Premium
Comparative characterization of UDP‐glucuronic acid (UDP‐GlcUA) binding‐site directed inhibitors with human UGT2B7 and 1A10.
Author(s) -
Bratton Stacie Moseley,
Laakkonen Liisa,
Patana AnneSisko,
Mazur Anna,
Miller Grover P.,
Finel Moshe,
RadominskaPandya Anna
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.750.4
Subject(s) - chemistry , glucuronic acid , homology modeling , gene isoform , biochemistry , binding site , glucosyltransferases , uridine , enzyme , stereochemistry , polysaccharide , rna , gene
Recent crystallography, homology modeling, and mutagenesis studies of human UGTs have demonstrated that UGT2B7 and 1A10 possess a number of distinctive UDP‐glucuronic acid contact amino acids. We have investigated the specificity of these co‐factor binding sites further using 8 bi‐dentate inhibitors containing a lipophilic and a uridine moiety. K i and IC 50 values were calculated for PP55B and inhibition types were determined. Models of the UGT1A10 UDP‐GlcUA binding site were built using the crystal structure of the UGT2B7 C‐terminal domain as a template and using sequence homology to available structures of plant glucosyltransferases with the GT‐B folding motif. We have detected potential differences in the tertiary structure/function of the C‐terminal domain of these two isoforms and subsequently docked PP55B at the UDP‐GlcUA binding site in order to model inhibitor complexes for each enzyme, including its possible location with respect to the N‐terminal domain. Establishing the roles of individual UGT isoforms is important for UGT‐based drug discovery. The goal of theses studies is aimed at the identification of potent, selective UGT inhibitors, which could help to define these roles and provide the basis for the design of therapeutic agents. NIH‐DK60109, GM075893 (AR‐P)