The Uridine Diphosphate Glucuronosyltransferase Multigene Family: Function and Regulation

Clarke, D.W.; Burchell, Brian

doi:10.1007/978-3-642-78429-3_1

Cited by 80 publications

(43 citation statements)

References 209 publications

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“…We found that both of these enzymes catalyze the transglycosylation reaction to benzoic acid, particularly under acidic conditions (Table 1). It is known so far that UDP-glucuronosyltransferase catalyzes the transfer of d-glucuronic acid to carboxylic acid using UDP-glucuronic acid as a donor molecule (Clarke & Burchell 1994). Our results are the first to show that other carbohydrate-active enzymes catalyze the transglycosylation reaction on carboxylic groups without nucleotide activated sugars.…”

Section: Glycosylation Of Benzoic Acid By Sucrose Phosphorylasesupporting

confidence: 52%

Sucrose phosphorylases catalyze transglycosylation reactions on carboxylic acid compounds

et al. 2008

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Two sucrose phosphorylases were employed for glycosylation of carboxylic acid compounds. Streptococcus mutans sucrose phosphorylase showed remarkable transglycosylating activity, especially under acidic conditions. Leuconostoc mesenteroides sucrose phosphorylase exhibited very weak transglycosylating activity. Three main products were detected from the reaction mixture using benzoic acid and sucrose as an acceptor and a donor molecule, respectively. These compounds were identified as 1 S. mutans sucrose phosphorylase showed broad acceptor-specificity. This sucrose phosphorylase catalyzed transglycosylation to various carboxylic compounds such as short-chain fatty acids, hydroxy acids, dicarboxylic acids, and phenolic carboxylic acids. 1-O-Acetyl α-D-glucopyranoside was also enzymatically synthesized by transglucosylation reaction of the enzyme. The sensory test of acetic acid and the glucosides revealed that the sour taste of acetic acid glucosides was significantly lower than that of acetic acid.

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Section: Glycosylation Of Benzoic Acid By Sucrose Phosphorylasesupporting

confidence: 52%

Sucrose phosphorylases catalyze transglycosylation reactions on carboxylic acid compounds

et al. 2008

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“…This indicates the variability of acceptor groups that can be conjugated to glucuronic acid in humans (3 (15). Seventeen steroids were tested and only four that had both 17p-and 3,-hydroxy substituents were glucuronidated (15).…”

Section: The Ugt Family Of Genes and Enzymesmentioning

confidence: 99%

“…(3). Indoles present in cruciferous vegetables (brussel sprouts and cabbage) appear to modestly enhance oxazepam and paracetamol glucuronidation (42).…”

Section: Xenobiotic Induction and Physiological Perturbation In Humansmentioning

confidence: 99%

“…Glucuronide formation is catalyzed by a family of UDPglucuronosyltransferases (UGTs) using thousands of endobiotic and xenobiotic compounds as substrates (3). The xenobiotic substrate range of an individual UGT isoform may be dictated by the evolved structure of an individual UGT to accept endobiotic substrates such as bilirubin or a steroid (4).…”

Section: Introductionmentioning

confidence: 99%

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Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

Burchell

Coughtrie

1997

Environ Health Perspect

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Glucuronidation and sulfation are phase 2 metabolic reactions catalyzed by large families of different isoenzymes in man. The textbook view that glucuronidation and sulfation lead to the production of harmless conjugates for simple excretion is not valid. Biologically active and toxic sulfates and glucuronides are produced and lead to adverse drug reactions, including immune hypersensitivity. Considerable variation in xenobiotic conjugation is observed as a result of altered expression of UDP-glucuronosyltransferases (UGTs) and sulfotransferases (STs). Recent cloning and expression of human cDNA encoding UGTs and STs has facilitated characterization of isoform substrate specificity, which has been further validated using specific antibodies and human tissue fractions. The availability of cloned/expressed human enzymes and specific antibodies has enabled the investigation of xenobiotic induction and metabolic disruption leading to adverse responses. Genetic polymorphisms of glucuronidation and sulfation are known to exist although the characterization and assessment of the importance of these variations are hampered by appropriate ethical studies in man with suitable safe model compounds. Genetic analysis has allowed molecular identification of defects in well-known hyperbilirubinemias. However, full characterization of the specific functional roles of human UGTs and STs requires rigorous kinetic and molecular analyses of the role of each enzyme in vivo through the use of specific antibodies and inhibitors. This will lead to the better prediction of variation of xenobiotic glucuronidation and sulfation in man. Environ Health Perspect 1 05(Suppl 4): 739-747 (1997)

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“…UDP-glucuronosyltransferases (UGTs, 2 EC 2.4.1.17) constitute a superfamily of enzymes that are involved in the phase II biotransformation pathway of many drugs and xenobiotics from natural or synthetic origin (1). UGTs are inverting glycosyltransferases belonging to the wide family 1 of NDP-sugar hexosyltransferases (2).…”

mentioning

confidence: 99%

Identification of Aspartic Acid and Histidine Residues Mediating the Reaction Mechanism and the Substrate Specificity of the Human UDP-glucuronosyltransferases 1A

Fournel‐Gigleux

Barré

et al. 2007

Journal of Biological Chemistry

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The human UDP-glucuronosyltransferase UGT1A6 is the primary phenol-metabolizing UDP-glucuronosyltransferase isoform. It catalyzes the nucleophilic attack of phenolic xenobiotics on UDP-glucuronic acid, leading to the formation of water-soluble glucuronides. The catalytic mechanism proposed for this reaction is an acid-base mechanism that involves an aspartic/glutamic acid and/or histidine residue. Here, we investigated the role of 14 highly conserved aspartic/glutamic acid residues over the entire sequence of human UGT1A6 by sitedirected mutagenesis. We showed that except for aspartic residues Asp-150 and Asp-488, the substitution of carboxylic residues by alanine led to active mutants but with decreased enzyme activity and lower affinity for acceptor and/or donor substrate. Further analysis including mutation of the corresponding residue in other UGT1A isoforms suggests that Asp-150 plays a major catalytic role. In this report we also identified a single active site residue important for glucuronidation of phenols and carboxylic acid substrates by UGT1A enzyme family. Replacing Pro-40 of UGT1A4 by histidine expanded the glucuronidation activity of the enzyme to phenolic and carboxylic compounds, therefore, leading to UGT1A3-type isoform in terms of substrate specificity. Conversely, when His-40 residue of UGT1A3 was replaced with proline, the substrate specificity shifted toward that of UGT1A4 with loss of glucuronidation of phenolic substrates. Furthermore, mutation of His-39 residue of UGT1A1 (His-40 in UGT1A4) to proline led to loss of glucuronidation of phenols but not of estrogens. This study provides a step forward to better understand the glucuronidation mechanism and substrate recognition, which is invaluable for a better prediction of drug metabolism and toxicity in human.

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The Uridine Diphosphate Glucuronosyltransferase Multigene Family: Function and Regulation

Cited by 80 publications

References 209 publications

Sucrose phosphorylases catalyze transglycosylation reactions on carboxylic acid compounds

Sucrose phosphorylases catalyze transglycosylation reactions on carboxylic acid compounds

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

Identification of Aspartic Acid and Histidine Residues Mediating the Reaction Mechanism and the Substrate Specificity of the Human UDP-glucuronosyltransferases 1A

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