HS3ST2

Summary

HS3ST2 (heparan sulfate-glucosamine 3-sulfotransferase 2, HGNC:5195) is a protein-coding gene on chromosome 16p12.2, encoding Heparan sulfate glucosamine 3-O-sulfotransferase 2 (Q9Y278). Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate.

Heparan sulfate biosynthetic enzymes are key components in generating a myriad of 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. This gene is expressed predominantly in brain and may play a role in the nervous system.

Source: NCBI Gene 9956 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 30 total
• MANE Select transcript: NM_006043

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5195
Approved symbol	HS3ST2
Name	heparan sulfate-glucosamine 3-sulfotransferase 2
Location	16p12.2
Locus type	gene with protein product
Status	Approved
Aliases	3OST2
Ensembl gene	ENSG00000122254
Ensembl biotype	protein_coding
OMIM	604056
Entrez	9956

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 nonsense_mediated_decay

ENST00000261374, ENST00000473392

RefSeq mRNA: 1 — MANE Select: NM_006043 NM_006043

CCDS: CCDS10606

Canonical transcript exons

ENST00000261374 — 2 exons

Exon	Start	End
ENSE00000829565	22814162	22815095
ENSE00001188294	22914944	22916338

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 87.85.

FANTOM5 (CAGE): breadth broad, TPM avg 9.6997 / max 998.8624, expressed in 491 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153148	9.6997	491

Top tissues by expression

273 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 46	UBERON:0006483	87.85	gold quality
orbitofrontal cortex	UBERON:0004167	87.74	gold quality
CA1 field of hippocampus	UBERON:0003881	87.49	gold quality
postcentral gyrus	UBERON:0002581	85.80	gold quality
type B pancreatic cell	CL:0000169	85.16	gold quality
olfactory bulb	UBERON:0002264	85.09	gold quality
superior frontal gyrus	UBERON:0002661	84.89	gold quality
parietal lobe	UBERON:0001872	84.00	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.62	gold quality
cingulate cortex	UBERON:0003027	83.56	gold quality
anterior cingulate cortex	UBERON:0009835	83.53	gold quality
endothelial cell	CL:0000115	83.48	silver quality
diaphragm	UBERON:0001103	83.25	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.25	gold quality
Brodmann (1909) area 23	UBERON:0013554	82.76	gold quality
prefrontal cortex	UBERON:0000451	82.22	gold quality
frontal cortex	UBERON:0001870	82.16	gold quality
neocortex	UBERON:0001950	81.74	gold quality
cortical plate	UBERON:0005343	81.26	gold quality
cerebral cortex	UBERON:0000956	80.59	gold quality
right frontal lobe	UBERON:0002810	80.47	gold quality
entorhinal cortex	UBERON:0002728	78.93	gold quality
visceral pleura	UBERON:0002401	78.32	gold quality
middle temporal gyrus	UBERON:0002771	78.01	silver quality
dorsal root ganglion	UBERON:0000044	77.67	gold quality
primary visual cortex	UBERON:0002436	77.67	gold quality
ascending aorta	UBERON:0001496	77.12	gold quality
thoracic aorta	UBERON:0001515	77.06	gold quality
occipital lobe	UBERON:0002021	76.55	gold quality
mucosa of urinary bladder	UBERON:0001259	76.38	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	2536.15
E-HCAD-30	no	172.76
E-ANND-3	no	2.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

54 targeting HS3ST2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-6794-3P	98.76	66.99	894
HSA-MIR-4635	98.74	67.63	1339

Literature-anchored findings (GeneRIF, showing 12)

