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SLC35A2  -  solute carrier family 35 (UDP-galactose...

Homo sapiens

Synonyms: CDG2M, CDGX, Solute carrier family 35 member A2, UDP-Gal-Tr, UDP-galactose translocator, ...
 
 
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Disease relevance of SLC35A2

 

High impact information on SLC35A2

  • This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism [6].
  • Identification of a genetic alteration in the code for bilirubin UDP-glucuronosyltransferase in the UGT1 gene complex of a Crigler-Najjar type I patient [7].
  • The UGT1 locus features a complex of six overlapping transcriptional units encoding transferases, each of which shares the four most 3' exons (2, 3, 4, and 5) specifying the 3' half of the transferase coding regions (condons 289-533) and the entire 3' untranslated region of each mRNA [7].
  • Interestingly, UGT activity toward tertiary amines and some steroid hormones was equal [8].
  • Nucleotide sequences of the genes for bilirubin UGT were analysed in six patients with Gilbert's syndrome [9].
 

Chemical compound and disease context of SLC35A2

 

Biological context of SLC35A2

  • These findings indicated that the regions which are critical for determining the substrate specificity of UGT and CST resided in different submolecular sites in the two transporters, and that these different determinants could be present within one protein without interfering with each other's function [15].
  • Amino acid sequence comparison revealed strong similarity (44.6% identity and 19.3% similarity) of CMP-Sia-Tr to the recently cloned human UDP-galactose transporter (UDP-Gal-Tr) [16].
  • Now we have characterized its isoform, hUGT2, that is most likely generated through the alternative splicing of a transcript derived from the UGT genomic gene, that also codes for hUGT1 [17].
  • Introduction of the open reading frame sequence of hUGT2 into a mouse cell line, Had-1, that lacks the UDP-galactose transporter, complemented the genetic defect of the mutant, as judged from the lectin-sensitivity spectra of the transformants and the nucleotide-sugar transporting activity of microsomal vesicles isolated from them [17].
  • Several novel UDP glycosyltransferase (UGT) genes, mainly UDP glucuronosyltransferases, have been identified in the human, mouse and rat genomes and in other mammalian species [18].
 

Anatomical context of SLC35A2

 

Associations of SLC35A2 with chemical compounds

  • For UGT activity, helices 1 and 8 of hUGT1 were necessary (but not sufficient), and helices 9 and 10 or helices 2, 3, and 7 derived from hUGT1 were also required to render the chimera competent for UDP-Gal transport [22].
  • The same was observed when UGT was expressed in human intestinal cells that have an endogenous ceramide galactosyltransferase [20].
  • Cotransfection with the human UGT1 greatly stimulated synthesis of lactosylceramide in the Golgi and of galactosylceramide in the endoplasmic reticulum [20].
  • Characterization of the UGT1 gene complex locus encoding both multiple bilirubin and phenol UDP-glucuronosyltransferases (transferases) has been critical in identifying mutations in the bilirubin isoforms [23].
  • Treatment of H4IIE cells with beta-naphthoflavone induced UGT protein expression but did not affect the rate of UDPGA uptake [21].
 

Other interactions of SLC35A2

 

Analytical, diagnostic and therapeutic context of SLC35A2

  • We described recently the molecular cloning of human UDP-galactose transporter 1 (hUGT1) [Miura, N. et al. (1996) J. Biochem. 120, 236-241] [17].
  • Using the hUGT1-specific antibodies, the subcellular localization of hUGT1 in the Golgi membrane was demonstrated by immunofluorescence microscopy and subcellular fractionation [19].
  • These studies led us to develop a simple procedure, based on Percoll density gradient centrifugation, for preparing functional Golgi vesicles from the hUGT1-transformed Had-1 cells, that will facilitate future biochemical analyses of the UDP-galactose transporter for the elucidation of its structure-function relationship [19].
  • Genetic defects at the UGT1 locus associated with Crigler-Najjar type I disease, including a prenatal diagnosis [23].
  • However, microsomal UGT activities in colon were up to 96-fold lower for many phenolic substrates, a finding that was not concordant with RT-PCR and Western blot analysis [8].

