Carbohydrate sulfotransferase explained

Symbol:Sulfotransfer_2
Carbohydrate Sulfotransferase family 2
Pfam:PF03567
Interpro:IPR005331
Membranome Family:495
Symbol:Sulfotransfer_1
Carbohydrate Sulfotransferase family 1
Interpro:IPR016469
Membranome Family:493

In biochemistry, carbohydrate sulfotransferases are enzymes within the class of sulfotransferases which catalyze the transfer of the sulfate functional group to carbohydrate groups in glycoproteins and glycolipids. Carbohydrates are used by cells for a wide range of functions from structural purposes to extracellular communication. Carbohydrates are suitable for such a wide variety of functions due to the diversity in structure generated from monosaccharide composition, glycosidic linkage positions, chain branching, and covalent modification.[1] Possible covalent modifications include acetylation, methylation, phosphorylation, and sulfation.[2] Sulfation, performed by carbohydrate sulfotransferases, generates carbohydrate sulfate esters . These sulfate esters are only located extracellularly, whether through excretion into the extracellular matrix (ECM) or by presentation on the cell surface.[3] As extracellular compounds, sulfated carbohydrates are mediators of intercellular communication, cellular adhesion, and ECM maintenance.

Enzyme mechanism

Sulfotransferases catalyze the transfer of a sulfonyl group from an activated sulfate donor onto a hydroxyl group (or an amino group, although this is less common) of an acceptor molecule. In eukaryotic cells the activated sulfate donor is 3'-phosphoadenosine-5'-phosphosulfate (PAPS) (Figure 1).[4]

PAPS is synthesized in the cytosol from ATP and sulfate through the sequential action of ATP sulfurylase and APS kinase.[5] ATP sulfurylase first generates adenosine-5'-phosphosulfate (APS) and then APS kinase transfers a phosphate from ATP to APS to create PAPS. The importance of PAPS and sulfation has been discerned in previous studies by using chlorate, an analogue of sulfate, as a competitive inhibitor of ATP sulfurylase.[6] PAPS is a cosubstrate and source of activated sulfate for both cytosolic sulfotransferases and carbohydrate sulfotransferases, which are located in the Golgi. PAPS moves between the cytosol and the Golgi lumen via PAPS/PAP (3’-phosphoadenosine-5’-phosphate) translocase, a transmembrane antiporter.[7]

The exact mechanism used by sulfotransferases is still being elucidated, but studies have indicated that sulfotransferases use an in-line sulfonyl-transfer mechanism that is analogous to the phosphoryl transfer mechanism used by many kinases, which is logical given the great level of structural and functional similarities between kinases and sulfotransferases (Figure 2).[8] In carbohydrate sulfotransferases a conserved lysine has been identified in the active PAPS binding site, which is analogous to a conserved lysine in the active ATP binding site of kinases.[9] [10] Protein sequence alignment studies indicate that this lysine is conserved in cytosolic sulfotransferases as well.

In addition to the conserved lysine, sulfotransferases have a highly conserved histidine in the active site.[11] Based on the conservation of these residues, theoretical models, and experimental measurements a theoretical transition state for catalyzed sulfation has been proposed (Figure 3).

Biological function

Carbohydrate sulfotransferases are transmembrane enzymes in the Golgi that modify carbohydrates on glycolipids or glycoproteins as they move along the secretory pathway. They have a short cytoplasmic N-terminal, one transmembrane domain, and a large C-terminal Golgi luminal domain. They are distinct from cytosolic sulfotransferases in both structure and function. While cytosolic sulfotransferases play a metabolic role by modifying small molecule substrates such as steroids, flavonoids, neurotransmitters, and phenols, carbohydrate sulfotransferases have a fundamental role in extracellular signalling and adhesion by generating unique ligands through the modification of carbohydrate scaffolds.[12] Since the substrates of carbohydrate sulfotransferases are larger, they have larger active sites than cytosolic sulfotransferases.

There are two major families of carbohydrate sulfotransferases: heparan sulfotransferases and galactose/N-acetylgalactosamine/N-acetylglucosamine 6-O-sulfotransferases (GSTs).[13] [14]

Heparan Sulfotransferases

Heparan sulfate is a glycosaminoglycan (GAG) that is linked by xylose to serine residues of proteins such as perlecan, syndecan, or glypican.[15] Sulfation of heparan sulfate GAGs helps give diversity to cell surface proteins and provides them with a unique sulfation pattern that allows them to specifically interact with other proteins. For example, in mast cells the AT-III-binding pentasaccharide is synthesized with essential heparan sulfate sulfation steps. The binding of the heparan sulfate in this pentasaccharide to AT-III inactivates the blood-coagulation factors thrombin and Factor Xa.[16] Heparan sulfates are also known to interact with growth factors, cytokines, chemokines, lipid and membrane binding proteins, and adhesion molecules.

