Glycosyltransferase structural biology and its role in the design of catalysts for glycosylation

Abstract

Glycosyltransferases (GTs) are ubiquitous in nature and are required for the transfer of sugars to a variety of important biomolecules. This essential enzyme family has been a focus of attention from both the perspective of a potential drug target as well as a catalyst for the development of vaccines, biopharmaceuticals and small molecule therapeutics. This review attempts to consolidate the emerging lessons from Leloir (nucleotide-dependent) GT structural biology studies and recent applications of these fundamentals toward rational engineering of glycosylation catalysts.

Glycosyltransferases and non-alcoholic fatty liver disease

“…They catalyze the transfer of one or multiple sugar residues to a wide range of acceptor molecules such as lipids, proteins, hormones, secondary metabolites, and oligosaccharides [47,48] , and mediate a wide range of functions from structure and storage to signaling [49] . Thus, they play a key role in many fundamental biological processes including cell signaling, cellular adhesion, carcinogenesis, and cell wall biosynthesis in human pathogens [50][51][52] . GTs are present in both prokaryotes and eukaryotes.…”

Structural Studies of Biopolymer Membrane Transport

“…As in GT-A folds, the acceptor-binding site often contains an acidic residue or a histidine at the tip of an alpha helix (Nα1 in Fig. 3b and d) to act as the catalytic base; however, the acceptor-binding site in GT-B folds is located on the Nterminal instead of the C-terminal domain (Chang et al, 2011). In GTs that use sugars as the acceptor, an aromatic residue is often found at the acceptor binding site where it stacks on top of the ring and provides stability through CH-pi stacking interactions (Chang et al, 2011).…”

“…In the case of GTs, the phosphate of the donor interacts with the proton of the acceptor hydroxyl, resulting in the decomposition into a carbocation at C att and a complex between the acceptor hydroxyl and phosphate leaving group. The acceptor then attacks the carbocation donor at the same face from which the phosphate left, giving the original stereochemistry at C att (Chang et al, 2011;Schuman et al, 2013). …”

“…While no sequence motifs are clear for this domain, there tends to be an alpha helix near the acceptor binding site (α6 in Fig. 3a and c) that contains an N-terminally capping Asp or Helices are colored green and β-strands purple (Chang et. al., 2011) Glu residue which forms the catalytic base for the glycosyl transfer reaction (Chang et al, 2011).…”

“…3a and c) that contains an N-terminally capping Asp or Helices are colored green and β-strands purple (Chang et. al., 2011) Glu residue which forms the catalytic base for the glycosyl transfer reaction (Chang et al, 2011). A prominent example of an enzyme with the GT-A fold is the mammalian xylotransferase, XXYLT1, which negatively regulates activation of the Notch receptor (Yu et al, 2015).…”