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Information on EC 2.8.2.23 - [heparan sulfate]-glucosamine 3-sulfotransferase 1 and Organism(s) Homo sapiens
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2.8.2.23 [heparan sulfate]-glucosamine 3-sulfotransferase 1IUBMB Comments
This enzyme differs from the other [heparan sulfate]-glucosamine 3-sulfotransferases [EC 2.8.2.29 ([heparan sulfate]-glucosamine 3-sulfotransferase 2) and EC 2.8.2.30 ([heparan sulfate]-glucosamine 3-sulfotransferase 3)] by being the most selective for a precursor of the antithrombin-binding site. It has a minimal acceptor sequence of: -> GlcNAc6S-> GlcA-> GlcN2S*+/-6S-> IdoA2S-> GlcN2S-> , the asterisk marking the target (symbols as in {iupac/2carb/38::2-Carb-38}) using +/- to mean the presence or absence of a substituent, and > to separate a predominant structure from a minor one. Thus Glc(N2S > NAc) means a residue of glucosamine where the N carries a sulfo group mainly but occasionally an acetyl group. [1-4]. It can also modify other precursor sequences within heparan sulfate but this action does not create functional antithrombin-binding sites. These precursors are variants of the consensus sequence: -> Glc(N2S > NAc)+/-6S-> GlcA-> GlcN2S*+/-6S-> GlcA > IdoA+/-2S-> Glc(N2S/NAc)+/-6S-> . If the heparan sulfate substrate lacks 2-O-sulfation of GlcA residues, then enzyme specificity is expanded to modify selected glucosamine residues preceded by IdoA as well as GlcA .
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Word Map
- 2.8.2.23
-
3-o-sulfation
- antithrombin
-
3-osts
-
hsact
-
n-sulfated
- 3'-phosphoadenosine
-
antithrombin-binding
- medicine
- pharmacology
- analysis
- synthesis
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
3-o-sulfotransferase, 3-ost-1, hs3st1, 3-ost-4, 3-o-sulfotransferase-1, heparan sulfate d-glucosaminyl 3-o-sulfotransferase, hs3st5, heparan sulfate 3-o-sulfotransferase-1, 3-o-sulfotransferase isoform 1, 3-ost1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
3'-phosphoadenylyl-sulfate:heparin-glucosamine 3-O-sulfotransferase
-
-
-
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3-OST-1
glucosaminyl 3-O-sulfotransferase
heparan sulfate D-glucosaminyl 3-O-sulfotransferase
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-
-
-
heparin-glucosamine 3-O-sulfotransferase
-
-
-
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HS3ST1
sulfotransferase, glucosaminyl 3-O-
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-
-
-
3-OST-1
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-
-
-
glucosaminyl 3-O-sulfotransferase
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-
-
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HS3ST1
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-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
sulfate group transfer
sulfate group transfer
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-
-
-
SYSTEMATIC NAME
IUBMB Comments
3'-phosphoadenylyl-sulfate:[heparan sulfate]-glucosamine 3-sulfotransferase
This enzyme differs from the other [heparan sulfate]-glucosamine 3-sulfotransferases [EC 2.8.2.29 ([heparan sulfate]-glucosamine 3-sulfotransferase 2) and EC 2.8.2.30 ([heparan sulfate]-glucosamine 3-sulfotransferase 3)] by being the most selective for a precursor of the antithrombin-binding site. It has a minimal acceptor sequence of: -> GlcNAc6S-> GlcA-> GlcN2S*+/-6S-> IdoA2S-> GlcN2S-> , the asterisk marking the target (symbols as in {iupac/2carb/38::2-Carb-38}) using +/- to mean the presence or absence of a substituent, and > to separate a predominant structure from a minor one. Thus Glc(N2S > NAc) means a residue of glucosamine where the N carries a sulfo group mainly but occasionally an acetyl group. [1-4]. It can also modify other precursor sequences within heparan sulfate but this action does not create functional antithrombin-binding sites. These precursors are variants of the consensus sequence: -> Glc(N2S > NAc)+/-6S-> GlcA-> GlcN2S*+/-6S-> GlcA > IdoA+/-2S-> Glc(N2S/NAc)+/-6S-> [5]. If the heparan sulfate substrate lacks 2-O-sulfation of GlcA residues, then enzyme specificity is expanded to modify selected glucosamine residues preceded by IdoA as well as GlcA [6].
