HS3ST5

Summary

HS3ST5 (heparan sulfate-glucosamine 3-sulfotransferase 5, HGNC:19419) is a protein-coding gene on chromosome 6q21-q22.1, encoding Heparan sulfate glucosamine 3-O-sulfotransferase 5 (Q8IZT8). Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to position 3 of glucosamine residues in heparan.

HS3ST5 belongs to a group of heparan sulfate 3-O-sulfotransferases (EC 2.8.2.23) that transfer sulfate from 3-prime-phosphoadenosine 5-prime phosphosulfate (PAPS) to heparan sulfate and heparin (Mochizuki et al., 2003 [PubMed 12740361]).

Source: NCBI Gene 222537 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 10 total
• MANE Select transcript: NM_153612

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19419
Approved symbol	HS3ST5
Name	heparan sulfate-glucosamine 3-sulfotransferase 5
Location	6q21-q22.1
Locus type	gene with protein product
Status	Approved
Aliases	3-OST-5
Ensembl gene	ENSG00000249853
Ensembl biotype	protein_coding
OMIM	609407
Entrez	222537

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 15 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000312719, ENST00000441954, ENST00000900060, ENST00000900061, ENST00000900062, ENST00000900063, ENST00000900064, ENST00000920560, ENST00000920563, ENST00000920564, ENST00000920566, ENST00000920567, ENST00000920569, ENST00000920571, ENST00000920573, ENST00000947070

RefSeq mRNA: 10 — MANE Select: NM_153612 NM_001387039, NM_001387040, NM_001387041, NM_001387042, NM_001387043, NM_001387044, NM_001387045, NM_001387046, NM_001387047, NM_153612

CCDS: CCDS34517

Canonical transcript exons

ENST00000312719 — 5 exons

Exon	Start	End
ENSE00002105537	114342195	114343023
ENSE00002228949	114228585	114228778
ENSE00002257181	114062739	114062877
ENSE00002260585	114055596	114058190
ENSE00002298747	114168351	114168462

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 84.62.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3632 / max 57.4145, expressed in 388 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75229	0.7552	286
75226	0.4630	191
75228	0.1286	68
75227	0.0164	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.62	gold quality
cortical plate	UBERON:0005343	78.00	gold quality
putamen	UBERON:0001874	77.95	gold quality
corpus callosum	UBERON:0002336	77.71	gold quality
caudate nucleus	UBERON:0001873	77.20	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.79	gold quality
spinal cord	UBERON:0002240	75.76	gold quality
prefrontal cortex	UBERON:0000451	73.95	gold quality
secondary oocyte	CL:0000655	73.37	gold quality
superior vestibular nucleus	UBERON:0007227	73.12	gold quality
nucleus accumbens	UBERON:0001882	72.48	gold quality
medulla oblongata	UBERON:0001896	71.23	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	70.76	silver quality
biceps brachii	UBERON:0001507	70.66	silver quality
Brodmann (1909) area 46	UBERON:0006483	70.10	gold quality
Brodmann (1909) area 9	UBERON:0013540	69.59	gold quality
dorsal plus ventral thalamus	UBERON:0001897	69.56	gold quality
frontal cortex	UBERON:0001870	68.93	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	68.56	gold quality
substantia nigra	UBERON:0002038	68.53	gold quality
midbrain	UBERON:0001891	68.39	gold quality
neocortex	UBERON:0001950	68.13	gold quality
subthalamic nucleus	UBERON:0001906	67.78	gold quality
pons	UBERON:0000988	67.70	gold quality
cerebral cortex	UBERON:0000956	67.03	gold quality
inferior vagus X ganglion	UBERON:0005363	66.29	gold quality
anterior cingulate cortex	UBERON:0009835	66.23	gold quality
hypothalamus	UBERON:0001898	65.95	gold quality
forebrain	UBERON:0001890	65.92	gold quality
primary visual cortex	UBERON:0002436	65.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

148 targeting HS3ST5, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7C-3P	99.95	73.42	2862

Literature-anchored findings (GeneRIF, showing 3)

• Recombinant 3-OST-5 only exhibited sulfotransferase activity toward heparan sulfate and heparin. 3-OST-5 was highly expressed in fetal brain, followed by adult brain and spinal cord, and at very low or undetectable levels in other tissues. (PMID:12740361)
• Results demonstrate that the human 3-O-sulfotransferase isoform 5 gene is capable of synthesizing anticoagulant heparan sulfate (HS) in CHO cells and may contribute to the biosynthesis of HS in humans. (PMID:15026143)
• Structural analysis of 3-OST-5 HS(act) revealed that the antithrombin-binding site of 3-OST-5 HS(act) is located within a domain clustered with N-sulfated glucosamine units. (PMID:16099108)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hs3st5	ENSMUSG00000044499
rattus_norvegicus	Hs3st5	ENSRNOG00000000605
drosophila_melanogaster	Hs3st-A	FBGN0053147
caenorhabditis_elegans		WBGENE00002030

