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Information on EC 2.8.2.5 - chondroitin 4-sulfotransferase and Organism(s) Homo sapiens
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EC Tree
2.8.2.5 chondroitin 4-sulfotransferaseIUBMB Comments
The sulfation takes place at the 4-position of N-acetyl-galactosamine residues of chondroitin. Not identical with EC 2.8.2.17 chondroitin 6-sulfotransferase.
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Word Map
- 2.8.2.5
- proteoglycans
- glycosaminoglycans
-
sulfotransferases
- keratan
- n-acetylgalactosamine
- 4-sulfate
-
chst15
-
4-o-sulfation
-
6-sulfotransferase
-
uronyl
-
2-o-sulfotransferase
-
iduronic
- medicine
- synthesis
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
c4st-1, chst11, carbohydrate sulfotransferase, chondroitin 4-sulfotransferase, c4st, c4st-2, chondroitin 4-o-sulfotransferase-1, chondroitin-4-sulfotransferase, chondroitin 4-o-sulfotransferase, chondroitin sulfotransferase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
C4ST
chondroitin sulfotransferase
-
-
-
-
CHST11
sulfotransferase, chondroitin
-
-
-
-
sulfotransferase, chondroitin 4-
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
sulfate group transfer
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-
SYSTEMATIC NAME
IUBMB Comments
3'-phosphoadenylyl-sulfate:chondroitin 4'-sulfotransferase
The sulfation takes place at the 4-position of N-acetyl-galactosamine residues of chondroitin. Not identical with EC 2.8.2.17 chondroitin 6-sulfotransferase.
CAS REGISTRY NUMBER
COMMENTARY
83589-04-2
-
9026-07-7
-
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 + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
3'-phosphoadenylylsulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
3'-phosphoadenylylsulfate + chondroitin sulfate C
adenosine 3',5'-bisphosphate + chondroitin sulfate C 4'-sulfate
3'-phosphoadenylylsulfate + chondroitin sulfate D
adenosine 3',5'-bisphosphate + chondroitin sulfate D 4'-sulfate
low activity
-
-
?
3'-phosphoadenylylsulfate + desulfated chondroitin sulfate A
adenosine 3',5'-bisphosphate + chondroitin sulfate A
3'-phosphoadenylylsulfate + desulfated chondroitin sulfate B
adenosine 3',5'-bisphosphate + chondroitin sulfate B
low activity
-
-
?
3'-phosphoadenylylsulfate + desulfated dermatan sulfate
adenosine 3',5'-bisphosphate + ?
-
113% of the activity with chondroitin
-
-
?
3'-phosphoadenylyl sulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
?
3'-phosphoadenylyl sulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
-
?
3'-phosphoadenylyl sulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
?
3'-phosphoadenylyl sulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
-
?
3'-phosphoadenylyl sulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
?
3'-phosphoadenylylsulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
-
?
3'-phosphoadenylylsulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
?
3'-phosphoadenylylsulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
?
3'-phosphoadenylylsulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
?
3'-phosphoadenylylsulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
isozyme C4ST1, best substrate
-
?
3'-phosphoadenylylsulfate + chondroitin sulfate C
adenosine 3',5'-bisphosphate + chondroitin sulfate C 4'-sulfate
-
-
-
?
3'-phosphoadenylylsulfate + chondroitin sulfate C
adenosine 3',5'-bisphosphate + chondroitin sulfate C 4'-sulfate
low activity
-
-
?
3'-phosphoadenylylsulfate + desulfated chondroitin sulfate A
adenosine 3',5'-bisphosphate + chondroitin sulfate A
-
-
-
?
3'-phosphoadenylylsulfate + desulfated chondroitin sulfate A
adenosine 3',5'-bisphosphate + chondroitin sulfate A
low activity
-
-
?
3'-phosphoadenylylsulfate + desulfated dermatan sulfate
?
-
-
-
?
3'-phosphoadenylylsulfate + desulfated dermatan sulfate
?
i.e. dermatan
-
-
?
3'-phosphoadenylylsulfate + partially desulfated dermatan sulfate
?
-
-
-
?
3'-phosphoadenylylsulfate + partially desulfated dermatan sulfate
?
isozyme C4ST2, best substrate
-
-
?
3'-phosphoadenylylsulfate + partially desulfated dermatan sulfate
?
isozyme C4ST3, very low activity
-
-
?
additional information
?
-
no activity with dermatan sulfate, keratan sulfate
-
-
?
additional information
?
-
no activity with dermatan sulfate, keratan sulfate
-
-
?
additional information
?
-
-
no activity with dermatan sulfate, keratan sulfate
-
-
?
additional information
?
