Stereochemical sensitivity of the human UDP-glucuronosyltransferases 2B7 and 2B17.
A set of 28 enantiomers comprising rigid and flexible secondary alcohols was synthesized by the asymmetric Corey-Bakshi-Shibata reduction. The enantiomerically pure alcohols were subjected to enzymatic glucuronidation assays employing the human UDP-glucuronosyltransferases (UGTs) 2B7 and 2B17. Both UGTs displayed high levels of stereoselectivity, favoring the conjugation of the (R)-enantiomers over their respective (S)-stereoisomers at eudismic ratios up to 256. The spatial arrangement of the hydroxy group determined the diastereoselectivity of the UGT2B17-catalyzed reaction in agreement with Pfeiffer's rule (eudismic activity quotient = 0.83 +/- 0.14). Inhibition studies revealed that the enantiomers had similar affinities toward the enzymes. The diastereoselectivity of the UGT-catalyzed conjugation stemmed, therefore, from the arrangement of the substrates in the catalytic site, rather than from distinct affinities toward the enzymes. Taken together, this study showed that metabolic enzymes that are generally conceived to be rather "flexible" in nature are capable of displaying high levels of chiral distinction.
Bichlmaier
Ingo
I
Faculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki, FI-00014 Helsinki, Finland.
Siiskonen
Antti
A
Finel
Moshe
M
Yli-Kauhaluoma
Jari
J
D000438:Alcohols / Q000138:chemical synthesis / Q000737:chemistry; D000873:Anthracenes / Q000737:chemistry; D002384:Catalysis; D002839:Chromans / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000737:chemistry*; D006801:Humans; D007189:Indans / Q000737:chemistry; D015778:Minor Histocompatibility Antigens; D009281:Naphthalenes / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D044024:Tetralones / Q000737:chemistry
D000438:Alcohols; D000873:Anthracenes; D002839:Chromans; D007189:Indans; D015778:Minor Histocompatibility Antigens; D009281:Naphthalenes; D044024:Tetralones; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human