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= Nucleotide Sugar Transporters =

Nucleotide Sugar Transporters (NST) are type III proteins which localise at the Golgi apparatus and/or the Endoplasmic reticulum (ER). These transporters have ten transmembrane helices and have their C- and N- terminals facing toward cytosol. Since nucleotide sugars cannot cross the lipid bilayer by themselves, transporters are required to carry them through the cell membrane. NSTs are also known as drug-metabolite transporter superfamily, and are present in both prokaryotes and eukaryotes. Thus, NST’s main function is to transport nucleotide sugars from the cytosol to the lumen of organelles in exchange for the corresponding nucleotide monophosphate.

Nucleotide sugars are essentially monosaccharides that are accompanied by a nucleoside mono- or di-phosphate and act as donors, which determine the rate of glycosylation and/or sulfation. Glycosylation is an enzymatic reaction that results in glycans being attached to proteins or lipids. It is responsible for the production of sugar chains for glycoconjugates (including glycoproteins, glycolipids, proteoglycans and polysaccharides). It is also one of the most frequent post-translational modifications of macromolecules. Molecules are modified by glycosyltransferases in the lumen of ER and Golgi apparatus. The substrate required by glycosyltransferases are nucleotide sugars activated by the addition of a nucleoside mono- or di-phosphate. Thus, glycosylation is essential for key biological processes and the overall operation of the body. Some of the transporters are very specific about their substrate (i.e. the molecules they carry), such as UDP-Gal of subfamily A.

The NST gene family can be divided into five subfamilies (A, B, C, D & E) based on differences in their amino acid. More recently, a journal article published by Nishihara ''et. al.'' (2015) suggested that there six subfamilies. However, transporters in subfamily G have also been identified and recorded in the database of HUGO Gene Nomenclature Committee. Most subfamilies have had at least one member’s function identified; except for subfamily E, subfamily F and subfamily G.

Mutations in NSTs have been suggested to cause tumour metastasis (secondary malignant cell growth away from the original site of cancer), decreased immunity, delayed organ development in children, and disorders associated with connective tissues and muscles.

Of the possible disorders, Leukocyte Adhesion Deficiency type II (LAD II) and Congenital Disorder Glycosylation type IIc (CDG IIc) are more notable, and are caused by defect in GDP-fucose transporter (subfamily C).

This article is part of the biochemistry WikiProject.

= Subfamily A =

SLC35A1-CST
SLC35A1-CST is in charge of transporting CMP-Sialic acid (CMP-Sia) and is expressed on chromosome 6 (6q15). CMP-Sia is the only nucleotide sugar synthesised in the nucleus (while other sugars are synthesised in the cytosol). This nucleotide sugar was first successfully transported across the membrane in a microsomal vesicle from mouse liver. Hereditary Inclusion Body Myopathy type II is a disorder associated with the mutation in UDP-N-acetylglucosamine 2-epimerase, which is an enzyme associated with the synthesis of CMP-Sia. Patients, which are mainly adults, experience onset muscular dystrophy. Besides the mutations in CMP-Sia synthesis, impairment in SLC35A1-CST (meaning a lack of CMP-Sia being transported) may also responsible for sporadic inclusion body myositis, however further research is needed to verify this.

SLC35A2-UGT
The SLC35A2-UGT transporter was discovered by Kuhn and White in 1976 and it is responsible for carrying uridine diphosphate galactose (UDP-Gal) and uridine diphosphate N-acetylglucosamine (UDP-GalNAc). It is expressed on the X chromosome (Xp11.23). SLC35A2-UGT transporter exhibit dual localisation in both the Golgi apparatus and the ER; where it will localise is dependent on the C-terminal amino acid sequence. Its activity was demonstrated several years later through a membrane vesicle isolated from rat liver. This transporter is engaged in the activity of Messenger RNA (mRNA). However, excessive UDP-Gal in mRNA means that the cell is “infected” and can have abnormal cell growth (i.e. become cancerous). These infected cells then adhere to inflammatory cells which then travel through the blood, causing haematogenous metastasis. Haematogenous metastasis happens most frequently with colon cancer (metastasis), therefore specific inhibitors are required to hinder infected cells from binding to inflammatory cells. However, it is unsure whether this result can be transferred to other types of cancers caused by haematogenous metastasis.

