UGT1A6 explained

UDP-glucuronosyltransferase 1-6 is an enzyme that in humans is encoded by the UGT1A6 gene.^{[1] [2] [3]}

Function

UDP-glucuronosyltransferase 1-6 is a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites.

This 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. The enzyme encoded by this gene is active on phenolic and planar compounds. Alternative splicing in the unique 5' end of this gene results in two transcript variants.

This enzyme is also responsible for the inactivation of popular analgesic drugs, such as aspirin and acetaminophen, by glucuronidation. The loss of a functional UGT1A6 gene in certain hypercarnivores, and particularly cats, renders the animals extremely sensitive to the adverse effects of these analgesics.^[4]

Further reading

• Tukey RH, Strassburg CP . Human UDP-glucuronosyltransferases: metabolism, expression, and disease . Annual Review of Pharmacology and Toxicology . 40 . 581–616 . 2000 . 10836148 . 10.1146/annurev.pharmtox.40.1.581 .
• King CD, Rios GR, Green MD, Tephly TR . UDP-glucuronosyltransferases . Current Drug Metabolism . 1 . 2 . 143–61 . September 2000 . 11465080 . 10.2174/1389200003339171 .
• Book: Bock KW, Köhle C . UDP-Glucuronosyltransferase 1A6: Structural, Functional, and Regulatory Aspects . Phase II Conjugation Enzymes and Transport Systems . Methods in Enzymology . 400 . 57–75 . 2006 . 16399343 . 10.1016/S0076-6879(05)00004-2 . 9780121828059 .
• Bosma PJ, Chowdhury JR, Huang TJ, Lahiri P, Elferink RP, Van Es HH, Lederstein M, Whitington PF, Jansen PL, Chowdhury NR . Mechanisms of inherited deficiencies of multiple UDP-glucuronosyltransferase isoforms in two patients with Crigler-Najjar syndrome, type I . FASEB Journal . 6 . 10 . 2859–63 . July 1992 . 1634050 . 10.1096/fasebj.6.10.1634050. free . 24007614 .
• Ritter JK, Crawford JM, Owens IS . Cloning of two human liver bilirubin UDP-glucuronosyltransferase cDNAs with expression in COS-1 cells . The Journal of Biological Chemistry . 266 . 2 . 1043–7 . January 1991 . 10.1016/S0021-9258(17)35280-8 . 1898728 . free .
• Harding D, Jeremiah SJ, Povey S, Burchell B . Chromosomal mapping of a human phenol UDP-glucuronosyltransferase, GNT1 . Annals of Human Genetics . 54 . Pt 1 . 17–21 . January 1990 . 2108603 . 10.1111/j.1469-1809.1990.tb00356.x . 35661967 .
• Harding D, Fournel-Gigleux S, Jackson MR, Burchell B . Cloning and substrate specificity of a human phenol UDP-glucuronosyltransferase expressed in COS-7 cells . Proceedings of the National Academy of Sciences of the United States of America . 85 . 22 . 8381–5 . November 1988 . 3141926 . 282461 . 10.1073/pnas.85.22.8381 . 1988PNAS...85.8381H . free .
• Moghrabi N, Clarke DJ, Boxer M, Burchell B . Identification of an A-to-G missense mutation in exon 2 of the UGT1 gene complex that causes Crigler-Najjar syndrome type 2 . Genomics . 18 . 1 . 171–3 . October 1993 . 8276413 . 10.1006/geno.1993.1451 .
• Aono S, Yamada Y, Keino H, Hanada N, Nakagawa T, Sasaoka Y, Yazawa T, Sato H, Koiwai O . Identification of defect in the genes for bilirubin UDP-glucuronosyl-transferase in a patient with Crigler-Najjar syndrome type II . Biochemical and Biophysical Research Communications . 197 . 3 . 1239–44 . December 1993 . 8280139 . 10.1006/bbrc.1993.2610 .
• Killard AJ, O'Kennedy R, Bogan DP . Analysis of the glucuronidation of 7-hydroxycoumarin by HPLC . . 14 . 11 . 1585–90 . August 1996 . 8877866 . 10.1016/0731-7085(96)01801-8 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Ciotti M, Marrone A, Potter C, Owens IS . Genetic polymorphism in the human UGT1A6 (planar phenol) UDP-glucuronosyltransferase: pharmacological implications . Pharmacogenetics . 7 . 6 . 485–95 . December 1997 . 9429234 . 10.1097/00008571-199712000-00007 .
• Münzel PA, Lehmköster T, Brück M, Ritter JK, Bock KW . Aryl hydrocarbon receptor-inducible or constitutive expression of human UDP glucuronosyltransferase UGT1A6 . Archives of Biochemistry and Biophysics . 350 . 1 . 72–8 . February 1998 . 9466822 . 10.1006/abbi.1997.0485 .
• Duffy CF, O'Kennedy R . Determination of 7-hydroxycoumarin and its glucuronide and sulphate conjugates in liver slice incubates by capillary zone electrophoresis . Journal of Pharmaceutical and Biomedical Analysis . 17 . 8 . 1279–84 . September 1998 . 9800648 . 10.1016/S0731-7085(98)00015-6 .
• Gong QH, Cho JW, Huang T, Potter C, Gholami N, Basu NK, Kubota S, Carvalho S, Pennington MW, Owens IS, Popescu NC . Thirteen UDPglucuronosyltransferase genes are encoded at the human UGT1 gene complex locus . Pharmacogenetics . 11 . 4 . 357–68 . June 2001 . 11434514 . 10.1097/00008571-200106000-00011 .

Notes and References

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 . The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence . Pharmacogenetics . 7 . 4 . 255–69 . August 1997 . 9295054 . 10.1097/00008571-199708000-00001 .
2. Ritter JK, Chen F, Sheen YY, Tran HM, Kimura S, Yeatman MT, Owens IS . A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini . The Journal of Biological Chemistry . 267 . 5 . 3257–61 . February 1992 . 10.1016/S0021-9258(19)50724-4 . 1339448 . free .
3. Web site: Entrez Gene: UGT1A6 UDP glucuronosyltransferase 1 family, polypeptide A6.
4. Shrestha B, Reed JM, Starks PT, Kaufman GE, Goldstone JV, Roelke ME, O'Brien SJ, Koepfli KP, Frank LG, Court MH . Evolution of a major drug metabolizing enzyme defect in the domestic cat and other felidae: phylogenetic timing and the role of hypercarnivory . PLOS ONE . 6 . 3 . e18046 . 2011 . 21464924 . 3065456 . 10.1371/journal.pone.0018046 . 2011PLoSO...618046S . Zanger . Ulrich . free .