Nucleotide-sugar transporters: structure, function and roles in vivo

Abstract

The glycosylation of glycoconjugates and the biosynthesis of polysaccharides depend on nucleotide-sugars which are the substrates for glycosyltransferases. A large proportion of these enzymes are located within the lumen of the Golgi apparatus as well as the endoplasmic reticulum, while many of the nucleotide-sugars are synthesized in the cytosol. Thus, nucleotide-sugars are translocated from the cytosol to the lumen of the Golgi apparatus and endoplasmic reticulum by multiple spanning domain proteins known as nucleotide-sugar transporters (NSTs). These proteins were first identified biochemically and some of them were cloned by complementation of mutants. Genome and expressed sequence tag sequencing allowed the identification of a number of sequences that may encode for NSTs in different organisms. The functional characterization of some of these genes has shown that some of them can be highly specific in their substrate specificity while others can utilize up to three different nucleotidesugars containing the same nucleotide. Mutations in genes encoding for NSTs can lead to changes in development in Drosophila melanogaster or Caenorhabditis elegans, as well as alterations in the infectivity of Leishmania donovani. In humans, the mutation of a GDP-fucose transporter is responsible for an impaired immune response as well as retarded growth. These results suggest that, even though there appear to be a fair number of genes encoding for NSTs, they are not functionally redundant and seem to play specific roles in glycosylation. Correspondence

Two Functionally Divergent UDP-Gal Nucleotide Sugar Transporters Participate in Phosphoglycan Synthesis in Leishmania major

“…2 and Table S3; data not shown). Although encouraging, this cluster contained transporters with specificities for a variety of UDP-sugars as well as CMP-sialic acid transporters (23), reinforcing prior observations that phylogeny is of only limited usefulness in predicting nucleotide sugar specificity in the NST family (20,21,49). Nonetheless, we used evolutionary relationship as a guide to focus on the two candidates showing the best homology to hUGT1, which we named LPG5A and LPG5B ( Properties of the LPG5A and LPG5B Open Reading FramesTypical eukaryotic NSTs are about 320 -400 amino acids in length; however, the predicted LPG5A and LPG5B proteins comprised 600 and 561 amino acids, respectively (Table 1).…”

“…Nucleotide sugar transporters (NSTs) transport cytoplasmically synthesized nucleotide sugars into the endoplasmic reticulum (ER) or Golgi lumen, where they are consumed in glycosylation reactions (19 -22). A large number of NSTs have been identified, and they now constitute a well characterized family of membrane proteins (20,23). Previously, we showed that the Leishmania LPG2 gene encoded the Golgi GDP-Man transporter, one of the earliest NSTs identified, and the first multispecific NST, since it was additionally able to transport GDP-D-Ara and GDP-L-Fuc (17).…”

Slc35c2 Promotes Notch1 Fucosylation and Is Required for Optimal Notch Signaling in Mammalian Cells

“…Alternatively, Slc35c2 might be induced to transport GDP-fucose by some other molecule. Although there is no example of a transporter chaperone to date, mammalian nucleotide sugar transporters may interact in the Golgi membrane and several of them, including Slc35b4 (34), transport more than one nucleotide sugar (55,56). Although there is also no example of a transporter that transports both UDP-and GDP-sugars, chimeric transporters have been constructed that transport UDP-Gal and CMP-sialic acid (57)(58)(59).…”

Roles of the Aspergillus nidulans UDP-galactofuranose transporter, UgtA in hyphal morphogenesis, cell wall architecture, conidiation, and drug sensitivity

“…For example, approximately 80% of secreted proteins are glycosylated (Caffaro and Hirschberg, 2006). Glycosylation requires a sugar donor that typically is a nucleotide diphosphate sugar (NDP-sugar) or nucleotide monophosphate sugar (Bakker et al, 2005;Handford et al, 2006). Many nucleotide sugars are synthesized in the cytosol, then translocated to the Golgi or endoplasmic reticulum lumen (Hirschberg, 1998) by nucleotide-sugar transporters (NSTs).…”

“…NSTs are integral proteins typically with six to ten transmembrane domains, that frequently are located at the Golgi apparatus (Handford et al, 2006). UDP-Galf is a nucleotide diphosphate sugar that is synthesized in the cytosol (El-Ganiny et al, 2010), so it must be translocated into an endomembrane organelle prior to incorporation into glycoconjugates.…”