References

  1. Increased expression of UDP-galactose transporter messenger RNA in human colon cancer tissues and its implication in synthesis of Thomsen-Friedenreich antigen and sialyl Lewis A/X determinants. Kumamoto, K., Goto, Y., Sekikawa, K., Takenoshita, S., Ishida, N., Kawakita, M., Kannagi, R. Cancer Res. (2001) [Pubmed]
  2. Correction of the UDP-glucuronosyltransferase gene defect in the gunn rat model of crigler-najjar syndrome type I with a chimeric oligonucleotide. Kren, B.T., Parashar, B., Bandyopadhyay, P., Chowdhury, N.R., Chowdhury, J.R., Steer, C.J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  3. Crigler-Najjar syndrome type II is inherited both as a dominant and as a recessive trait. Koiwai, O., Aono, S., Adachi, Y., Kamisako, T., Yasui, Y., Nishizawa, M., Sato, H. Hum. Mol. Genet. (1996) [Pubmed]
  4. Potential genoprotective role for UDP-glucuronosyltransferases in chemical carcinogenesis: initiation of micronuclei by benzo(a)pyrene and benzo(e)pyrene in UDP-glucuronosyltransferase-deficient cultured rat skin fibroblasts. Vienneau, D.S., DeBoni, U., Wells, P.G. Cancer Res. (1995) [Pubmed]
  5. Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and association with breast cancer among African Americans. Guillemette, C., Millikan, R.C., Newman, B., Housman, D.E. Cancer Res. (2000) [Pubmed]
  6. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Tukey, R.H., Strassburg, C.P. Annu. Rev. Pharmacol. Toxicol. (2000) [Pubmed]
  7. Identification of a genetic alteration in the code for bilirubin UDP-glucuronosyltransferase in the UGT1 gene complex of a Crigler-Najjar type I patient. Ritter, J.K., Yeatman, M.T., Ferreira, P., Owens, I.S. J. Clin. Invest. (1992) [Pubmed]
  8. UDP-glucuronosyltransferase activity in human liver and colon. Strassburg, C.P., Nguyen, N., Manns, M.P., Tukey, R.H. Gastroenterology (1999) [Pubmed]
  9. Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome. Aono, S., Adachi, Y., Uyama, E., Yamada, Y., Keino, H., Nanno, T., Koiwai, O., Sato, H. Lancet (1995) [Pubmed]
  10. Gilbert's disease and atazanavir: From phenotype to UDP-glucuronosyltransferase haplotype. Lankisch, T.O., Moebius, U., Wehmeier, M., Behrens, G., Manns, M.P., Schmidt, R.E., Strassburg, C.P. Hepatology (2006) [Pubmed]
  11. Regulation of steroid glucuronosyltransferase activities and transcripts by androgen in the human prostatic cancer LNCaP cell line. Guillemette, C., Hum, D.W., Bélanger, A. Endocrinology (1996) [Pubmed]
  12. Estrogen regulation of the glucuronidation enzyme UGT2B15 in estrogen receptor-positive breast cancer cells. Harrington, W.R., Sengupta, S., Katzenellenbogen, B.S. Endocrinology (2006) [Pubmed]
  13. Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins. Cummings, J., Zelcer, N., Allen, J.D., Yao, D., Boyd, G., Maliepaard, M., Friedberg, T.H., Smyth, J.F., Jodrell, D.I. Biochem. Pharmacol. (2004) [Pubmed]
  14. Galactose is needed only for expression of co-receptors used by Theiler's murine encephalomyelitis virus as the virus does not directly bind galactose or use the UDP-galactose transporter as a receptor. Reddi, H.V., Kallio, P., Lipton, H.L. J. Gen. Virol. (2003) [Pubmed]
  15. Substrate recognition by UDP-galactose and CMP-sialic acid transporters. Different sets of transmembrane helices are utilized for the specific recognition of UDP-galactose and CMP-sialic acid. Aoki, K., Ishida, N., Kawakita, M. J. Biol. Chem. (2001) [Pubmed]
  16. Molecular cloning of the hamster CMP-sialic acid transporter. Eckhardt, M., Gerardy-Schahn, R. Eur. J. Biochem. (1997) [Pubmed]
  17. Molecular cloning and characterization of a novel isoform of the human UDP-galactose transporter, and of related complementary DNAs belonging to the nucleotide-sugar transporter gene family. Ishida, N., Miura, N., Yoshioka, S., Kawakita, M. J. Biochem. (1996) [Pubmed]
  18. Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Mackenzie, P.I., Walter Bock, K., Burchell, B., Guillemette, C., Ikushiro, S., Iyanagi, T., Miners, J.O., Owens, I.S., Nebert, D.W. Pharmacogenet. Genomics (2005) [Pubmed]
  19. Expression of the human UDP-galactose transporter in the Golgi membranes of murine Had-1 cells that lack the endogenous transporter. Yoshioka, S., Sun-Wada, G.H., Ishida, N., Kawakita, M. J. Biochem. (1997) [Pubmed]
  20. Association of the Golgi UDP-galactose transporter with UDP-galactose:ceramide galactosyltransferase allows UDP-galactose import in the endoplasmic reticulum. Sprong, H., Degroote, S., Nilsson, T., Kawakita, M., Ishida, N., van der Sluijs, P., van Meer, G. Mol. Biol. Cell (2003) [Pubmed]
  21. Molecular and functional characterization of microsomal UDP-glucuronic acid uptake by members of the nucleotide sugar transporter (NST) family. Kobayashi, T., Sleeman, J.E., Coughtrie, M.W., Burchell, B. Biochem. J. (2006) [Pubmed]
  22. Substrate recognition by nucleotide sugar transporters: further characterization of substrate recognition regions by analyses of UDP-galactose/CMP-sialic acid transporter chimeras and biochemical analysis of the substrate specificity of parental and chimeric transporters. Aoki, K., Ishida, N., Kawakita, M. J. Biol. Chem. (2003) [Pubmed]
  23. Genetic defects at the UGT1 locus associated with Crigler-Najjar type I disease, including a prenatal diagnosis. Ciotti, M., Obaray, R., Martín, M.G., Owens, I.S. Am. J. Med. Genet. (1997) [Pubmed]
  24. The human gene CGT encoding the UDP-galactose ceramide galactosyl transferase (cerebroside synthase): cloning, characterization, and assignment to human chromosome 4, band q26. Bosio, A., Binczek, E., Le Beau, M.M., Fernald, A.A., Stoffel, W. Genomics (1996) [Pubmed]
  25. UDP-galactose:ceramide galactosyltransferase is a class I integral membrane protein of the endoplasmic reticulum. Sprong, H., Kruithof, B., Leijendekker, R., Slot, J.W., van Meer, G., van der Sluijs, P. J. Biol. Chem. (1998) [Pubmed]
 
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