In-Silico Analysis of Binding Site Features and Substrate Selectivity in Plant Flavonoid-3-O Glycosyltransferases (F3GT) through Molecular Modeling, Docking and Dynamics Simulation Studies

Abstract

Flavonoids are a class of plant secondary metabolites that act as storage molecules, chemical messengers, as well as participate in homeostasis and defense processes. They possess pharmaceutical properties important for cancer treatment such as antioxidant and anti-tumor activities. The drug-related properties of flavonoids can be improved by glycosylation. The enzymes glycosyltransferases (GTs) glycosylate acceptor molecules in a regiospecific manner with the help of nucleotide sugar donor molecules. Several plant GTs have been characterized and their amino acid sequences determined. However, three-dimensional structures of only a few are reported. Here, phylogenetic analysis using amino acid sequences have identified a group of GTs with the same regiospecific activity. The structures of these closely related GTs were modeled using homologous GT structures. Their substrate binding sites were elaborated by docking flavonoid acceptor and UDP-sugar donor molecules in the modeled structures. Eight regions near the acceptor binding site in the N- and C- terminal domain of GTs have been identified that bind and specifically glycosylate the 3-OH group of acceptor flavonoids. Similarly, a conserved motif in the C-terminal domain is known to bind a sugar donor substrate. In certain GTs, the substitution of a specific glutamine by histidine in this domain changes the preference of sugar from glucose to galactose as a result of changed pattern of interactions. The molecular modeling, docking, and molecular dynamics simulation studies have revealed the chemical and topological features of the binding site and thus provided insights into the basis of acceptor and donor recognition by GTs.

Functional specialization of UDP‐glycosyltransferase 73P12 in licorice to produce a sweet triterpenoid saponin, glycyrrhizin

“…Homology modeling of three‐dimensional protein structures provides further insights into the structural basis of UGT proteins (Osmani et al ., ; Sharma et al ., ; Itkin et al ., ). Therefore, we constructed homology models of the canonical and variant UGT73P12 proteins using the automated SWISS‐MODEL pipeline (Biasini et al ., ) and estimated the spatial arrangements of the eight variant residues within the three‐dimensional structure of the UGT73P12 proteins.…”

Natural Compounds From Djiboutian Medicinal Plants as Inhibitors of Covid-19 by in Silico Investigations

“…This high number of rutin binding is linked to its hydroxyl group richness (10 OH). Glycosylated phenolics have better docking than their corresponding aglucone [25]. Furthermore, knowledge of the pharmacokinetic parameters and the degree of toxicity of the candidate compounds to become a drug is crucial.…”

Genome-Wide Identification and Tissue-Specific Expression Analysis of UDP-Glycosyltransferases Genes Confirm Their Abundance in Cicer arietinum (Chickpea) Genome

“…In the combined dendrogram of 96 Ca UGTs and 38 selected plant UGTs, the identified UGTs clustered into 15 groups (designated A to O) ( Figure 4 , Table S5 ). Previously, we have used a strategy of comparing eight substrate binding regions of UGTs combined with clustering to identify flavonoid-3-O glycosyltransferases (F3GTs) in the database [50] . We have used a similar strategy here to identify UGT specificity.…”