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
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
Mutations in this gene cause serious metabolic problems for bilirubin xenobiotic 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) previously was most commonly associated with a 2-bp insertion (TA) mutation of promoter region of UGT1A1 gene, but further studies showed that over 40% of population have the same mutation and never develop UGT1A1-associated hyperbilirubinemia, so it appears that this mutation alone is a necessary but not sufficient factor in GS, while combined with other UGT1A1 mutation(s) it increases chances of developing GS. A special phenobarbital-responsive enhancer module NR3 region (gtPBREM NR3) helps to increase UDPGT enzyme production, which makes it possible to medically control bilirubin level if necessary (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]
See also
External links
References
- ^ 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. PMID 9295054.
- ^ 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. PMID 9535849.
- ^ a b "Entrez Gene: UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54658.
- ^ a b c d e Online 'Mendelian Inheritance in Man' (OMIM) UDP-glycosyltransferase 1 family, polypeptide A1; UGT1A1 -191740
- ^ Online 'Mendelian Inheritance in Man' (OMIM) Gilbert syndrome -143500
- ^ Online 'Mendelian Inheritance in Man' (OMIM) Crigler-Najjar syndrome, type I -218800
- ^ Online 'Mendelian Inheritance in Man' (OMIM) Crigler-Najjar syndrome, type II -606785
- ^ Online 'Mendelian Inheritance in Man' (OMIM) Hyperbilirubinemia, transient familial neonatal -237900
Further reading
- Tukey RH, Strassburg CP (2000). "Human UDP-glucuronosyltransferases: metabolism, expression, and disease.". Annu. Rev. Pharmacol. Toxicol. 40: 581–616. doi:10.1146/annurev.pharmtox.40.1.581. PMID 10836148.
- Kadakol A, Ghosh SS, Sappal BS, et al. (2000). "Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype.". Hum. Mutat. 16 (4): 297–306. doi:10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z. PMID 11013440.
- King CD, Rios GR, Green MD, Tephly TR (2001). "UDP-glucuronosyltransferases.". Curr. Drug Metab. 1 (2): 143–61. PMID 11465080.
- Bosma PJ (2003). "Inherited disorders of bilirubin metabolism.". J. Hepatol. 38 (1): 107–17. PMID 12480568.
- Innocenti F, Ratain MJ (2003). "Irinotecan treatment in cancer patients with UGT1A1 polymorphisms.". Oncology (Williston Park, N.Y.) 17 (5 Suppl 5): 52–5. PMID 12800608.
- Lee W, Lockhart AC, Kim RB, Rothenberg ML (2005). "Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development.". Oncologist 10 (2): 104–11. doi:10.1634/theoncologist.10-2-104. PMID 15709212.
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Transferases: glycosyltransferases (EC 2.4) |
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| 2.4.1: Hexosyltransferases |
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B3GAT1, B3GAT2, B3GAT3
UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10
UGT2A1, UGT2A2, UGT2A3, UGT2B4, UGT2B7, UGT2B10, UGT2B11, UGT2B15, UGT2B17, UGT2B28
Hyaluronan synthase: HAS1 · HAS2 · HAS3
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| 2.4.2: Pentosyltransferases |
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| 2.4.99: Sialyltransferases |
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