Protein Information

ID 517
Name UDP glucuronosyltransferase
Synonyms GNT1; UGT 1; UGT1; GNT1; UDPGT; UDP glucuronosyltransferase; UDP glycosyltransferase 1 family polypeptide A10; UDP glucuronosyltransferase 1 10…

Compound Information

ID 1693
Name 1-naphthol
CAS 1-naphthalenol

Reference

PubMed Abstract RScore(About this table)
20089735 Itaaho K, Laakkonen L, Finel M: How many and which amino acids are responsible for the large activity differences between the highly homologous UDP-glucuronosyltransferases (UGT) 1A9 and UGT1A10?. Drug Metab Dispos. 2010 Apr;38(4):687-96. Epub 2010 Jan 20.
The amino acid sequences of the human UDP-glucuronosyltransferases (UGTs) 1A9 and 1A10 are 93% identical, yet there are large differences in their activity and substrate selectivity. For example, the regioselectivity in propranolol glucuronidation, the regioselectivity in dobutamine glucuronidation, and the glucuronidation rate of alpha- and beta-estradiol differ greatly between UGT1A9 and UGT1A10. To identify the residue responsible for the activity differences, we divided the N-terminal half of the two UGTs into five comparable segments by inserting four unique restriction sites at identical positions in both genes and constructing chimeras in which segments of UGT1A9 were individually replaced by the corresponding segments from UGT1A10. Activity analyses of the resulting mutants, 910A [1A10 ((1-83))/1A9 ((84-285))], 910B [1A9 ((1-83))/1A10 ((84-147))/1A9 ((148-285))], 910C [1A9 ((1-147))/1A10 ((148-181))/1A9 ((182-285))], 910D [1A9 ((1-181))/1A10 ((182-235))/1A9 ((236-285))], and 910E [1A9 ((1-235))/1A10 ((236-285))] indicated that more than one residue is responsible for the differences between UGT1A9 and UGT1A10. We next prepared four double chimeras, in which two of the above UGT1A9 segments were replaced simultaneously by the corresponding UGT1A10 segments. However, none of the double chimeras glucuronidated either estradiol, propranolol, or dobutamine at rates that resembled those of UGT1A10. On the other hand, studying the kinetics of 1-naphthol glucuronidation yielded more focused results, indicating that residues within segment B (84-147) contribute directly to the K (m) value for this substrate. Further mutagenesis and activity assays suggested that Phe117 of UGT1A9 participates in 1-naphthol binding. In addition, it appears that residues within segment C of the N-terminal domain, mainly at positions 152 and 169, contribute to the higher glucuronidation rates of UGT1A10.
7(0,0,0,7)