• These results showed that silencing of 3-OST-2 was present in a wide range of human cancersFrom the high incidence, silencing of the 3-OST-2 gene is expected to have high diagnostic, and potentially therapeutic, values. (PMID:12527896)
• results raise the possibility of a role of 3-OST-2 in the spread of HSV-1 infection in the brain (PMID:16336986)
• 3-OST-2 and 3-OST-4 are the major neural gD-type 3-OSTs, and so are prime candidates for participating in HS-dependent neurobiologic events. (PMID:17482450)
• The 3OST-2 and -4 are specifically expressed in brain. (PMID:18757372)
• HS3ST2 hypermethylation may be an independent prognostic indicator for overall survival in node-negative stage I-II NSCLC (PMID:24265783)
• HS3ST2 and CCNA1 genes may play important roles in HPV-induced cervical cancer and patients with specific hypermethylated genes may have a greater risk of progressing to invasive cervical cancer. (PMID:25198553)
• By interacting with tau at the intracellular level, the 3-O-sulphated heparan sulphates produced by HS3ST2 might act as molecular chaperones allowing the abnormal phosphorylation of tau (PMID:25842390)
• In primary macrophages, HS3ST2 was clearly visualized at the plasma membrane. Its truncated form remained in the Golgi apparatus, meaning that the catalytic domain might support correct addressing of HS3ST2 to cell surface. HS3ST2 partly co-localized with syndecan-2 in HeLa cells and primary macrophages suggesting that this enzyme may participate in discrete processes that occur at the cell surface. (PMID:29660372)
• Methylation status of KLF4 and HS3ST2 genes as predictors of endometrial cancer and hyperplastic endometrial lesio (PMID:30221668)
• CpG Islands Methylation Analysis of CDH11, EphA5, and HS3ST2 Genes in Gastric Adenocarcinoma Patients. (PMID:31407253)
• Hsa-miR-194-5p might be involved in the pathogenesis of atopic dermatitis by regulating HS3ST2 expression. (PMID:31903950)
• HS3ST2 expression induces the cell autonomous aggregation of tau. (PMID:35760982)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hs3st2	ENSDARG00000059616
mus_musculus	Hs3st2	ENSMUSG00000046321
rattus_norvegicus	Hs3st2	ENSRNOG00000017659
drosophila_melanogaster	sfl	FBGN0020251
caenorhabditis_elegans		WBGENE00002028

Paralogs (10): HS3ST1 (ENSG00000002587), NDST1 (ENSG00000070614), HS3ST3B1 (ENSG00000125430), NDST4 (ENSG00000138653), HS3ST3A1 (ENSG00000153976), HS3ST6 (ENSG00000162040), NDST3 (ENSG00000164100), NDST2 (ENSG00000166507), HS3ST4 (ENSG00000182601), HS3ST5 (ENSG00000249853)

Protein

Protein identifiers

Heparan sulfate glucosamine 3-O-sulfotransferase 2 — Q9Y278 (reviewed: Q9Y278)

Alternative names: Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 2

All UniProt accessions (2): H3BMR2, Q9Y278

UniProt curated annotations — full annotation on UniProt →

Function. Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate. Catalyzes the O-sulfation of glucosamine in GlcA2S-GlcNS. Unlike HS3ST1/3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Highly expressed in the brain and weakly expressed in the heart, placenta, lung and skeletal muscle.

Similarity. Belongs to the sulfotransferase 1 family.

RefSeq proteins (1): NP_006034* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000863	Sulfotransferase_dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR037359	NST/OST	Family

Pfam: PF00685

Enzyme classification (BRENDA):

• EC 2.8.2.29 — [heparan sulfate]-glucosamine 3-sulfotransferase 2 (BRENDA: 3 organisms, 7 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• alpha-D-glucosaminyl-heparan sulfate + 3’-phosphoadenylyl sulfate = 3-sulfo-alpha-D-glucosaminyl-heparan sulfate + adenosine 3’,5’-bisphosphate + H(+) (RHEA:15461)

UniProt features (19 total): binding site 7, glycosylation site 4, topological domain 2, chain 1, disulfide bond 1, sequence variant 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y278-F1	84.18	0.69

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (7): 213; 245–246; 330–334; 124–128; 146–152; 177–180; 205

Disulfide bonds (1): 313–325

Glycosylation sites (4): 102, 193, 235, 306

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2022928	HS-GAG biosynthesis

MSigDB gene sets: 151 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, ATF_B, AP1_01, BENPORATH_ES_WITH_H3K27ME3, PAX4_01, NKX25_02, CREBP1_Q2, GGGTGGRR_PAX4_03, ONDER_CDH1_TARGETS_3_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_AMINOGLYCAN_BIOSYNTHETIC_PROCESS, CREB_Q4, AP1_Q4_01, ATF1_Q6, GOBP_HEPARAN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS

GO Biological Process (2): glycosaminoglycan biosynthetic process (GO:0006024), heparan sulfate proteoglycan biosynthetic process (GO:0015012)

GO Molecular Function (3): sulfotransferase activity (GO:0008146), [heparan sulfate]-glucosamine 3-sulfotransferase activity (GO:0008467), transferase activity (GO:0016740)

