Chiral distinction between the enantiomers of bicyclic alcohols by UDP-glucuronosyltransferases 2B7 and 2B17.
The stereoselective binding and transformation of optically pure bicyclic alcohols by human UDP-glucuronosyltransferases from subfamily 2B were investigated. The enantiomers of 1-indanol, 1-tetralol, and 1-benzosuberol were synthesized by asymmetric Corey-Bakshi-Shibata reduction and subjected to glucuronidation assays. The alcohols studied were primarily glucuronidated by UGT2B7 and UGT2B17. The catalytic transformation by UGT2B17 was highly stereoselective, favoring conjugation of the (R)-enantiomers. UGT2B7, on the other hand, did not exhibit stereoselectivity toward 1-benzosuberol, the best substrate in this series. To assess binding affinities to the enzymes, the six different compounds were tested for their efficiency as inhibitors of either UGT2B7 or UGT2B17. The results of the latter analyses indicated that the affinities of both enantiomers of each pair towards UGT2B7 and UGT2B17 were of the same order of magnitude. Therefore, the findings of this study suggest that the spatial arrangement of the hydroxy group plays an important role in the glucuronic acid transfer reaction, but not necessarily in substrate binding to the UGTs.
Bichlmaier
Ingo
I
Faculty of Pharmacy, Division of Pharmaceutical Chemistry, P.O. Box 56, FI-00014 University of Helsinki, Finland.
Siiskonen
Antti
A
Kurkela
Mika
M
Finel
Moshe
M
Yli-Kauhaluoma
Jari
J
D000438:Alcohols / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D020723:Glucuronic Acid / Q000737:chemistry / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D015778:Minor Histocompatibility Antigens; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000438:Alcohols; D015778:Minor Histocompatibility Antigens; D020723:Glucuronic Acid; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human