Homology Modeling of Human Uridine-5′-diphosphate-glucuronosyltransferase 1A6 Reveals Insights into Factors Influencing Substrate and Cosubstrate Binding

The elimination of
numerous endogenous compounds and xenobiotics
via glucuronidation by uridine-5′-diphosphate glycosyltransferase
enzymes (UGTs) is an essential process of the body’s chemical
defense system. UGTs have distinct but overlapping substrate preferences,
but the molecular basis for their substrate specificity remains poorly
understood. Three-dimensional protein structures can greatly enhance
our understanding of the interactions between enzymes and their substrates,
but because of the inherent difficulties in purifying and crystallizing
integral endoplasmic reticulum membrane proteins, no complete mammalian
UGT structure has yet been produced. To address this problem, we have
created a homology model of UGT1A6 using I-TASSER to explore, in detail,
the interactions of human UGT1A6 with its substrates. Ligands were
docked into our model in the presence of the cosubstrate uridine-5′-diphosphate-glucuronic
acid, interacting residues were examined, and poses were compared
to those cocrystallized with various plant and bacterial glycosyltransferases
(GTs). Our model structurally resembles other GTs, and docking experiments
replicated many of the expected UGT-substrate interactions. Some bias
toward the template structures’ protein–substrate interactions
and binding preferences was evident.