CAS REGISTRY NUMBER
COMMENTARY
118113-79-4
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3'-phosphoadenylyl sulfate + GlcA-beta-(1->4)-GlcNS6S-beta-(1->4)-GlcA-beta-(1->4)-GlcNS6S-alpha-(CH2)5NH2
adenosine 3',5'-bisphosphate + GlcA-beta-(1->4)-GlcNS3S6S-beta-(1->4)-GlcA-beta-(1->4)-GlcNS6S-alpha-(CH2)5NH2
-
-
-
-
?
3'-phosphoadenylyl sulfate + GlcA-beta-(1->4)-GlcNS6S-beta-(1->4)-IdoA-beta-(1->4)-GlcNS6S-alpha-(CH2)5NH2
adenosine 3',5'-bisphosphate + GlcA-beta-(1->4)-GlcNS3S6S-beta-(1->4)-IdoA-beta-(1->4)-GlcNS6S-alpha-(CH2)5NH2
-
-
-
-
?
3'-phosphoadenylyl sulfate + GlcA-beta-(1->4)-GlcNS6S-beta-(1->4)-IdoA-beta-(1->4)-GlcNS6S-beta-(1->4)-GlcA-beta-(1->4)-GlcNS6S-alpha-(CH2)5NH2
adenosine 3',5'-bisphosphate + GlcA-beta-(1->4)-GlcNS3S6S-beta-(1->4)-IdoA-beta-(1->4)-GlcNS3S6S-beta-(1->4)-GlcA-beta-(1->4)-GlcNS6S-alpha-(CH2)5NH2
-
-
-
-
?
3'-phosphoadenylyl sulfate + GlcA-beta-(1->4)-GlcNS6S-beta-(1->4)-IdoA2S-beta-(1->4)-GlcNS6S-alpha-(CH2)5NH2
adenosine 3',5'-bisphosphate + GlcA-beta-(1->4)-GlcNS3S6S-beta-(1->4)-IdoA2S-beta-(1->4)-GlcNS6S-alpha-(CH2)5NH2
-
-
-
-
?
3'-phosphoadenylyl sulfate + IdoA-beta-(1->4)-GlcNS6S-beta-(1->4)-IdoA-beta-(1->4)-GlcNS6S-alpha-(CH2)5NH2
adenosine 3',5'-bisphosphate + IdoA-beta-(1->4)-GlcNS3S6S-beta-(1->4)-IdoA-beta-(1->4)-GlcNS6S-alpha-(CH2)5NH2
-
-
-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-glucosamine 3-sulfate
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-glucosamine 3-sulfate
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-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-glucosamine 3-sulfate
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-
-
?
additional information
?
-
use of a chemoenzymatic synthetic approach to synthesize six 3-O-sulfated oligosaccharides, including three hexasaccharides and three octasaccharides. The synthesis is achieved by rearranging the enzymatic modification sequence to accommodate the substrate specificity of 3-O-sulfotransferase 3, analysis of the impact of 3-O-sulfation on the conformation of the pyranose ring of 2-O-sulfated iduronic acid using NMR spectroscopy, and on the correlation between ring conformation and anticoagulant activity. An octasaccharide interacts with antithrombin and displays antifactor Xa activity. The two 3-O-sulfotransferase (3-OST) isoforms, 3-OST-1 and 3-OST-3 (EC 2.8.2.30), are employed to install the GlcNS3S±6S residue into different saccharide sequences. The 3-OST-1 enzyme introduces a sulfation to form a GlcNS3S6S residue that is linked to a GlcA residue at the nonreducing end, forming the disaccharide unit of -GlcAGlcNS3S6S-, whereas the 3-OST-3 enzyme introduces a sulfation to form a GlcNS3S residue that is linked to an IdoA2S residue at the nonreducing end, forming the disaccharide unit of -IdoA2S-GlcNS3S-. Structural and conformational analysis of oligosaccharides, overview
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-
-
additional information
?
