The Human UDP-Glucuronosyltransferases: Structural Aspects and Drug Glucuronidation

Ouzzine, Mohamed; Barré, Lydia; Netter, Patrick; Magdalou, Jacques; Fournel‐Gigleux, Sylvie

doi:10.1081/dmr-120026397

Cited by 61 publications

(42 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mutations to residues predicted to interact with the diphosphate and glucuronic acid moieties of UDP-GlcUA preferentially abolished activity, whereas mutations to residues predicted to interact with the uracil group only moderately reduced activity. In a separate study, the highly conserved His 371 residue within the C-terminal domain of UGT1A6 was predicted to play a role in catalysis (Ouzzine et al, 2003) but was later shown to be involved in binding UDP-GlcUA along with the highly conserved Glu 379 (Patana et al, 2007). In the work reported here, we have used site-directed mutagenesis, modeling, and kinetic analyses to identify which amino acids in UGT1A10 are critical for UDP-GlcUA binding.…”

mentioning

confidence: 99%

The First Aspartic Acid of the DQxD Motif for Human UDP-Glucuronosyltransferase 1A10 Interacts with UDP-Glucuronic Acid during Catalysis

Xiong¹,

Patana²,

Miley³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 99%

The First Aspartic Acid of the DQxD Motif for Human UDP-Glucuronosyltransferase 1A10 Interacts with UDP-Glucuronic Acid during Catalysis

Xiong¹,

Patana²,

Miley³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…The glucuronides formed are more hydrophilic than the parent aglycones, so that they are more readily excreted from the body through the urine or bile. Glucuronidation is catalyzed by the UGTs, a family of membranebound enzymes of the endoplasmic reticulum (Radominska-Pandya et al, 1999;Tukey and Strassburg, 2000;Ouzzine et al, 2003;Wells et al, 2004).…”

mentioning

confidence: 99%

Prominent but Reverse Stereoselectivity in Propranolol Glucuronidation by Human UDP-Glucuronosyltransferases 1A9 and 1A10

Sten¹,

Qvisen²,

Uutela³

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Propranolol is a nonselective ␤-adrenergic blocker used as a racemic mixture in the treatment of hypertension, cardiac arrhythmias, and angina pectoris. For study of the stereoselective glucuronidation of this drug, the two propranolol glucuronide diastereomers were biosynthesized, purified, and characterized. A screen of 15 recombinant human UDP-glucuronosyltransferases (UGTs) indicated that only a few isoforms catalyze propranolol glucuronidation. Analysis of UGT2B4 and UGT2B7 revealed no significant stereoselectivity, but these two enzymes differed in glucuronidation kinetics. The glucuronidation kinetics of R-propranolol by UGT2B4 exhibited a sigmoid curve, whereas the glucuronidation of the same substrate by UGT2B7 was inhibited by substrate concentrations above 1 mM. Among the UGTs of subfamily 1A, UGT1A9 and UGT1A10 displayed high and, surprisingly, opposite stereoselectivity in the glucuronidation of propranolol enantiomers. UGT1A9 glucuronidated S-propranolol much faster than R-propranolol, whereas UGT1A10 exhibited the opposite enantiomer preference. Nonetheless, the K m values for the two enantiomers, both for UGT1A9 and for UGT1A10, were in the same range, suggesting similar affinities for the two enantiomers. Unlike UGT1A9, the expression of UGT1A10 is extrahepatic. Hence, the reverse stereoselectivity of these two UGTs may signify specific differences in the glucuronidation of propranolol enantiomers between intestine and liver microsomes. Subsequent experiments confirmed this hypothesis: human liver microsomes glucuronidated S-propranolol faster than R-propranolol, whereas human intestine microsomes glucuronidated S-propranolol faster. These findings suggest a contribution of intestinal UGTs to drug metabolism, at least for UGT1A10 substrates.

show abstract

“…This conserved proteins domains are essential to preserve the fundamental glucuronic acid transferase function (Ouzzine, Barre, Netter, Magdalou, & Fournel-Gigleux, 2003;Patana, Kurkela, Goldman, & Finel, 2007;Radominska-Pandya, Czernik, Little, Battaglia, & Mackenzie, 1999).…”

Section: The Human Ugt1a Family Membersmentioning

confidence: 99%

UGT genomic diversity: beyond gene duplication

Guillemette

Lévesque

Harvey

et al. 2009

Drug Metabolism Reviews

121

View full text Add to dashboard Cite

The Human UDP-Glucuronosyltransferases: Structural Aspects and Drug Glucuronidation

Cited by 61 publications

References 47 publications

The First Aspartic Acid of the DQxD Motif for Human UDP-Glucuronosyltransferase 1A10 Interacts with UDP-Glucuronic Acid during Catalysis

The First Aspartic Acid of the DQxD Motif for Human UDP-Glucuronosyltransferase 1A10 Interacts with UDP-Glucuronic Acid during Catalysis

Prominent but Reverse Stereoselectivity in Propranolol Glucuronidation by Human UDP-Glucuronosyltransferases 1A9 and 1A10

UGT genomic diversity: beyond gene duplication

Contact Info

Product

Resources

About