identification and characterization of the novel extrahepatic UGT1A8". J. Biol. Chem. 273 (15): 8719–26. doi:10.1074/jbc.273.15.8719. PMID 9535849. 
  3. ^ a b "Entrez Gene: UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1". 
  4. ^ a b c d e Online 'Mendelian Inheritance in Man' (OMIM) UDP-glycosyltransferase 1 family, polypeptide A1; UGT1A1 -191740
  5. ^ Online 'Mendelian Inheritance in Man' (OMIM) Gilbert syndrome -143500
  6. ^ Online 'Mendelian Inheritance in Man' (OMIM) Crigler-Najjar syndrome, type I -218800
  7. ^ Online 'Mendelian Inheritance in Man' (OMIM) Crigler-Najjar syndrome, type II -606785
  8. ^ Online 'Mendelian Inheritance in Man' (OMIM) Hyperbilirubinemia, transient familial neonatal -237900

External links[edit]

Further reading[edit]