SLC35A3
SLC35A3 is also responsible for transporting UDP-GlcNAc and is expressed on chromosome 1 (1p21.2). Maszczak-Seneczko et al. (2013) found that a lack of UDP-GlcNAc transporter lead to decrease in production of keratan sulfate, which consists of repeating units of galactose and N-acetylglucosamine (GlcNAc). The lack of UDP-GlcNAc also lead to reduce in tri- and tetra-antennary N-glycan but an increase in di-antennary N-glycans. Recently, Thomsen et al. (2005) discovered that a missense mutation (error in a single nucleotide which alters the codon, hence codes for a different amino acid) in the SLC35A3 gene possibly causes complex vertebral malformation in animals; however, more research is needed to confirm this.

SLC35A4
SLC35A4 is expressed on chromosome 5 (5q31.3) and localise in the Golgi apparatus.

SLC35A5
SLC35A5 is expressed on chromosome 3 (3q13.2).

= Subfamily B =

SLC35B1-UGTrel1
SLC35B1-UGTrel1 is responsible for transporting uridine 5'diphosphoglucuronic acid trisodium (UDP-GlcA) and is located in the ER. It may be involved in protein folding. It is expressed on chromosome 17 (17q21.33). Dejima et al. (2009) conducted an experiment where they isolated the gene hut-1 in worms (equivalent to SLC35B1-UGTrel1 in humans) and found that a lack of hut-1 affected larval growth, the structure of ER and some protein did not to respond to folding signals (unable to fold properly). They further confirmed that this result can be translated to humans. They also found out that other nucleotide sugar transporters cannot compensate for hut-1 deficiency.

SLC35B2-PAPST1
SLC35B2-PAPST1 is responsible for transporting 3’-phosphoadenosine 5’-phosphosulfate (PAPS) and is located in the Golgi Apparatus. PAPS is a common sulfate donor and determines the rate of sulfation. It is expressed on chromosome 6 (6p21.1). Sulfation is an essential biological process and the sulfation of glycans requires PAPS binding to PAPS sulfurylase. Chlorate is an inhibitor of PAPS sulfurylase (meaning PAPS is unable to bind) and when this occurs, it reduces the signalling of fibroblast and Wnt signalling channels, which are important growth factors.

SLC35B3-PAPST2
SLC35B3-PAPST2 has similar functions to SLC35B2-PAPST1; it is also responsible for transporting PAPS and is located in the Golgi Apparatus. However, its gene expression is on a slightly different part of chromosome 6; it is expressed on locus 6p24.3.

SLC35B4-huYEA4
SLC35B4-huYEA4 is responsible for transporting UDP-GlcNAc, UDP-GlcA & UDP-Xyl (produced by decarboxylation of UDP-GlcA in the ER and Golgi apparatus) and is located in the Golgi Apparatus. It is expressed on chromosome 7 (7q33). Vesicles isolated from yeast cells showed uptake of its transporter substrates. The role of this transporter is to deliver UDP-Xyl to the Golgi apparatus.

To date, transporters in subfamily B have not been identified to cause any diseases/disorders.

= Subfamily C =

SLC35C1-FUCT1
The SLC35C1-FUC1 transporter is expressed on chromosome 11 (11p11.2) and mutations in this gene expression cause congenital disorders such as LAD II and CDG IIc, which leads to a lack of GDP-Fuc being transported, which is required in fucosylated glycoconjugates. This is due to mutated amino acid changing its configuration and greatly reducing the transport activity. Patients diagnosed with LAD II or CDG-IIc usually have flat facial features, display delayed physical and mental growth, poor coordination and vulnerable to infections (immunodeficiency).