GO Cellular Component (3): Golgi membrane (GO:0000139), membrane (GO:0016020), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Heparan sulfate/heparin (HS-GAG) metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aminoglycan biosynthetic process	1
glycosaminoglycan metabolic process	1
proteoglycan biosynthetic process	1
heparan sulfate proteoglycan metabolic process	1
protein O-linked glycosylation via xylose	1
transferase activity, transferring sulphur-containing groups	1
heparan sulfate sulfotransferase activity	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

692 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HS3ST2	SULT1C3	Q6IMI6	763
HS3ST2	SULT1C4	O75897	755
HS3ST2	SULT1B1	O43704	731
HS3ST2	HS2ST1	Q7LGA3	681
HS3ST2	K7EP71	K7EP71	576
HS3ST2	HS6ST1	O60243	575
HS3ST2	GLCE	O94923	535
HS3ST2	SULF2	Q8IWU5	529
HS3ST2	RASSF1	Q9NS23	507
HS3ST2	UST	Q9Y2C2	502
HS3ST2	EXT1	Q16394	488
HS3ST2	HS6ST3	Q8IZP7	488
HS3ST2	TMEFF2	Q9UIK5	470
HS3ST2	ACKR1	Q16570	466
HS3ST2	EXT2	Q93063	459

IntAct

8 interactions, top by confidence:

A	B	Type	Score
HS3ST2	HSPA5	psi-mi:“MI:0914”(association)	0.350
SCARA5	COLGALT2	psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
HS3ST4	IPO13	psi-mi:“MI:0914”(association)	0.350
HS3ST2	PIGA	psi-mi:“MI:0914”(association)	0.350
HS3ST6	LRRC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): HS3ST2 (Affinity Capture-MS), GINM1 (Affinity Capture-MS), UBR2 (Affinity Capture-MS), MANEAL (Affinity Capture-MS), PIGA (Affinity Capture-MS), NRM (Affinity Capture-MS), ATL3 (Affinity Capture-MS), TMEM132A (Affinity Capture-MS), TMEM214 (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), HS3ST2 (Affinity Capture-MS), UBR2 (Affinity Capture-MS), PIGA (Affinity Capture-MS), SEPN1 (Affinity Capture-MS)

ESM2 similar proteins: A5PK45, A6NFA1, B1ATG9, O00587, O09008, O09009, O09010, O12971, O12972, O54951, P16442, P61315, Q0GA42, Q2KJ92, Q3TMX7, Q5BK01, Q5IGR7, Q5IS64, Q5JXM2, Q5QQ50, Q5QQ51, Q673U1, Q6KFX9, Q6NW40, Q6P988, Q6ZQ11, Q6ZRP7, Q80W66, Q812F8, Q86X52, Q8BKN6, Q8BQB4, Q8CCB5, Q8K297, Q8NBJ5, Q8NES3, Q8R087, Q8R116, Q924T4, Q9EPI0

Diamond homologs: O14792, O35310, O95803, O97583, Q5GFD5, Q673U1, Q80W66, Q8BKN6, Q8BSL4, Q8IZT8, Q96QI5, Q9EQW8, Q9ESG5, Q9H3R1, Q9QZS6, Q9Y278, Q9Y661, Q9Y662, Q9Y663, P52849, Q60V90, Q966W3, Q9EQH7, Q9V3L1, P52848, P52850, Q02353, Q3UHN9, Q5U4X8, Q6GQK9, Q55GK8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

30 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

861 predictions. Top by Δscore:

