Structure and function of nucleotide sugar transporters: Current progress

Abstract

The proteomes of eukaryotes, bacteria and archaea are highly diverse due, in part, to the complex post-translational modification of protein glycosylation. The diversity of glycosylation in eukaryotes is reliant on nucleotide sugar transporters to translocate specific nucleotide sugars that are synthesised in the cytosol and nucleus, into the endoplasmic reticulum and Golgi apparatus where glycosylation reactions occur. Thirty years of research utilising multidisciplinary approaches has contributed to our current understanding of NST function and structure. In this review, the structure and function, with reference to various disease states, of several NSTs including the UDP-galactose, UDP-N-acetylglucosamine, UDP-N-acetylgalactosamine, GDP-fucose, UDP-N-acetylglucosamine/UDP-glucose/GDP-mannose and CMP-sialic acid transporters will be described. Little is known regarding the exact structure of NSTs due to difficulties associated with crystallising membrane proteins. To date, no three-dimensional structure of any NST has been elucidated. What is known is based on computer predictions, mutagenesis experiments, epitope-tagging studies, in-vitro assays and phylogenetic analysis. In this regard the best-characterised NST to date is the CMP-sialic acid transporter (CST). Therefore in this review we will provide the current state-of-play with respect to the structure–function relationship of the (CST). In particular we have summarised work performed by a number groups detailing the affect of various mutations on CST transport activity, efficiency, and substrate specificity.

Neurological Aspects of Human Glycosylation Disorders

“…Most of the transporters appear to be mono-specific while several in C. elegans and one in mammalian cells have a broader specificity (Caffaro et al 2008, Hadley et al 2014). Mutations in a UDP-GlcNAc transporter SLC35A3 were found in one large kindred displaying epilepsy and autism spectrum disorders (Edvardson et al 2013a).…”

UDP-galactose (SLC35A2) and UDP-N-acetylglucosamine (SLC35A3) Transporters Form Glycosylation-related Complexes with Mannoside Acetylglucosaminyltransferases (Mgats)

“…This protein post-translational modification increases solubility and structural stability, protects against proteolysis, and assists in protein folding. It also plays a crucial role in the immune response, cell-cell and cell-extracellular matrix recognition, and selective protein targeting (1). The glycan moiety is synthesized and modified by glycosyltransferases acting in the lumen of the endoplasmic reticulum (ER) 3 and Golgi apparatus.…”

Synthesis of potential inhibitors of glycosyltransferases representing UDP-GlcNAc

“…This group of enzymes is mainly involved in the biosynthesis of O-and N-linked complex oligosaccharides of glycoproteins leading to the formation of a new glycosidic linkage (Beyer et al, 1981;Kleene & Berger, 1993;Montreuil et al, 1995;Breton et al, 2012;Hadley et al, 2014). Glycosylation, catalyzed by GTs and controlled by both the cell and the structure of the protein itself, proceeds in a stepwise manner.…”