The UDP-Glucuronosyltransferases as Oligomeric Enzymes

Abstract

The UDP-glucuronosyltransferases (UGTs) are integral membrane proteins of the endoplasmic reticulum that play important roles in the defense against potentially hazardous xenobiotics. The UGTs also participate in the metabolism and homeostasis of many endogenous compounds, including bilirubin and steroid hormones. Most human UGTs can glucuronidate several substrates the chemical structures of which may vary significantly. Understanding the structural basis for the complex substrate specificity of the UGTs is a major challenge that is hampered by the lack of sufficient structural information on these enzymes. Nevertheless, there is currently a broad interest in the structure and function of the UGTs and here we have focused on their oligomeric state. The question whether or not the UGTs are oligomeric enzymes, either dimeric or tetrameric, was frequently addressed in the past, as well as in recent studies. The current knowledge of protein-protein interactions among the UGTs is limited, however, primarily due to considerable difficulties in purifying individual recombinant UGTs as fully active and mono-dispersed proteins. Such hurdles in studying the oligomeric state of the UGTs prompted researchers to develop less direct approaches for examining the quaternary structure of the UGTs and its functional significance. In this article we have reviewed, sometimes critically, most of the available studies about the oligomeric state of the UGTs. Concluding that the UGTs are oligomeric enzymes, we discuss hetero-oligomerization among UGTs and its possible implications for the structure, function and substrate specificity of the enzymes.

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

“…However, underlying factors (LATFs, liver-enriched transcription factors as well as genetic diversity [64]) are difficult to distinguish. In addition, recent evidence supports the concept that UGT proteins interact as dimers/oligomers which may have implications for structure, function and substrate specificity of UGTs [65]. Moreover, UGT activity may be controlled by regulated phosphorylation [66].…”

Topological aspects of oligomeric UDP-glucuronosyltransferases in endoplasmic reticulum membranes: Advances and open questions

“…Loose interaction may explain why tetramers have not been detected in cross-linking studies [20]. Nevertheless, as discussed previously [23], high molecular weight bands possibly corresponding to tetramers can be seen by close inspection of the cross-linking studies of Gosh et al…”

“…Functional implications of dimer formation were studied in several ways: for example, co-expression of an inactive mutant of UGT1A6 (the only enzyme catalyzing serotonin glucuronidation [26]) and of UGT1A4 restored UGT1A6-mediated serotonin glucuronidation, suggesting tight interaction between the two recombinant enzymes. Interestingly, these dimers did not share substrate binding sites [23,24]. Heterodimerization has been shown to up-or down-regulate UGT activity [25].…”

“…Nearest neighbor crosslinking studies followed by gel filtration provided evidence that UGTs form dimers in microsomes [19,20]. Using a variety of techniques evidence was obtained that oligomers may function as homo- [20,21] or hetero-oligomers [21][22][23][24][25].…”

“…UGTs as oligomeric enzymes were critically discussed [23]. Functional implications of dimer formation were studied in several ways: for example, co-expression of an inactive mutant of UGT1A6 (the only enzyme catalyzing serotonin glucuronidation [26]) and of UGT1A4 restored UGT1A6-mediated serotonin glucuronidation, suggesting tight interaction between the two recombinant enzymes.…”