Insights on membrane topology and structure/function of UDP-glucuronosyltransferases.
The main characteristic of uridine diphosphate (UDP)-glucuronosyltransferases is their potency to glucuronidate a large array of structurally unrelated substances with various nucleophilic groups. The activity of these enzymes strongly depends on their tight association to the membrane of the endoplasmic reticulum. In light of recent data, this review is focused on the membrane-assembly process, which is a prerequisite for activity, and on the amino acids that govern substrate recognition and catalysis at the active site. The major implication of the highly variable N-terminal domain of UDP-glucuronosyltransferases in the substrate specificity of these enzymes is highlighted. In the absence of crystal data of the N-terminal domain, multidisciplinary approaches of genetic-/protein-engineering techniques, homology modeling with glycosyltransferases, and quantitative structure-activity relationships allowed us to point out crucial amino acids. On the basis of these results, possible reaction mechanisms for the glucuronidation of xenobiotics, involving histidine and aspartic acid residues, have been built and are discussed.
Magdalou
Jacques
J
UMR 7561 CNRS-Université Henri Poincaré-Nancy-1, Faculté de Médecine, Vandoeuvre-lès-Nancy, France. Jacques.Magdalou@medecine.uhp-nancy.fr
Fournel-Gigleux
Sylvie
S
Ouzzine
Mohamed
M
D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D020134:Catalytic Domain; D004721:Endoplasmic Reticulum / Q000737:chemistry* / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000737:chemistry*; D006639:Histidine / Q000737:chemistry; D008566:Membranes / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014530:Uridine Diphosphate / Q000737:chemistry*; D015262:Xenobiotics / Q000378:metabolism
D015262:Xenobiotics; D001224:Aspartic Acid; D006639:Histidine; D014530:Uridine Diphosphate; D014453:Glucuronosyltransferase