-
no activity with desulfated and N-sulfated heparin, and desulfated and N-acetylated heparin
-
-
?
additional information
?
-
no activity with desulfated and N-sulfated heparin, and desulfated and N-acetylated heparin
-
-
?
additional information
?
-
-
no activity with desulfated and N-sulfated heparin, and desulfated and N-acetylated heparin
-
-
?
additional information
?
-
-
no substrate: chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate. Enzyme mainly transfers sulfate to position 4 of the GalNAc residue located at the GlcA-GalNAc-GlcA sequence
-
-
?
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 + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
3'-phosphoadenylyl sulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
?
3'-phosphoadenylyl sulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
-
?
3'-phosphoadenylyl sulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
?
3'-phosphoadenylyl sulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
-
?
3'-phosphoadenylyl sulfate + chondroitin
adenosine 3',5'-bisphosphate + chondroitin 4'-sulfate
-
-
-
?
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00125
3'-phosphoadenylyl sulfate
pH 7.0, 37°C, recombinant enzyme expressed in Escherichia coli
0.036
3'-phosphoadenylyl sulfate
pH 7.0, 37°C, recombinant enzyme expressed in Pichia pastoris
0.0038
chondroitin
pH 7.0, 37°C, recombinant enzyme expressed in Escherichia coli
0.157
chondroitin
pH 7.0, 37°C, recombinant enzyme expressed in Pichia pastoris
additional information
additional information
two-substrate Michaelis-Menten kinetic analysis
-
additional information
additional information
-
two-substrate Michaelis-Menten kinetic analysis
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.8
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
28
37
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
isozyme C4ST3 shows very poor activity with chondroitin and partially desulfated dermatan sulfate as substrates at 37°C compared to 28°C
additional information
isozyme C4ST3 shows very poor activity with chondroitin and partially desulfated dermatan sulfate as substrates at 37°C compared to 28°C
additional information
isozyme C4ST3 shows very poor activity with chondroitin and partially desulfated dermatan sulfate as substrates at 37°C compared to 28°C
additional information
-
isozyme C4ST3 shows very poor activity with chondroitin and partially desulfated dermatan sulfate as substrates at 37°C compared to 28°C
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
isozyme C4ST3, high content in adult, low content in fetal liver
additional information
additional information
analysis of the content of chondroitin sulfate (CS) in the cells, disaccharide composition analysis of CS, the expression level of CS is expressed as total amounts of unsaturated disaccharides, overview
additional information
C4ST-1 is predominantly expressed in spleen, thymus, bone marrow, peripheral blood leukocytes, lymph node, heart, brain, lung, and placenta
additional information
-
C4ST-1 is predominantly expressed in spleen, thymus, bone marrow, peripheral blood leukocytes, lymph node, heart, brain, lung, and placenta
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
there are three major C4ST isoforms in Homo sapiens, C4ST-1, C4ST-2, and C4ST-3. Based on a general amino acid sequence analysis, C4STs contain a single cytoplasmic domain followed by helical transmembrane domain and a lumenal domain. C4ST-1 has two additional variants, and both are capable of sulfating unsulfated chondroitin and dermatan with a preference of D-glucuronic acid (GlcA)->GalNAc over L-iduronic acid (IdoA)->GalNAc. C4ST-2 has a lower activity towards unsulfated dermatan than does C4ST-1
malfunction
metabolism
physiological function
malfunction
C4ST-1 activity and C4S production are upregulated in human glioma tissues, when compared to normal brain tissue, and the extent of upregulation positively correlates with glioma malignancy. Inhibition of expression of the two CS synthetic enzymes chondroitin 4-O-sulfotransferase-1 (C4ST-1/CHST11) and chondroitin 6-O-sulfotransferase-1 (C6ST-1/CHST3, EC 2.8.2.17) suppress cell viability, migration and invasion, reduce MMP-2 and MMP-9 expression, and reduce N-cadherin expression, but increase E-cadherin levels. Clinicopathological features, overview
malfunction
even though C4ST-1 and C4ST-2 exhibit broad and overlapping mRNA expression patterns, indicating the functional redundancy of these enzymes, a deficiency or experimental knockdown of C4ST-1 results in a dramatic decrease of cellular and whole-body levels of chondroitin 4'-sulfate. The enzyme completely loses activity when deglycosylated by treatment with PNGase F
malfunction
the ratio of 4-O-sulfation to 6-O-sulfation (4S/6S) and CS chain length, that occur during the aging process, are decreased in polyamine-depleted cells. In addition, decreased levels of chondroitin synthase 1 (CHSY1, EC 2.4.1.175) and chondroitin 4-O-sulfotransferase 2 proteins are also observed on polyamine depletion. The destabilization of G4 structures by polyamines (i.e. putrescine, spermidine and spermine) stimulates CHSY1 synthesis and, at least in part, contributes to the maturation of CS chains
metabolism
C4ST-1 is believed to play a distinct regulatory role not only in CS 4-O-sulfation but also in the amount of CS synthesis since none of the other family member C4ST-2 and C4ST-3 can compensate for the loss of C4ST-1
metabolism