Paralogs (10): HS3ST1 (ENSG00000002587), NDST1 (ENSG00000070614), HS3ST2 (ENSG00000122254), HS3ST3B1 (ENSG00000125430), NDST4 (ENSG00000138653), HS3ST3A1 (ENSG00000153976), HS3ST6 (ENSG00000162040), NDST3 (ENSG00000164100), NDST2 (ENSG00000166507), HS3ST4 (ENSG00000182601)

Protein

Protein identifiers

Heparan sulfate glucosamine 3-O-sulfotransferase 5 — Q8IZT8 (reviewed: Q8IZT8)

Alternative names: Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 5

All UniProt accessions (1): Q8IZT8

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 position 3 of glucosamine residues in heparan. Catalyzes the rate limiting step in the biosynthesis of heparan sulfate (HSact). This modification is a crucial step in the biosynthesis of anticoagulant heparan sulfate as it completes the structure of the antithrombin pentasaccharide binding site. Also generates GlcUA-GlcNS or IdoUA-GlcNS and IdoUA2S-GlcNH2. The substrate-specific O-sulfation generates an enzyme-modified heparan sulfate which acts as a binding receptor to Herpes simplex virus-1 (HSV-1) and permits its entry.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Highly expressed in skeletal muscle and fetal brain, and also found in adult brain, spinal cord, cerebellum and colon.

Similarity. Belongs to the sulfotransferase 1 family.

RefSeq proteins (10): NP_001373968, NP_001373969, NP_001373970, NP_001373971, NP_001373972, NP_001373973, NP_001373974, NP_001373975, NP_001373976, NP_705840* (*=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 2.8.2.23 — [heparan sulfate]-glucosamine 3-sulfotransferase 1 (BRENDA: 5 organisms, 26 substrates, 5 inhibitors, 3 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3’-PHOSPHOADENOSINE 5’-PHOSPHOSULFATE	0.01	1
GLCNSO3(6-OSO3)-GLCA-GLCNSO3(6-OSO3)-IDOA(2-OSO3	0.006	1

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 (46 total): helix 14, strand 9, binding site 8, mutagenesis site 6, topological domain 2, turn 2, chain 1, glycosylation site 1, disulfide bond 1, sequence variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3BD9	X-RAY DIFFRACTION	2.3
7SCE	X-RAY DIFFRACTION	2.75
7SCD	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZT8-F1	85.95	0.71

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 (8): 293; 309–313; 100–104; 122–128; 155–158; 183; 191; 226–227

Disulfide bonds (1): 294–304

Glycosylation sites (1): 287

Mutagenesis-validated functional residues (6):

Position	Phenotype
99	reduces enzyme activity by over 99%.
104	reduces enzyme activity by 93%,.
155	reduces enzyme activity by over 99%.
195	reduces enzyme activity by over 99%.
309	loss of enzyme activity.
311	reduces enzyme activity by 98%.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2022928	HS-GAG biosynthesis

MSigDB gene sets: 144 (showing top): GOBP_REGULATION_OF_COAGULATION, GOZGIT_ESR1_TARGETS_DN, MEF2_02, GOBP_SULFATION, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_COAGULATION, EVI1_05, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_REGULATION_OF_BIOLOGICAL_PROCESS_INVOLVED_IN_SYMBIOTIC_INTERACTION, BRN2_01, GOBP_HEPARAN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GATA6_01, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTERACTION_WITH_HOST, GOBP_VIRAL_LIFE_CYCLE

GO Biological Process (4): protein sulfation (GO:0006477), heparan sulfate proteoglycan biosynthetic process (GO:0015012), regulation of viral entry into host cell (GO:0046596), negative regulation of coagulation (GO:0050819)

GO Molecular Function (5): [heparan sulfate]-glucosamine 3-sulfotransferase activity (GO:0008467), 3’-phosphoadenosine 5’-phosphosulfate binding (GO:0050656), protein binding (GO:0005515), sulfotransferase activity (GO:0008146), 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
protein modification process	1
sulfation	1
proteoglycan biosynthetic process	1
heparan sulfate proteoglycan metabolic process	1
protein O-linked glycosylation via xylose	1
symbiont entry into host cell	1
modulation by symbiont of entry into host	1
regulation of viral life cycle	1
coagulation	1
regulation of coagulation	1
negative regulation of multicellular organismal process	1
heparan sulfate sulfotransferase activity	1
adenyl ribonucleotide binding	1
anion binding	1
sulfur compound binding	1
binding	1
transferase activity, transferring sulphur-containing groups	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

