TAILIEUCHUNG - Báo cáo khoa học: Substrate specificity of the human UDP-glucuronosyltransferase UGT2B4 and UGT2B7 Identification of a critical aromatic amino acid residue at position 33

The human UDP-glucuronosyltransferase (UGT) isoforms UGT2B4 and UGT2B7 play a major role in the detoxification of bile acids, steroids and phenols. These two isoforms present distinct but overlapping substrate spe-cificity, sharing common substrates such as the bile acid hyodeoxycholic acid (HDCA) and catechol-estrogens. | ễFEBS Journal Substrate specificity of the human UDP-glucuronosyltransferase UGT2B4 and UGT2B7 Identification of a critical aromatic amino acid residue at position 33 Lydia Barre1 Sylvie Fournel-Gigleux1 Moshe Finel2 Patrick Netter1 Jacques Magdalou1 and Mohamed Ouzzine1 1 UMR 7561 CNRS Université Henri Poincare - Nancy I Faculte de Medecine Vandoeuvre-les-Nancy France 2 Drug Discovery and Development Technology Center DDTC Faculty of Pharmacy University of Helsinki Finland Keywords site-directed mutagenesis substrate specificity UDP-glucuronosyltransferase UGT2B4 UGT2B7 Correspondence M. Ouzzine UMR 7561 CNRS-UHP-Nancy I Faculte de Medecine BP 184 F-54505 Vandoeuvre-les-Nancy cedex France Fax 33 3 83683959 Tel 33 3 83683972 E-mail ouzzine@ Received 10 November 2006 revised 21 December 2006 accepted 22 December 2006 doi The human UDP-glucuronosyltransferase UGT isoforms UGT2B4 and UGT2B7 play a major role in the detoxification of bile acids steroids and phenols. These two isoforms present distinct but overlapping substrate specificity sharing common substrates such as the bile acid hyodeoxycholic acid HDCA and catechol-estrogens. Here we show that in UGT2B4 substitution of phenylalanine 33 by leucine suppressed the activity towards HDCA and impaired the glucuronidation of several substrates including 4-hydroxyestrone and 17-epiestriol. On the other hand the substrate specificity of the mutant UGT2B4F33Y in which phenylalanine was replaced by tyrosine as found at position 33 of UGT2B7 was similar to wild-type UGT2B4. In the case of UGT2B7 replacement of tyrosine 33 by leucine strongly reduced the activity towards all the tested substrates with the exception of 17-epiestriol. In contrast mutation of tyrosine 33 by phenylalanine exhibited similar or even somewhat higher activities than wildtype UGT2B7. Hence the results strongly indicated that the presence of an aromatic residue at position 33 is important for the

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