GSTs

GSTs catalyze sulfation at the 6-hydroxyl group of galactose, N-acetylgalactosamine, or N-acetylglucosamine. Like heparan sulfotransferases, GSTs are responsible for post-translational protein sulfation that assists in cell-signaling. GSTs are also responsible for the sulfation of extracellular matrix (ECM) proteins that assist with maintaining the structure between cells[17] For example, GSTs catalyze the sulfation of glycoproteins displaying the L-selectin binding epitope 6-sulfo sialyl Lewis x, which recruits leukocytes to areas of chronic inflammation. GSTs are also responsible for the proper function of the ECM in the cornea; improper sulfation by GSTs can lead to opaque corneas.

Disease Relevance

Carbohydrate sulfotransferases are of great interest as drug targets because of their essential roles in cell-cell signalling, adhesion, and ECM maintenance. Their roles in blood coagulation, chronic inflammation, and cornea maintenance mentioned in the Biological Function section above are all of interest for potential therapeutic purposes. In addition to these roles, carbohydrate sulfotransferases are of pharmacological interest because of their roles in viral infection, including herpes simplex virus 1 (HSV-1) and human immunodeficiency virus 1 (HIV-1). Heparan sulfate sites have been shown to be essential for HSV-1 binding that leads to the virus entering the cell.[18] In contrast, heparan sulfate complexes have been shown to bind to HIV-1 and prevent it from entering the cell through its intended target, the CD4 receptor.

Mutation in Carbohydrate sulfotransferases 6 (CHST6) is associated with Macular Corneal Dystrophy (MCD) Inheritance: Autosomal recessive. Genetic Locus: 16q22 Online Mendelian Inheritance in man (OMIM) Entry OMIM #217800