chondroitin sulfate (CS) biosynthesis is initiated once GalNAc is transferred by CSGalNAcT1 or 2 to the common linkage tetrasaccharide, GlcAbeta1-3galactose (Gal)beta1-3Galbeta1-4xylose (Xyl)beta1-O-serine in proteoglycans and chain elongation is then catalyzed by the chondroitin synthase (CHSY) 1-3/chondroitin-polymerizing factor (CHPF) heterodimer. After synthase-catalyzed polymerization, the majority of the GalNAc residues are 4-O-sulfated by chondroitin 4-O-sulfotransferases (C4ST1, 2 and 3) or 6-O-sulfated by chondroitin 6-O-sulfotransferases (C6ST1 and 2). In addition, resulting A- or C-unit can be further sulfated by GalNAc 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) or chondroitin uronyl 2-O-sulfotransferase (UST), generating di-sulfated disaccharides, E-unit or D-unit, respectively. Structural changes in CS, particularly the ratio of 4-O-sulfation to 6-O-sulfation (4S/6S), occur during normal embryonic development, during growth, and in aging. For example, the 4S/6S ratios of CS (or DS) present in human skin and cartilage decrease from birth to age 20
physiological function
chondroitin sulfates are linear sulfated polysaccharides called glycosaminoglycans. They are important nutraceutical and pharmaceutical products that are biosynthesized through the action of chondroitin sulfotransferases on either an unsulfated chondroitin or a dermatan polysaccharide precursor. The major chondroitin-4-sulfotransferase in Homo sapiens is C4ST-1
physiological function
key molecules promoting migration and invasion exist in the extracellular matrix, and include chondroitin 4-sulfate (C4S) and chondroitin 6-sulfate (C6S), functionally important carbohydrate chains of chondroitin sulfate proteoglycans that participate in regulating cancer development. The C4S- and C6S-enhanced epithelial-tomesenchymal transition and expression of MMP-2 occur via activation of the PI3K/AKT signaling pathway, known to be involved in promoting cell migration and invasion. C4S and C6S increase the numbers of living glioma cells and promote proliferation, they promote colony formation of glioma cells, phenotypes, overview
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). CHSTB_HUMAN
352
1
41555
Swiss-Prot
Secretory Pathway (Reliability: 2)
CHSTC_HUMAN
414
1
48414
Swiss-Prot
Secretory Pathway (Reliability: 1)
CHSTD_HUMAN
341
1
38920
Swiss-Prot
Mitochondrion (Reliability: 5)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
four potential glycosylation sites in human C4ST-1: Asn205, Asn223, Asn321, and Asn342. Enzyme C4ST-1 requires glycosylation for its activity. The enzyme completely loses activity when deglycosylated by treatment with PNGase F. In particular, the glycosylation site Asn342 near the C-terminus is believed to be essential to the activity of C4ST-1 since the mutant devoid of this site lost significant activity compared to the wild-type enzyme. Asn223 and Asn342 are thought to contribute mainly to the stability of the protein rather than to the production of the active enzyme. The recombinant glycosylated form of C4ST-1 shows lower stability than the non-glycosylated form
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
translocations t(12,14)(q23,q32) in a patient with B-cell chronic lymphocytic leukemia result in expression of two truncated forms of enzyme protein, resulting in disturbance of the cellular distribution of enzyme, and further in deregulation of a chondroitin-sulfate dependent pathway specific to the hematopoietic lineage
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His6-tagged C4ST-1 from Escherichia coli strain BL21 Star(DE3) by nickel affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA sequence determination and analysis, chromosome mapping at p22 region of chromosome 7, expression in CHO cells
DNA sequence determination and analysis, located on chromosome 3, genomic organisation, expression as myc- and His-tagged enzyme in CHO cells
DNA sequence dtermination and analysis, chromosome mapping at q23 region of chromosome 12, expression in CHO cells
expression as N-terminally truncated enzyme, lacking the first 57 amino acids, in COS-1 cells
expression as N-terminally truncated enzyme, lacking the first 76 amino acids, in COS-1 cells
recombinant expression of non-glycosylated and glycosylated His6-tagged C4ST-1 construct in Escherichia coli strain BL21 Star(DE3), recombinant expression in Pichia pastoris strain ATCC 76273, both in its non-glycosylated and glycosylated forms, leads to an unstable enzyme. Glycosylation of the yeast-expressed sulfotransferase does not improve its overall stability. The activity of the purified Pichia pastoris expressing C4ST-1 is completely lost after 72 h
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
a decline in arylsulfatase B reduces chondroitin-4-sulfotransferase mRNA expression. Inhibition of bone morphogenetic protein 4 also reduces enzyme expression
a significantly higher mRNA expression of CHST11 is measured in ovarian cancer samples in comparison to non-malignant ones
polyamines stimulate the synthesis of C4ST2 in HCT-116 cells, C4ST2 is stimulated at the transcriptional level
the expression levels of C4ST2 mRNA and protein decrease in DFMO-treated HCT-116 cells
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
translocations t(12,14)(q23,q32) in a patient with B-cell chronic lymphocytic leukemia result in expression of two truncated forms of enzyme protein, resulting in disturbance of the cellular distribution of enzyme, and further in deregulation of a chondroitin-sulfate dependent pathway specific to the hematopoietic lineage
medicine
the enzyme is an independent unfavorable prognostic factor for ovarian cancer progression
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hiraoka, N.; Nakagawa, H.; Ong, E.; Akama, T.O.; Fukuda, M.N.; Fukuda, M.
