Carbohydrate sulfotransferase

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Carbohydrate Sulfotransferase family 2
1T8U.jpg
Example carbohydrate sulfotransferase with PAPS cosubstrate and carbohydrate substrate: Crystal Structure of human 3-O-Sulfotransferase-3 with bound PAPS and tetrasaccharide substrate. Enzyme chain A (blue), Enzyme chain B (green), PAPS (red), tetrasaccharide substrate (white), sodium ion (purple sphere). [1]
Identifiers
SymbolSulfotransfer_2
Pfam PF03567
InterPro IPR005331
Membranome 495
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Carbohydrate Sulfotransferase family 1
Identifiers
SymbolSulfotransfer_1
InterPro IPR016469
Membranome 493

In biochemistry, carbohydrate sulfotransferases are enzymes within the class of sulfotransferases which catalyze the transfer of the sulfate (−SO3) 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. [2] Possible covalent modifications include acetylation, methylation, phosphorylation, and sulfation. [3] Sulfation, performed by carbohydrate sulfotransferases, generates carbohydrate sulfate esters (−O−SO3). These sulfate esters are only located extracellularly, whether through excretion into the extracellular matrix (ECM) or by presentation on the cell surface. [4] As extracellular compounds, sulfated carbohydrates are mediators of intercellular communication, cellular adhesion, and ECM maintenance.

Contents

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. [4] In eukaryotic cells the activated sulfate donor is 3'-phosphoadenosine-5'-phosphosulfate (PAPS) (Figure 1). [5]

Figure 1: A general carbohydrate sulfotransferase reaction. PAPS is shown as the activated sulfate donor; PAPS is the sulfate donor in eukaryotic cells. Overall Sulfotransferase Reaction.jpg
Figure 1: A general carbohydrate sulfotransferase reaction. PAPS is shown as the activated sulfate donor; PAPS is the sulfate donor in eukaryotic cells.

PAPS is synthesized in the cytosol from ATP and sulfate through the sequential action of ATP sulfurylase and APS kinase. [6] 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. [7] 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. [8]

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). [9] 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. [10] [11] Protein sequence alignment studies indicate that this lysine is conserved in cytosolic sulfotransferases as well. [4]

In addition to the conserved lysine, sulfotransferases have a highly conserved histidine in the active site. [12] Based on the conservation of these residues, theoretical models, and experimental measurements a theoretical transition state for catalyzed sulfation has been proposed (Figure 3). [12]

Figure 2: The mechanism by which carbohydrate sulfotransferase catalyzes the transfer of a sulfonyl group to a carbohydrate group in a glycoprotein or glycolipid is analogous to the mechanism by which a kinase catalyzes a phosphoryl group. Both enzymes use a lysine residue in their active sites to coordinate to their cosubstrates; the ATP cosubstrate in the kinase mechanism is analogous to the PAPS in the carbohydrate sulfotransferase mechanism (green). Red shows the group being transferred; note that the transfer is coordinated around the lysine. Black is the substrate. Sia stands for sialic acid. Kinase mechanism vs sulfotransferase mechanism.jpg
Figure 2: The mechanism by which carbohydrate sulfotransferase catalyzes the transfer of a sulfonyl group to a carbohydrate group in a glycoprotein or glycolipid is analogous to the mechanism by which a kinase catalyzes a phosphoryl group. Both enzymes use a lysine residue in their active sites to coordinate to their cosubstrates; the ATP cosubstrate in the kinase mechanism is analogous to the PAPS in the carbohydrate sulfotransferase mechanism (green). Red shows the group being transferred; note that the transfer is coordinated around the lysine. Black is the substrate. Sia stands for sialic acid.
Figure 3: Transition state for catalyzed sulfation as proposed by Chapman et al. 2004. Note the use of the conserved lysine and histidine residues. Transition state proposed by Chapman et al 2004 for sulfotransferase.png
Figure 3: Transition state for catalyzed sulfation as proposed by Chapman et al. 2004. Note the use of the conserved lysine and histidine residues.

Biological function

Carbohydrate sulfotransferases are transmembrane enzymes in the Golgi that modify carbohydrates on glycolipids or glycoproteins as they move along the secretory pathway. [4] They have a short cytoplasmic N-terminal, one transmembrane domain, and a large C-terminal Golgi luminal domain. [6] 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. [4] [13] 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). [14] [15]

Heparan Sulfotransferases

Heparan sulfate is a glycosaminoglycan (GAG) that is linked by xylose to serine residues of proteins such as perlecan, syndecan, or glypican. [16] 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. [12] 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. [17] Heparan sulfates are also known to interact with growth factors, cytokines, chemokines, lipid and membrane binding proteins, and adhesion molecules. [12]

GSTs

GSTs catalyze sulfation at the 6-hydroxyl group of galactose, N-acetylgalactosamine, or N-acetylglucosamine. [15] 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 [4] [18] 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. [18] GSTs are also responsible for the proper function of the ECM in the cornea; improper sulfation by GSTs can lead to opaque corneas. [18]

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). [12] Heparan sulfate sites have been shown to be essential for HSV-1 binding that leads to the virus entering the cell. [19] 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. [12]

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

Related Research Articles

Tyrosine sulfation is a posttranslational modification where a sulfate group is added to a tyrosine residue of a protein molecule. Secreted proteins and extracellular parts of membrane proteins that pass through the Golgi apparatus may be sulfated. Sulfation was first discovered by Bettelheim in bovine fibrinopeptide B in 1954 and later found to be present in animals and plants but not in prokaryotes or in yeast.

