The crystal structure of human UDP-glucuronosyltransferase 2B7 C-terminal end is the first mammalian UGT target to be revealed: the significance for human UGTs from both the 1A and 2B families

Abstract

Human UDP-glucuronosyltransferases (EC 2.4.1.17) (UGTs) are major phase II metabolism enzymes that detoxify a multitude of endo- and xenobiotics through the covalent addition of a glucuronic acid moiety. UGTs are promiscuous enzymes that regulate the levels of numerous important endobiotics in a range of tissues, and inactivate most therapeutic compounds in concert with phase I enzymes. In spite of the importance of these enzymes, we have only a limited understanding of the molecular mechanisms governing their substrate specificity and catalytic activity. Until recently, no three-dimensional structural information was available for any mammalian UGT. The 1.8-Å resolution apo crystal structure of the UDP-glucuronic acid binding domain of human UGT2B7 (2B7CT) is the only structure of a mammalian UGT target determined to date. In this review, we summarize what has been learned about human UGT function from the analysis of this and other related glycosyltransferase (GT) crystal structures.

Pyrethroid activity-based probes for profiling cytochrome P450 activities associated with insecticide interactions

“…There is accruing evidence that orchestrated interactions between P450s and UGTs, which lie opposite P450s on the luminal side of the endoplasmic reticulum, may facilitate the channeling and excretion of toxic and reactive intermediate metabolites (28)(29)(30). This is supported here by the interactions of UDP-glucuronosyltransferases 2B2, 2B3, 2B4 and 2B5 (UDP-g 2Bs 2-5) with P7RS ( Fig.…”

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

“…Because i2 and i4 lack the transmembrane domain 493 VIG-FLLVCVATVIFIV 509 (Mackenzie, 1986;Radominska-Pandya et al, 2010), their presence in Golgi and ER membranes and not exclusively in the cytosol observed by immunofluorescence could seem unexpected; (Barbier et al, 2000) (Supplemental Fig. 1 displays Eadie-Hofstee plots).…”

Comparative analysis of the UDP-glycosyltransferase multigene family in insects

“…More specifically, the nucleotide component of the UDP-glucuronic acid is known to be associated with UGT2B7 residues S308 (S324 on the alignment of Fig. 8), W356 (W377), Q359 (Q380), and E382 (E403); the a-phosphate group interacts with T373 (T394) and the b-phosphate group with H374 (H395); and the glucuronic acid O2 0 /O3 0 interacts with D398 (D419) and O3 0 /O4 0 with Q399 (Q420) (Radominska-Pandya et al, 2010). These important residues for the sugar donor binding are also conserved in insect UGTs, suggesting each of these residues in insects might also play an important role in sugar binding.…”