-
-
use of a chemoenzymatic synthetic approach to synthesize six 3-O-sulfated oligosaccharides, including three hexasaccharides and three octasaccharides. The synthesis is achieved by rearranging the enzymatic modification sequence to accommodate the substrate specificity of 3-O-sulfotransferase 3, analysis of the impact of 3-O-sulfation on the conformation of the pyranose ring of 2-O-sulfated iduronic acid using NMR spectroscopy, and on the correlation between ring conformation and anticoagulant activity. An octasaccharide interacts with antithrombin and displays antifactor Xa activity. The two 3-O-sulfotransferase (3-OST) isoforms, 3-OST-1 and 3-OST-3 (EC 2.8.2.30), are employed to install the GlcNS3S±6S residue into different saccharide sequences. The 3-OST-1 enzyme introduces a sulfation to form a GlcNS3S6S residue that is linked to a GlcA residue at the nonreducing end, forming the disaccharide unit of -GlcAGlcNS3S6S-, whereas the 3-OST-3 enzyme introduces a sulfation to form a GlcNS3S residue that is linked to an IdoA2S residue at the nonreducing end, forming the disaccharide unit of -IdoA2S-GlcNS3S-. Structural and conformational analysis of oligosaccharides, overview
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-glucosamine 3-sulfate
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-glucosamine 3-sulfate
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-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-glucosamine 3-sulfate
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-
-
?
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
5-aza-2'-deoxycytidine
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exposure of chondrosarcoma cells to the DNA-methyltransferase inhibitor 5-Aza-dc up-regulates expression of 3-OST1 mRNA
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
high expression level of HS3ST1 and low expression level of ZNF263
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
HS3STs represent the largest family of HS-modifying enzymes, and yet the reaction of 3-O-sulfation is the rarest maturation step, when compared to other sulfations. Seven HS3STs have been characterized in human, for which the expression is dependent on cell type and tissue environment
malfunction
metabolism
physiological function
additional information
malfunction
enhanced 3-O-sulfation increases binding to antithrombin, which enhances Factor Xa inhibition, and binding of neuropilin-1
malfunction
expression of the genes encoding HS-modifying enzymes is frequently dysregulated in cancer and other diseases. The enzymes show either anti-oncogenic or tumor-promoting effects
malfunction
expression of the genes encoding HS-modifying enzymes is frequently dysregulated in cancer and other diseases. The enzymes show either anti-oncogenic or tumor-promoting effects. Hypermethylation in proximal regions of the HS3ST1 gene in chondrosarcoma. Exposure to a demethylating agent restores its expression, confirming that aberrant methylation has affected its transcription
malfunction
expression of the genes encoding HS-modifying enzymes is frequently dysregulated in cancer and other diseases. The enzymes show either anti-oncogenic or tumor-promoting effects. Re-expression of HS3ST4 in MDA-MB-231 cells leads to an increase in cell viability and invasion, MDA-MB-231 cells carrying HS3ST4 expression display a significant increase in proliferation and survival
metabolism
HS3ST-mediated 3-O-sulfation leads to at least two distinct forms of 3-O-sulfated motifs. HS3ST1 and HS3ST5 participate in the generation of anticoagulant-active HS/heparin sequences for antithrombin-III, while HS3ST2, HS3ST3A, HS3ST3B, HS3ST4, and HS3ST6 are described to provide the HS-binding motifs for the glycoprotein gD of herpes simplex virus-1 (HSV-1). HS3ST regulations in cancer cells, cell proliferation, and tumor progression, overview
metabolism
the sulfation at the 3-OH position of glucosamine is an important modification in forming structural domains for heparan sulfate to enable its biological functions. Seven 3-O-sulfotransferase isoforms in the human genome are involved in the biosynthesis of 3-O-sulfated heparan sulfate