SLC35C2-OVCOV1
SLC35C2-OVCOV1 transporter is expressed on chromosome 20 (20q13.12) and is involved in early stages of pregnancy. The OVCOV1 is key to successful embryonic implantation on to the uterus lining. It is responsible for early development of trophoblast cells in the embryo, and the proliferation and differentiation of trophoblast is upregulated by a positive gradient of oxygen tension. When the embryo is exposed to hypoxic condition (low in oxygen), its chance of implanting itself on to the uterus lining is significantly reduced.

= Subfamily D =

SLC35D1-UGT related gene 7 (UGTrel7)
SLC35D1-UGTrel7 transporter is expressed on chromosome 1 (1p31.3) and in charge of transporting glucuronic acid (UDP-GlcUA) and UDP-GalNAc which are utilised in the lengthening of the chondroitin sulfate chain (i.e. synthesising repeats). Chondroitin sulfate chains are vital for cartilage and skeletal development. Deficiency in UGTrel7 transporter can turn into lethal forms of skeletal dysplasia with under-developed limbs. In humans, one form of this disorder is known as Schneckenbecken dysplasia. Experiments were conducted on mice where a mutant UGTrel7 mRNA strand was used to synthesis a complementary DNA strand. That group of mice experienced severe retardation during the prenatal period and did not survive for long into the neonatal period. These results can be transferred to human applications since the UGTrel7 amino acid present in mice and humans are 97% identical.

SLC35D2-HFRC1
SLC35D2-HFRC1 is expressed on chromosome 9 (9p22.32) and is responsible for transporting uridine diphosphate glucose (UDP-Glc) & UDP-GlcNAc and is located in the Golgi Apparatus. The frc transporter in fruit flies is similar to the SLC35D2 transporter in humans, and it is involved in glycosaminoglycan biosynthesis, ontogenesis (development before being full mature) and organogenesis. Thus, scientists predict that the SLC35D2-HFRC1 transporter in humans may have a similar role; however, more research is needed to verify this.

SLC35D3
SLC35D3 is expressed on chromosome 6 (6q23.3) and is located in the ER and early endosomes. It interacts with membrane dopamine receptor D1 (D1R). D1R is involved in metabolic control by regulating dopamine signalling. There has been research proposing that mutation on the gene, coupled with reduced membrane dopamine receptors (cause reduced/impaired dopamine signalling), can be linked to obesity and metabolic syndromes (MetS). Experiments have been carried out on ros striatal D1 neurons and the lack of SLC35D3 transporter caused the accumulation of D1R on the surface of the ER and its exits are blocked.

= Subfamily E, subfamily F and subfamily G = SLC35E1 is expressed on chromosome 19 (19p13.11). SLC35E2A and SLC35E2B are expressed on chromosome 1 (1p36.33). SLC35E3 is expressed on chromosome 12 (12q15). SLC35E4 is expressed on chromosome 22 (22q12.2).

SLC35F1 is expressed on chromosome 6 (6q22.2 to 6q22.31). SLC35F2 is expressed on chromosome 11 (11q22.3). SLC35F3 is expressed on chromosome 1 (1q42.2). SLC35F4 is expressed on chromosome 14 (14q22.3 to 14q23.1). SLC35F5 is expressed on chromosome 2 (2q14.1). SLC35F6 is expressed on chromosome 2 (2p23.3).

SLC35G1 is expressed on chromosome 10 (10q23.33). SLC35G2 is expressed on chromosome 3 (3q22.3). SLC35G3 is expressed on chromosome 17 (17q12). SLC35G4 is expressed on chromosome 18 (18p11.21). SLC35G5 is expressed on chromosome 8 (8p23.1). SLC35G6 is expressed on chromosome 17 (17p13.1).

Not much information is known about NSTs in subfamily E to G.

= Cloning = The first NST to be cloned was murine CMP-Sia and NSTs can be cloned from various types of organisms. For example, the UDP-GlcNAc transporter was successfully cloned from yeast, while the GDP-Man transporter was cloned from Leishmania (protozoan).

= References = Manual of style used: Wikipedia

= External links =


 * https://www.genenames.org/

Category:Metabolism Category:Coenzymes Category:Nucleotides