<span class="mw-page-title-main">Heparan sulfate</span> Macromolecule

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. In this form, HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.

<span class="mw-page-title-main">Sulfatase</span> Class of enzymes which break up sulfate esters by hydrolysis

In biochemistry, sulfatases EC 3.1.6.- are a class of enzymes of the esterase class that catalyze the hydrolysis of sulfate esters into an alcohol and a bisulfate:

Sulfation is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected less directly. Regardless of the mechanism, the installation of a sulfate-like group on a substrate leads to substantial changes.

<span class="mw-page-title-main">Tyrosylprotein sulfotransferase</span> Enzyme

Tyrosylprotein sulfotransferase is an enzyme that catalyzes tyrosine sulfation.

In enzymology, a [heparan sulfate]-glucosamine 3-sulfotransferase 1 is an enzyme that catalyzes the chemical reaction

In enzymology, a [heparan sulfate]-glucosamine 3-sulfotransferase 2 is an enzyme that catalyzes the chemical reaction

In enzymology, a [heparan sulfate]-glucosamine 3-sulfotransferase 3 is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">PAPSS1</span> Protein-coding gene in the species Homo sapiens

Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthetase 1 is an enzyme that in humans is encoded by the PAPSS1 gene.

<span class="mw-page-title-main">CHST4</span> Protein-coding gene in the species Homo sapiens

Carbohydrate sulfotransferase 4 is an enzyme that in humans is encoded by the CHST4 gene.

<span class="mw-page-title-main">CHST1</span> Protein-coding gene in the species Homo sapiens

Carbohydrate sulfotransferase 1 is an enzyme that in humans is encoded by the CHST1 gene.

<span class="mw-page-title-main">GALNAC4S-6ST</span> Protein-coding gene in the species Homo sapiens

Carbohydrate sulfotransferase 15 is an enzyme that in humans is encoded by the CHST15 gene. It belongs to the N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase enzyme class.

<span class="mw-page-title-main">HS3ST3A1</span> Protein-coding gene in the species Homo sapiens

Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 is an enzyme that in humans is encoded by the HS3ST3A1 gene.

<span class="mw-page-title-main">HS3ST1</span> Protein-coding gene in the species Homo sapiens

Heparan sulfate glucosamine 3-O-sulfotransferase 1 is an enzyme that in humans is encoded by the HS3ST1 gene.

<span class="mw-page-title-main">GAL3ST4</span> Protein-coding gene in the species Homo sapiens

Galactose-3-O-sulfotransferase 4 is an enzyme that in humans is encoded by the GAL3ST4 gene.

<span class="mw-page-title-main">HS3ST3B1</span> Protein-coding gene in the species Homo sapiens

Heparan sulfate glucosamine 3-O-sulfotransferase 3B1 is an enzyme that in humans is encoded by the HS3ST3B1 gene. Heparan sulfate biosynthetic enzymes are key components in generating myriad distinct heparan sulfate fine structures that carry out multiple biologic activities. The enzyme encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. It is a type II integral membrane protein and possesses heparan sulfate glucosaminyl 3-O-sulfotransferase activity ( HS3ST3A1). The Sulfotransferase domain of this enzyme is highly similar to the same domain of heparan sulfate D-glucosaminyl 3-O-sulfotransferase 3A1 and these two enzymes sulfate an identical disaccharide. This gene is widely expressed, with the most abundant expression in liver and placenta.

<span class="mw-page-title-main">GAL3ST3</span> Protein-coding gene in the species Homo sapiens

Galactose-3-O-sulfotransferase 3 is an enzyme that in humans is encoded by the GAL3ST3 gene.

<span class="mw-page-title-main">HS3ST2</span> Protein-coding gene in the species Homo sapiens

Heparan sulfate glucosamine 3-O-sulfotransferase 2 is an enzyme that in humans is encoded by the HS3ST2 gene.

Heparan sulfate 2-O-sulfotransferase is a sulfotransferase enzyme. Heparan sulfate (HS) is a long unbranched polysaccharide found covalently attached to various proteins at the cell surface and in the extracellular matrix, where it acts as a co-receptor for a number of growth factors, morphogens, and adhesion proteins. HS-O-sulfotransferase (Hs2st) occupies a critical position in the succession of enzymes responsible for the biosynthesis of HS, catalysing the transfer of sulfate to the C2-position of selected hexuronic acid residues within the nascent HS chain. Mice that lack HS2ST undergo developmental failure after midgestation, the most dramatic effect being the complete failure of kidney development. This family is related to InterPro: IPR005331.

<span class="mw-page-title-main">Carbohydrate (chondroitin 4) sulfotransferase 13</span>

Carbohydrate sulfotransferase 13 is a protein that is encoded in humans by the CHST13 gene.

References

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This article incorporates text from the public domain Pfam and InterPro: IPR005331