metabolism
ZNF263, a C2H2 zinc finger protein, is a negative transcriptional regulator of heparin and heparan sulfate biosynthesis, which shows distinctively low expression in mast cells compared with other (non-heparin-producing) immune cells. ZNF263 is a transcriptional repressor, and its inactivation or silencing enhances mRNA expression of HS3ST1 and HS3ST3A1 (EC 2.8.2.30), enzymes involved in the formation of binding sites for antithrombin and neuropilin-1 (NRP1) and glycoprotein D of herpes simplex virus, respectively. Heparan sulfate (HS) biosynthetic genes exhibit the ZNF263 consensus motif
physiological function
the enzyme is involved in heparan sulfate biosynthesis
physiological function
HS3ST1 encodes a sulfotransferase that catalyzes the addition of a 3-O-sulfate group on a specific glucosamine unit in heparin and heparan sulfate (HS) that generates the antithrombin-binding site, and thus controls its anticoagulant activity. HS3ST1 is a key enzyme involved in imparting anticoagulant activity to heparin
physiological function
isozymes HS3ST2, HS3ST3B, and HS3ST4 may exhibit a broader selectivity. The HS3ST4 gene is identified as a transcriptional target of TRF2, and increasing TRF2 level leads to an upregulation of HS3ST4 gene expression. Exogenous expression of either TRF2 or HS3ST4 in various tumor cell lines similarly results in increased tumor growth in xenografted mice, which suggests that the expression of this enzyme may be part of a pro-oncogenic pathway. The tumor-promoting effects of HS3ST2, HS3ST3B, and HS3ST4 are related to sustained activation of Src, Akt, and NF-kappaB, and upregulation of the anti-apoptotic proteins survivin and XIAP. Importantly, all these signalling molecules have been well described to play a critical role in promoting tumor growth and resistance to apoptosis
additional information
to date, only a few ligands are known to selectively interact with 3-O-sulfated motifs, whereas hundreds of HS-binding proteins have been identified
additional information
to date, only a few ligands are known to selectively interact with 3-O-sulfated motifs, whereas hundreds of HS-binding proteins have been identified
additional information
to date, only a few ligands are known to selectively interact with 3-O-sulfated motifs, whereas hundreds of HS-binding proteins have been identified
additional information
to date, only a few ligands are known to selectively interact with 3-O-sulfated motifs, whereas hundreds of HS-binding proteins have been identified
additional information
-
to date, only a few ligands are known to selectively interact with 3-O-sulfated motifs, whereas hundreds of HS-binding proteins have been identified
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). HS3S1_HUMAN
307
0
35773
Swiss-Prot
Secretory Pathway (Reliability: 2)
HS3S4_HUMAN
456
0
49799
Swiss-Prot
Mitochondrion (Reliability: 5)
HS3S5_HUMAN
346
1
40408
Swiss-Prot
Secretory Pathway (Reliability: 1)
HS3S6_HUMAN
342
0
37186
Swiss-Prot
other Location (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
3-OST1 cDNA is inserted into the expression vector pCDNA3.1 for transfection of HEMC cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
exposure of chondrosarcoma cells to 5-aza-2'-deoxycytidine up-regulates expression of 3-OST1 mRNA
-
expression of the genes encoding HS-modifying enzymes is frequently dysregulated in cancer and other diseases
increasing TRF2 level leads to an upregulation of HS3ST4 gene expression
the overall transcriptional activity of the main heparan sulfate biosynthesis-involved genes (EXT1, EXT2, NDST1, NDST2, GLCE, HS2ST1, HS3ST1, HS3ST2, HS6ST1, HS6ST2, SULF1, SULF2, HPSE) is decreased by 1.5-2fold in Grade II-III glioma (p < 0.01) and by 3-fold in Grade IV glioma (glioblastoma multiforme, GBM) (p < 0.05), as compared with the para-tumourous tissue
