The glycosidation of xenobiotics and endogenous compounds: Versatility and redundancy in the UDP glycosyltransferase superfamily

Meech, Robyn; Miners, John O.; Lewis, Benjamin C.; Mackenzie, Peter I.

doi:10.1016/j.pharmthera.2012.01.009

Cited by 100 publications

(75 citation statements)

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“…However, there is evidence demonstrating that a number of drugs and other compounds cleared by glucuronidation also undergo glucosidation (Meech et al, 2012). Both glucuronidation and glucosidation have been reported for AS-3201 (R-(2)2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-39-pyrrolidine-1,29,3,59-tetrone; an aldose reductase inhibitor), bilirubin, hyodeoxycholic acid, ibuprofen, mycophenolic acid, varenicline, and an experimental endothelin ET A receptor antagonist (Toide et al, 2004;Fevery et al, 1977;Shipkova et al, 1999Shipkova et al, , 2001Mackenzie et al, 2003;Tang et al, 2003;Obach et al, 2006;Buchheit et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Morphine Glucuronidation and Glucosidation Represent Complementary Metabolic Pathways That Are Both Catalyzed by UDP-Glucuronosyltransferase 2B7: Kinetic, Inhibition, and Molecular Modeling Studies

Chau

Elliot

Lewis

et al. 2014

J Pharmacol Exp Ther

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Morphine 3-b-D-glucuronide (M3G) and morphine 6-b-D-glucuronide (M6G) are the major metabolites of morphine in humans. More recently, morphine-3-b-D-glucoside (M-3-glucoside) was identified in the urine of patients treated with morphine. Kinetic and inhibition studies using human liver microsomes (HLM) and recombinant UGTs as enzyme sources along with molecular modeling were used here to characterize the relationship between morphine glucuronidation and glucosidation. The M3G to M6G intrinsic clearance (CL int ) ratio (∼5.5) from HLM supplemented with UDP-glucuronic acid (UDP-GlcUA) alone was consistent with the relative formation of these metabolites in humans. The mean CL int values observed for M-3-glucoside by incubations of HLM with UDP-glucose (UDP-Glc) as cofactor were approximately twice those for M6G formation. However, although the M3G-to-M6G CL int ratio remained close to 5.5 when human liver microsomal kinetic studies were performed in the presence of a 1: 1 mixture of cofactors, the mean CL int value for M-3-glucoside formation was less than that of M6G. Studies with UGT enzymeselective inhibitors and recombinant UGT enzymes, along with effects of BSA on morphine glycosidation kinetics, were consistent with a major role of UGT2B7 in both morphine glucuronidation and glucosidation. Molecular modeling identified key amino acids involved in the binding of UDP-GlcUA and UDP-Glc to UGT2B7. Mutagenesis of these residues abolished morphine glucuronidation and glucosidation. Overall, the data indicate that morphine glucuronidation and glucosidation occur as complementary metabolic pathways catalyzed by a common enzyme (UGT2B7). Glucuronidation is the dominant metabolic pathway because the binding affinity of UDP-GlcUA to UGT2B7 is higher than that of UDP-Glc.

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Section: Introductionmentioning

confidence: 99%

Morphine Glucuronidation and Glucosidation Represent Complementary Metabolic Pathways That Are Both Catalyzed by UDP-Glucuronosyltransferase 2B7: Kinetic, Inhibition, and Molecular Modeling Studies

Chau

Elliot

Lewis

et al. 2014

J Pharmacol Exp Ther

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“…The zebrafish has also emerged as a popular toxicological model for drug discovery, endocrinology, and environmental chemical defense studies James, 2011;Peterson and Macrae, 2012;Tokarz et al, 2013). The UDP-glucuronosyltransferases (UGTs) are an important class of diverse phase II drug-metabolizing and detoxification enzymes that affect the drug toxicity as well as its oral bioavailability (Wu et al, 2011;Meech et al, 2012). In mammals, UGTs are encoded by two gene clusters: Ugt1 and Ugt2 (Mackenzie et al, 2005;Owens et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…The mammalian UGT enzymes catalyze the glucuronidation of a vast number of lipophilic endobiotics and xenobiotics with the UDP glucuronic acid (UDPGA) as a donor cofactor (Meech et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…For example, fish glucuronidate one or both propionic groups of the pigmental bilirubin and excrete the conjugated bilirubin through bile (Dutton, 1980;Clarke et al, 1992). To date, limited information is available on the specific piscine UGT isoforms that are responsible for the glucuronidation of various xenobiotics and endobiotics (Wu et al, 2011;Meech et al, 2012). We recently reported identification of the complete repertoire of 40 Ugt genes and 5 Ugt pseudogenes in the zebrafish and found that teleosts have many more Ugt genes than mammals (Huang and Wu, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the ZebrafishUgtRepertoire Reveals a New Class of Drug-Metabolizing UDP Glucuronosyltransferases

