The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence

Mackenzie, Peter I.; Owens, Ida S.; Burchell, Brian; Bock, K. W.; Bairoch, Amos Marc; Bélanger, Alain; Fournel‐Gigleux, Sylvie; Green, Mitchell; Hum, Dean W.; Iyanagi, Takashi; Lancet, Doron; Louisot, Pierre; Magdalou, Jacques; Chowdhury, Jayanla Roy; Ritter, Joseph K.; Schachter, Harry; Tephly, Thomas R.; Tipton, Keith F.; Nebert, Daniel W.

doi:10.1097/00008571-199708000-00001

Cited by 1,039 publications

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“…11,[76][77][78][79][80] The molecular genetics of human UGTs is now more clearly understood, with evidence for the existence of distinct subfamilies, which comprise more than 26 genes or cDNAs (Figure 2). Eighteen of them correspond to functional proteins and are encoded by two gene families, UGT1 and UGT2 that are, based on their sequence similarities, further divided into three subfamilies: UGT1A, UGT2A and UGT2B (for detailed information see Mackenzie et al 81 ). In contrast to the UGT2B subfamily, which comprises several independent genes, 82-84 the entire UGT1 family is derived from a single gene locus (UGT1) spanning about 210 kb on chromosome 2 (2q37), which is composed of 17 exons.…”

Section: A Brief Overview Of the Glucuronidation Pathway And Human Ugtsmentioning

confidence: 99%

“…Several UGT2Bs were isolated from liver as well from extrahepatic tissues. 76,[81][82][83][84][96][97][98][99][100][101] In addition, numerous homologous pseudogenes have been found, 83 all of which are clustered with UGT2B genes encoding functional proteins on chromosome 4 (4q13). Similar to the UGT1 family, members of the UGT2B subfamily share a high degree of similarity in the C-terminal portion of the protein and the highest degree of divergence in sequences encoded by exons 1.…”

Section: A Brief Overview Of the Glucuronidation Pathway And Human Ugtsmentioning

confidence: 99%

“…184,195 In addition to being associated with elevated bilirubin plasma levels, the UGT1A1*28 allele has been linked to various diseases including glucose-6-phosphate dehydrogenase (G6PD) deficiency, neonatal jaundice, hereditary spherocytosis, cholelithiasis in children with sickle cell anemia and b-thalassemia. 196-201 a Mackenzie et al 81 .…”

Section: Ugt1a1mentioning

confidence: 99%

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Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse endogenous and exogenous chemicals. Glucuronidation is one of the major phase II drug-metabolizing reactions that contributes to drug biotransformation. This biochemical process is also involved in the protection against environmental toxicants, carcinogens, dietary toxins and participates in the homeostasis of numerous endogenous molecules, including bilirubin, steroid hormones and biliary acids. Over the years, significant progress was made in the field of glucuronidation, especially with regard to the identification of human UGTs, study of their tissue distribution and substrate specificities. More recently, the degree of allelic diversity has also been revealed for several human UGT genes. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced adverse reactions and cancer susceptibility. This review focuses on human UGTs, the description of the nature of polymorphic variations and their functional impact. The pharmacogenomic implication of polymorphic UGTs is presented, more specifically the role of UGT polymorphisms in modifying cancer risk and their impact on individual risk to drug-induced toxicities.

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Section: A Brief Overview Of the Glucuronidation Pathway And Human Ugtsmentioning

confidence: 99%

Section: A Brief Overview Of the Glucuronidation Pathway And Human Ugtsmentioning

confidence: 99%

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Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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“…The carbohydrate-active enzymes database (www.cazy.org) currently itemises 89 sequence-based families (Campbell et al 1997;Coutinho et al 2003) with over 20,000 entries. GTs belonging to Family 1 (UGTs) display a conserved amino acid motif near the C-terminus, use UDP-activated sugars (mainly UDP-glucose) as donors, and various types of low molecular-weight molecules as acceptors (Mackenzie et al 1997). Plant UGTs possess an adjusted version of the conserved amino acid region named PSPG motif (plant secondary product glycosyltransferase) (Hughes and Hughes 1994;Paquette et al 2003), and acceptors include metabolites like plant hormones, phenylpropanoids, Xavonoids, coumarins, terpenoids, cyanohydrins, thiohydroxamates, and alkaloids (Vogt and Jones 2000;Bowles et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Recombinant expression and functional characterisation of regiospecific flavonoid glucosyltransferases from Hieracium pilosella L.

Witte

Moco

Vervoort

et al. 2009

Planta

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Five glucosyltransferases were cloned by RT-PCR ampliWcation using total RNA from Hieracium pilosella L. (Asteraceae) inXorescences as template. Expression was accomplished in Escherichia coli, and three of the HIS-tagged enzymes, UGT90A7, UGT95A1, and UGT72B11 were partially puriWed and functionally characterised as UDP-glucose:Xavonoid O-glucosyltransferases. Both UGT90A7 and UGT95A1 preferred luteolin as substrate, but possessed diVerent regiospeciWcity proWles. UGT95A1 established a new subgroup within the UGT family showing high regiospeciWcity towards the C-3Ј hydroxyl group of luteolin, while UGT90A7 primarily yielded the 4Ј-O-glucoside, but concomitantly catalysed also the formation of the 7-O-glucoside, which could account for this Xavones glucoside in H. pilosella Xower heads. Semi quantitative expression proWles revealed that UGT95A1 was expressed at all stages of inXorescence development as well as in leaf and stem tissue, whereas UGT90A7 transcript abundance was nearly limited to Xower tissue and started to develop with the pigmentation of closed buds. Other than these enzymes, UGT72B11 showed rather broad substrate acceptance, with highest activity towards Xavones and Xavonols which have not been reported from H. pilosella. As umbelliferone was also readily accepted, this enzyme could be involved in the glucosylation of coumarins and other metabolites.

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“…UGTs are members of a superfamily of glycosyltransferases that catalyze the conjugation of a variety of hydrophobic aglycone substrates with glucuronic acid donated by UDPglucuronic acid [5]. This reaction results in the formation of a hydrosoluble J3-D-glucuronide that is easily excreted into bile or urine.…”

Section: Introductionmentioning

confidence: 99%

Expression of a functionally active human hepatic UDP‐glucuronosyltransferase (UGT1A6) lacking the N‐terminal signal sequence in the endoplasmic reticulum

et al. 1999

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UDP-glucuronosyltransferase 1A6 (UGT1A6) is a membrane glycoprotein of the endoplasmic reticulum playing a key role in drug metabolism. It is synthesized as a precursor with an N-terminal cleavable signal peptide. We demonstrate that deletion of the signal peptide sequence does not prevent membrane targeting and integration of this human isoform when expressed in an in vitro transcription-translation system, as shown by N-glycosylation, resistance to alkaline treatment and protease protection. Furthermore, UGT1A6 lacking the signal peptide (UGT1A6Asp) was targeted to the endoplasmic reticulum in mammalian ceils as shown by immunofluorescence microscopy and was catalytically active with kinetic constants for 4-methylumbelliferone glucuronidation similar to that of the wildtype. These results provide evidence that the signal peptide is not essential for the membrane assembly and activity of UGTIA6 suggesting that additional topogenic element(s) mediate(s) this process.

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The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence

Cited by 1,039 publications

References 0 publications

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Recombinant expression and functional characterisation of regiospecific flavonoid glucosyltransferases from Hieracium pilosella L.

Expression of a functionally active human hepatic UDP‐glucuronosyltransferase (UGT1A6) lacking the N‐terminal signal sequence in the endoplasmic reticulum

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