602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HS3ST5	ACKR1	Q16570	790
HS3ST5	HS2ST1	Q7LGA3	737
HS3ST5	HS6ST1	O60243	635
HS3ST5	HS6ST3	Q8IZP7	606
HS3ST5	GLCE	O94923	605
HS3ST5	K7EP71	K7EP71	563
HS3ST5	UST	Q9Y2C2	526
HS3ST5	EXT1	Q16394	522
HS3ST5	HS6ST2	Q96MM7	522
HS3ST5	EXTL3	O43909	503
HS3ST5	SULT1C3	Q6IMI6	486
HS3ST5	OR52E2	Q8NGJ4	470
HS3ST5	SULT1C4	O75897	457
HS3ST5	SULT1B1	O43704	456
HS3ST5	SLC9A6	Q92581	449

IntAct

0 interactions, top by confidence:

BioGRID (3): HS3ST5 (Affinity Capture-MS), HS3ST5 (Positive Genetic), HS3ST5 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RPR8, O14792, O35310, O43529, O54702, O93403, P09958, P23188, P83088, Q14BT6, Q16WU7, Q24157, Q29G54, Q3U435, Q5EA41, Q5F2N2, Q5RBZ6, Q5U3T0, Q5YB40, Q5ZIE4, Q6AXM1, Q6GNS1, Q6PGK7, Q6W3E9, Q6W3F0, Q70AG8, Q75UG4, Q7Q297, Q7T3S5, Q7Z4N8, Q805E5, Q80V53, Q8BGT9, Q8BSL4, Q8C7U7, Q8IXK2, Q8IZT8, Q8NCG5, Q8NCH0, Q8NCL4

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2277 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:114057371:C:A	K309N	1.000
6:114057371:C:G	K309N	1.000
6:114057387:C:G	C304S	1.000
6:114057388:A:G	C304R	1.000
6:114057388:A:T	C304S	1.000
6:114057416:G:C	C294W	1.000
6:114057417:C:G	C294S	1.000
6:114057417:C:T	C294Y	1.000
6:114057418:A:T	C294S	1.000
6:114057422:A:C	F292L	1.000
6:114057422:A:T	F292L	1.000
6:114057424:A:G	F292L	1.000
6:114057501:A:G	L266P	1.000
6:114057525:A:G	L258P	1.000
6:114057540:A:T	V253D	1.000
6:114057577:A:G	W241R	1.000
6:114057577:A:T	W241R	1.000
6:114057602:G:C	S232R	1.000
6:114057602:G:T	S232R	1.000
6:114057604:T:G	S232R	1.000
6:114057830:G:C	S156R	1.000
6:114057830:G:T	S156R	1.000
6:114057832:T:G	S156R	1.000
6:114057998:T:A	K100N	1.000
6:114057998:T:G	K100N	1.000
6:114057999:T:A	K100I	1.000
6:114058008:C:T	G97E	1.000
6:114058026:G:T	P91H	1.000
6:114057372:T:A	K309M	0.999
6:114057386:G:C	C304W	0.999

dbSNP variants (sampled 300 via entrez): RS1000001846 (6:114264416 C>G), RS1000013636 (6:114340025 G>T), RS1000020413 (6:114136322 A>G), RS1000051471 (6:114249539 T>C), RS1000057590 (6:114090001 G>A,C), RS1000065728 (6:114127588 T>A), RS1000066542 (6:114136489 A>G), RS1000068286 (6:114237032 A>G), RS1000090820 (6:114172979 T>C), RS1000091418 (6:114304669 C>T), RS1000102127 (6:114249233 A>T), RS1000120067 (6:114221103 C>G,T), RS1000124799 (6:114082915 G>T), RS1000160821 (6:114083195 C>A,G), RS1000166754 (6:114113060 C>G)

Disease associations

OMIM: gene MIM:609407 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002203_1	Gray matter volume (schizophrenia interaction)	7.000000e-07
GCST002783_52	Body mass index	7.000000e-06
GCST003075_11	Cognitive decline rate in late mild cognitive impairment	3.000000e-08
GCST003075_125	Cognitive decline rate in late mild cognitive impairment	9.000000e-08
GCST011494_34	Daytime nap	5.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005420	grey matter volume measurement
EFO:0004340	body mass index
EFO:0007710	cognitive decline measurement
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
entinostat	decreases expression, increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
OTX015	decreases expression	1
trichostatin A	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Copper	affects binding, decreases expression	1
Lipopolysaccharides	increases expression, affects cotreatment, decreases reaction	1
Quercetin	decreases expression	1
Tretinoin	increases expression	1
Urethane	decreases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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