Wang¹,

Huang²,

Wu³

2014

Mol Pharmacol

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The zebrafish genome contains a gene superfamily of 40 Ugt genes that can be divided into Ugt1, Ugt2, and Ugt5 families. Because the encoded zebrafish UDP glucuronosyltransferase (UGT) proteins do not display orthologous relationships to any of the mammalian and avian UGT enzymes based on molecular phylogeny, it is difficult to predict their substrate specificity. Here, we mapped their tissue-specific expression patterns. We showed that the zebrafish UGT enzymes can be glycosylated. We determined their substrate specificity and catalytic activity toward diverse aglycone substrates. Specifically, we measured mRNA levels of each of the 40 zebrafish Ugt genes in 11 adult tissues and found that they are expressed in a tissue-specific manner. Moreover, functional analyses with the donor of UDP glucuronic acid (UDPGA) for each of the 40 zebrafish UGT proteins revealed their substrate specificity toward 10 important aglycones. In particular, UGT1A1, UGT1A7, and UGT1B1 displayed good glucuronidation activities toward most phenolic aglycones (4-methylumbelliferone, 4-nitrophenol, 1-naphthol, bisphenol A, and mycophenolic acid) and the two carboxylic acids (bilirubin and diclofenac). Importantly, some members of the UGT5, a novel UGT family identified recently, are capable of glucuronidating multiple aglycones with the donor cofactor of UDPGA. In particular, UGT5A5, UGT5B2, and UGT5E1 glucuronidate phenols and steroids with high specificity toward steroid hormones of estradiol and testosterone and estrogenic alkylphenols 4-tert-octylphenol. These results shed new insights into the mechanisms by which fish species defend themselves against vast numbers of xenobiotics via glucuronidation conjugations and may facilitate the establishment of zebrafish as a model vertebrate in toxicological, developmental, and pathologic studies.

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“…Bacterial P-UGTs have been exploited as enzymatic tools that can be used in glycodiversification and combinatorial applications to produce novel and bioactive glycosylated products (8)(9)(10). In plants, numerous soluble cytosolic UGTs have been studied and were determined to play a vital role in the structural modification of secondary metabolites (11)(12)(13). In mammals, membrane-bound UGTs are regarded as the dominant phase II drugmetabolizing enzymes, transferring activated sugars to a large number of xenobiotics as well as endobiotics (14,15).…”

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confidence: 99%

Two Novel Fungal Phenolic UDP Glycosyltransferases from Absidia coerulea and Rhizopus japonicus

Xie

Dou

Chen

et al. 2017

Appl Environ Microbiol

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In the present study, two novel phenolic UDP glycosyltransferases (PUGTs), UGT58A1 and UGT59A1, which can transfer sugar moieties from active donors to phenolic acceptors to generate corresponding glycosides, were identified in the fungal kingdom. UGT58A1 (from Absidia coerulea) and UGT59A1 (from Rhizopus japonicas) share a low degree of homology with known UGTs from animals, plants, bacteria, and viruses. These two P-UGTs are membrane-bound proteins with an N-terminal signal peptide and a transmembrane domain at the C terminus. Recombinant UGT58A1 and UGT59A1 are able to regioselectively and stereoselectively glycosylate a variety of phenolic aglycones to generate the corresponding glycosides. Phylogenetic analysis revealed the novelty of UGT58A1 and UGT59A1 in primary sequences in that they are distantly related to other UGTs and form a totally new evolutionary branch. Moreover, UGT58A1 and UGT59A1 represent the first members of the UGT58 and UGT59 families, respectively. Homology modeling and mutational analysis implied the sugar donor binding sites and key catalytic sites, which provided insights into the catalytic mechanism of UGT58A1. These results not only provide an efficient enzymatic tool for the synthesis of bioactive glycosides but also create a starting point for the identification of P-UGTs from fungi at the molecular level.IMPORTANCE Thus far, there have been many reports on the glycosylation of phenolics by fungal cells. However, no P-UGTs have ever been identified in fungi. Our study identified fungal P-UGTs at the molecular level and confirmed the existence of the UGT58 and UGT59 families. The novel sequence information on UGT58A1 and UGT59A1 shed light on the exciting and new P-UGTs hiding in the fungal kingdom, which would lead to the characterization of novel P-UGTs from fungi. Molecular identification of fungal P-UGTs not only is theoretically significant for a better understanding of the evolution of UGT families but also can be applied as a powerful tool in the glycodiversification of bioactive natural products for drug discovery.

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The glycosidation of xenobiotics and endogenous compounds: Versatility and redundancy in the UDP glycosyltransferase superfamily

Cited by 100 publications

References 155 publications

Morphine Glucuronidation and Glucosidation Represent Complementary Metabolic Pathways That Are Both Catalyzed by UDP-Glucuronosyltransferase 2B7: Kinetic, Inhibition, and Molecular Modeling Studies

Morphine Glucuronidation and Glucosidation Represent Complementary Metabolic Pathways That Are Both Catalyzed by UDP-Glucuronosyltransferase 2B7: Kinetic, Inhibition, and Molecular Modeling Studies

Characterization of the ZebrafishUgtRepertoire Reveals a New Class of Drug-Metabolizing UDP Glucuronosyltransferases

Two Novel Fungal Phenolic UDP Glycosyltransferases from Absidia coerulea and Rhizopus japonicus

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