Variant	Effect	Δscore
16:22914942:A:AG	acceptor_gain	1.0000
16:22914943:G:GG	acceptor_gain	1.0000
16:22914943:GGA:G	acceptor_gain	1.0000
16:22914943:GGAGC:G	acceptor_gain	1.0000
16:22815092:ACAGG:A	donor_loss	0.9900
16:22815094:AGGTA:A	donor_loss	0.9900
16:22815096:GTAA:G	donor_loss	0.9900
16:22815097:T:G	donor_loss	0.9900
16:22895474:G:T	donor_gain	0.9900
16:22914933:T:TA	acceptor_gain	0.9900
16:22914939:CACA:C	acceptor_loss	0.9900
16:22914940:A:AG	acceptor_gain	0.9900
16:22914940:ACAG:A	acceptor_gain	0.9900
16:22914941:C:G	acceptor_gain	0.9900
16:22914941:CAGG:C	acceptor_gain	0.9900
16:22914942:AG:A	acceptor_gain	0.9900
16:22914942:AGGA:A	acceptor_gain	0.9900
16:22914943:GG:G	acceptor_gain	0.9900
16:22914943:GGAG:G	acceptor_gain	0.9900
16:22815093:CAG:C	donor_gain	0.9800
16:22891764:A:AG	donor_gain	0.9800
16:22914938:A:AG	acceptor_gain	0.9800
16:22914939:C:G	acceptor_gain	0.9800
16:22815066:G:GT	donor_gain	0.9700
16:22815096:G:GG	donor_gain	0.9700
16:22835109:G:GG	donor_gain	0.9600
16:22891217:TCAG:T	acceptor_gain	0.9500
16:22914940:ACAGG:A	acceptor_gain	0.9500
16:22816851:G:GT	donor_gain	0.9400
16:22891218:CAGT:C	acceptor_gain	0.9400

AlphaMissense

2369 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:22814971:G:C	G121R	1.000
16:22814972:G:A	G121D	1.000
16:22814979:G:C	K123N	1.000
16:22814979:G:T	K123N	1.000
16:22814981:A:T	K124M	1.000
16:22814982:G:C	K124N	1.000
16:22814982:G:T	K124N	1.000
16:22814983:G:A	G125R	1.000
16:22814983:G:C	G125R	1.000
16:22814983:G:T	G125W	1.000
16:22814986:G:C	G126R	1.000
16:22814987:G:A	G126D	1.000
16:22814990:C:T	T127I	1.000
16:22814993:G:C	R128P	1.000
16:22814996:C:A	A129D	1.000
16:22815002:T:C	L131P	1.000
16:22815052:C:G	H148D	1.000
16:22815055:T:C	F149L	1.000
16:22815056:T:C	F149S	1.000
16:22815057:C:A	F149L	1.000
16:22815057:C:G	F149L	1.000
16:22815058:T:C	F150L	1.000
16:22815059:T:C	F150S	1.000
16:22815060:T:A	F150L	1.000
16:22815060:T:G	F150L	1.000
16:22815091:T:C	Y161H	1.000
16:22914994:C:A	P179H	1.000
16:22915072:G:C	R205P	1.000
16:22915078:C:A	P207H	1.000
16:22915086:C:A	R210S	1.000

dbSNP variants (sampled 300 via entrez): RS1000027963 (16:22860637 C>A), RS1000057788 (16:22891045 A>T), RS1000079076 (16:22867134 T>C), RS1000099504 (16:22834853 T>G), RS1000128538 (16:22908592 G>A), RS1000128957 (16:22838064 A>G), RS1000131374 (16:22866869 G>A), RS1000157196 (16:22854600 T>A,C), RS1000189116 (16:22896148 C>A,G), RS1000206583 (16:22902986 G>T), RS1000208849 (16:22884292 T>C), RS1000248221 (16:22862361 T>C), RS1000379996 (16:22889351 A>G), RS1000459724 (16:22908804 C>G,T), RS1000463478 (16:22831374 G>A)

Disease associations

OMIM: gene MIM:604056 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002002_2	Adverse response to chemotherapy (neutropenia/leucopenia) (cyclophosphamide)	4.000000e-06
GCST010574_3	Evening vs. morning chronotype (self-assessed)	1.000000e-06
GCST011741_20	LDL cholesterol levels in HIV infection	9.000000e-06
GCST011741_5	LDL cholesterol levels in HIV infection	9.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, affects cotreatment, decreases expression, increases abundance, increases expression	4
Arsenic	increases abundance, increases expression, affects cotreatment, decreases expression	2
Silicon Dioxide	increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
Particulate Matter	decreases expression	2
fluorene-9-bisphenol	increases expression	1
bisphenol A	decreases methylation	1
sodium arsenate	increases abundance, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	increases expression	1
Air Pollutants	increases expression	1
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases methylation	1
Cadmium	increases abundance, increases expression	1
Copper	affects binding, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Disulfiram	decreases expression, affects binding	1
Fonofos	increases methylation	1
Estradiol	affects cotreatment, increases expression	1
Folic Acid	increases methylation	1
Lead	affects expression	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	increases expression	1
Sodium Dodecyl Sulfate	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.