Human proteins from this family

Notes and References

  1. Nelson. R M. Venot. A. Bevilacqua. M P. Linhardt. R J. Stamenkovic. I. Carbohydrate-Protein Interactions in Vascular Biology. Annual Review of Cell and Developmental Biology. 11. 1. 1995. 601–631. 1081-0706. 10.1146/annurev.cb.11.110195.003125. 8689570.
  2. Hooper. L.V.. Baenziger. J.U.. Sulfotransferase and Glycosyltransferase Analyses Using a 96-Well Filtration Plate. Analytical Biochemistry. 212. 1. 1993. 128–133. 0003-2697. 10.1006/abio.1993.1301. 8368484.
  3. Bowman. K. Bertozzi. C. Carbohydrate sulfotransferases: mediators of extracellular communication. Chemistry & Biology. 6. 1. 1999. R9–R22. 1074-5521. 10.1016/S1074-5521(99)80014-3. 9889154. free.
  4. Klaassen . CD. . Boles . JW. . Sulfation and sulfotransferases 5: the importance of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) in the regulation of sulfation . FASEB J . 11 . 6 . 404–18 . May 1997 . 10.1096/fasebj.11.6.9194521. free . 9194521 . 2714626 .
  5. Hemmerich. Stefan. Carbohydrate sulfotransferases: novel therapeutic targets for inflammation, viral infection and cancer. Drug Discovery Today. 6. 1. 2001. 27–35. 1359-6446. 10.1016/S1359-6446(00)01581-6. 11165170.
  6. Baeuerle . PA. . Huttner . WB. . Chlorate--a potent inhibitor of protein sulfation in intact cells . Biochem Biophys Res Commun . 141 . 2 . 870–7 . Dec 1986 . 10.1016/s0006-291x(86)80253-4. 3026396 .
  7. Ozeran . JD. . Westley . J. . Schwartz . NB. . Identification and partial purification of PAPS translocase . Biochemistry . 35 . 12 . 3695–703 . Mar 1996 . 10.1021/bi951303m . 8619989 .
  8. Kakuta . Y. . Petrotchenko . EV. . Pedersen . LC. . Negishi . M. . The sulfuryl transfer mechanism. Crystal structure of a vanadate complex of estrogen sulfotransferase and mutational analysis . J Biol Chem . 273 . 42 . 27325–30 . Oct 1998 . 10.1074/jbc.273.42.27325. 9765259 . free .
  9. Kamio . K. . Honke . K. . Makita . A. . Pyridoxal 5'-phosphate binds to a lysine residue in the adenosine 3'-phosphate 5'-phosphosulfate recognition site of glycolipid sulfotransferase from human renal cancer cells . Glycoconj J . 12 . 6 . 762–6 . Dec 1995 . 10.1007/bf00731236. 8748152 . 23756686 .
  10. Sueyoshi. Tatsuya. Kakuta. Yoshimitsu. Pedersen. Lars C.. Wall. Frances E.. Pedersen. Lee G.. Negishi. Masahiko. A role of Lys614 in the sulfotransferase activity of human heparan sulfate N-deacetylase/N-sulfotransferase. FEBS Letters. 433. 3. 1998. 211–214. 0014-5793. 10.1016/S0014-5793(98)00913-2. 9744796. 9055616. free.
  11. Chapman. Eli. Best. Michael D.. Hanson. Sarah R.. Wong. Chi-Huey. Sulfotransferases: Structure, Mechanism, Biological Activity, Inhibition, and Synthetic Utility. Angewandte Chemie International Edition. 43. 27. 2004. 3526–3548. 1433-7851. 10.1002/anie.200300631. 15293241.
  12. Falany . CN. . Enzymology of human cytosolic sulfotransferases . FASEB J . 11 . 4 . 206–16 . Mar 1997 . 10.1096/fasebj.11.4.9068609. free . 9068609 . 8983883 .
  13. Shworak . NW. . Liu . J. . Petros . LM. . Zhang . L. . Kobayashi . M. . Copeland . NG. . Jenkins . NA. . Rosenberg . RD. . Multiple isoforms of heparan sulfate D-glucosaminyl 3-O-sulfotransferase. Isolation, characterization, and expression of human cdnas and identification of distinct genomic loci . J Biol Chem . 274 . 8 . 5170–84 . Feb 1999 . 10.1074/jbc.274.8.5170. 9988767 . free .
  14. Hemmerich . S. . Rosen . SD. . Carbohydrate sulfotransferases in lymphocyte homing . Glycobiology . 10 . 9 . 849–56 . Sep 2000 . 10.1093/glycob/10.9.849. 10988246 . free .
  15. Rosenberg . RD. . Shworak . NW. . Liu . J. . Schwartz . JJ. . Zhang . L. . Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated? . J Clin Invest . 99 . 9 . 2062–70 . May 1997 . 10.1172/JCI119377 . 9151776 . 508034.
  16. Liu . J. . Shworak . NW. . Fritze . LM. . Edelberg . JM. . Rosenberg . RD. . Purification of heparan sulfate D-glucosaminyl 3-O-sulfotransferase . J Biol Chem . 271 . 43 . 27072–82 . Oct 1996 . 10.1074/jbc.271.43.27072. 8900198 . free .
  17. Grunwell. Jocelyn R.. Rath. Virginia L.. Rasmussen. Jytte. Cabrilo. Zeljka. Bertozzi. Carolyn R.. Characterization and Mutagenesis of Gal/GlcNAc-6-O-sulfotransferases†. Biochemistry. 41. 52. 2002. 15590–15600. 0006-2960. 10.1021/bi0269557. 12501187.
  18. Shukla . D. . Liu . J. . Blaiklock . P. . Shworak . NW. . Bai . X. . Esko . JD. . Cohen . GH. . Eisenberg . RJ. . Rosenberg . RD. . Spear . P. G. . A novel role for 3-O-sulfated heparan sulfate in herpes simplex virus 1 entry . Cell . 99 . 1 . 13–22 . Oct 1999 . 10.1016/S0092-8674(00)80058-6. 10520990 . 14139940 . 8 . free .
  19. Fukuda M, Hiraoka N, Hindsgaul O, Misra A, Belot F . R in both N- and O-glycans . Glycobiology . 11 . 6 . 495–504. 2001 . 11445554 . 10.1093/glycob/11.6.495. free .
  20. Ong E, Fukuda M, Yeh JC, Ding Y, Hindsgaul O . Expression cloning of a human sulfotransferase that directs the synthesis of the HNK-1 glycan on the neural cell adhesion molecule and glycolipids . J. Biol. Chem. . 273 . 9 . 5190–5. 1998 . 9478973 . 10.1074/jbc.273.9.5190. free .
  21. Ong E, Fukuda M, Fukuda MN, Nakagawa H, Hiraoka N, Akama TO . Molecular cloning and expression of two distinct human chondroitin 4-O-sulfotransferases that belong to the HNK-1 sulfotransferase gene family . J. Biol. Chem. . 275 . 26 . 20188–96. 2000 . 10781601 . 10.1074/jbc.M002443200. free .
  22. Baenziger JU, Xia G, Evers MR, Kang HG, Schachner M . Molecular cloning and characterization of a dermatan-specific N-acetylgalactosamine 4-O-sulfotransferase . J. Biol. Chem. . 276 . 39 . 36344–53. 2001 . 11470797 . 10.1074/jbc.M105848200. free .

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