ZNF263 is a transcriptional regulator of heparin and heparan sulfate biosynthesis. CRISPR-mediated targeting and siRNA knockdown of ZNF263 in mammalian cell lines and human primary cells leads to dramatically increased expression levels of HS3ST1. LC-MS analysis of lyase-resistant 3-O-sulfated tetrasaccharides derived from ZNF263-/- cells
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
the results provide evidence for specific epigenetic regulation of 3-OST genes resulting in altered heparan sulfate proteoglycans and point to a defect of heparan sulfate-3-O-sulfation as a factor in cancer progression
pharmacology
use of a chemoenzymatic synthetic approach to synthesize six 3-O-sulfated oligosaccharides, including three hexasaccharides and three octasaccharides. The synthesis is achieved by rearranging the enzymatic modification sequence to accommodate the substrate specificity of 3-O-sulfotransferase 3, analysis of the impact of 3-O-sulfation on the conformation of the pyranose ring of 2-O-sulfated iduronic acid using NMR spectroscopy, and on the correlation between ring conformation and anticoagulant activity. An octasaccharide interacts with antithrombin and displays anti factor Xa activity. The octasaccharide displays a faster clearance rate than fondaparinux, an FDA-approved pentasaccharide drug, in a rat model, making this octasaccharide a potential short-acting anticoagulant drug candidate that could reduce bleeding risk. The presence of the -GlcNS3S6S-IdoA2S- disaccharide unit is required for anticoagulant activity
synthesis
use of a chemoenzymatic synthetic approach to synthesize six 3-O-sulfated oligosaccharides, including three hexasaccharides and three octasaccharides. The synthesis is achieved by rearranging the enzymatic modification sequence to accommodate the substrate specificity of 3-O-sulfotransferase 3, analysis of the impact of 3-O-sulfation on the conformation of the pyranose ring of 2-O-sulfated iduronic acid using NMR spectroscopy, and on the correlation between ring conformation and anticoagulant activity. An octasaccharide interacts with antithrombin and displays anti factor Xa activity. The octasaccharide displays a faster clearance rate than fondaparinux, an FDA-approved pentasaccharide drug, in a rat model, making this octasaccharide a potential short-acting anticoagulant drug candidate that could reduce bleeding risk
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Bui, C.; Ouzzine, M.; Talhaoui, I.; Sharp, S.; Prydz, K.; Coughtrie, M.W.; Fournel-Gigleux, S.
Epigenetics: methylation-associated repression of heparan sulfate 3-O-sulfotransferase gene expression contributes to the invasive phenotype of H-EMC-SS chondrosarcoma cells
FASEB J.
24
436-450
2010
Homo sapiens
Nguyen, T.K.; Arungundram, S.; Tran, V.M.; Raman, K.; Al-Mafraji, K.; Venot, A.; Boons, G.J.; Kuberan, B.
A synthetic heparan sulfate oligosaccharide library reveals the novel enzymatic action of D-glucosaminyl 3-O-sulfotransferase-3a
Mol. Biosyst.
8
609-614
2012
Homo sapiens
Ushakov, V.; Tsidulko, A.; De La Bourdonnaye, G.; Kazanskaya, G.; Volkov, A.; Kiselev, R.; Kobozev, V.; Kostromskaya, D.; Gaytan, A.; Krivoshapkin, A.; Aidagulova, S.; Grigorieva, E.
Heparan sulfate biosynthetic system is inhibited in human glioma due to EXT1/2 and HS6ST1/2 down-regulation
Int. J. Mol. Sci.
18
2301
2017
Homo sapiens (O14792)
Denys, A.; Allain, F.
The emerging roles of heparan sulfate 3-O-sulfotransferases in cancer
Front. Oncol.
9
507
2019
Homo sapiens (O14792), Homo sapiens (Q8IZT8), Homo sapiens (Q96QI5), Homo sapiens (Q9Y661), Homo sapiens
Wang, Z.; Hsieh, P.H.; Xu, Y.; Thieker, D.; Chai, E.J.E.; Xie, S.; Cooley, B.; Woods, R.J.; Chi, L.; Liu, J.
Synthesis of 3-O-sulfated oligosaccharides to understand the relationship between structures and functions of heparan sulfate
J. Am. Chem. Soc.
139
5249-5256
2017
Homo sapiens (O14792), Homo sapiens
Weiss, R.J.; Spahn, P.N.; Toledo, A.G.; Chiang, A.W.T.; Kellman, B.P.; Li, J.; Benner, C.; Glass, C.K.; Gordts, P.L.S.M.; Lewis, N.E.; Esko, J.D.
ZNF263 is a transcriptional regulator of heparin and heparan sulfate biosynthesis
Proc. Natl. Acad. Sci. USA
117
9311-9317
2020
Homo sapiens (O14792), Homo sapiens
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