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
20188-20196
2000
Homo sapiens (Q9NPF2), Homo sapiens (Q9NRB3), Homo sapiens
Kang, H.G.; Evers, M.R.; Xia, G.; Baenziger, J.U.; Schachner, M.
Molecular cloning and characterization of chondroitin-4-O-sulfotransferase-3. A novel member of the HNK-1 family of sulfotransferases
J. Biol. Chem.
277
34766-34772
2002
Homo sapiens (Q8NET6), Homo sapiens (Q9NPF2), Homo sapiens (Q9NRB3), Homo sapiens
Mikami, T.; Mizumoto, S.; Kago, N.; Kitagawa, H.; Sugahara, K.
Specificities of three distinct human chondroitin/dermatan N-acetylgalactosamine 4-O-sulfotransferases demonstrated using partially desulfated dermatan sulfate as an acceptor. Implication of differential roles in dermatan sulfate biosynthesis
J. Biol. Chem.
278
36115-36127
2003
Homo sapiens (Q8NET6), Homo sapiens (Q9NPF2), Homo sapiens (Q9NRB3), Homo sapiens
Yamada, T.; Ohtake, S.; Sato, M.; Habuchi, O.
Chondroitin 4-sulphotransferase-1 and chondroitin 6-sulphotransferase-1 are affected differently by uronic acid residues neighbouring the acceptor GalNAc residues
Biochem. J.
384
567-575
2004
Homo sapiens
Schmidt, H.H.; Dyomin, V.G.; Palanisamy, N.; Itoyama, T.; Nanjangud, G.; Pirc-Danoewinata, H.; Haas, O.A.; Chaganti, R.S.
Deregulation of the carbohydrate (chondroitin 4) sulfotransferase 11 (CHST11) gene in a B-cell chronic lymphocytic leukemia with a t(12;14)(q23;q32)
Oncogene
23
6991-6996
2004
Homo sapiens
Bhattacharyya, S.; Feferman, L.; Tobacman, J.K.
Regulation of chondroitin-4-sulfotransferase (CHST11) expression by opposing effects of arylsulfatase B on BMP4 and Wnt9A
Biochim. Biophys. Acta
1849
342-352
2015
Homo sapiens (Q9NPF2), Homo sapiens, Mus musculus (Q9JME2)
Oliveira-Ferrer, L.; Hessling, A.; Trillsch, F.; Mahner, S.; Milde-Langosch, K.
Prognostic impact of chondroitin-4-sulfotransferase CHST11 in ovarian cancer
Tumour Biol.
36
9023-9030
2015
Homo sapiens (Q9NPF2), Homo sapiens
He, W.; Zhu, Y.; Shirke, A.; Sun, X.; Liu, J.; Gross, R.A.; Koffas, M.A.G.; Linhardt, R.J.; Li, M.
Expression of chondroitin-4-O-sulfotransferase in Escherichia coli and Pichia pastoris
Appl. Microbiol. Biotechnol.
101
6919-6928
2017
Homo sapiens (Q9NPF2), Homo sapiens
Yamaguchi, K.; Asakura, K.; Imamura, M.; Kawai, G.; Sakamoto, T.; Furihata, T.; Linhardt, R.J.; Igarashi, K.; Toida, T.; Higashi, K.
Polyamines stimulate the CHSY1 synthesis through the unfolding of the RNA G-quadruplex at the 5-untraslated region
Biochem. J.
475
3797-3812
2018
Homo sapiens (Q9NRB3)
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