NDST4

Summary

NDST4 (N-deacetylase and N-sulfotransferase 4, HGNC:20779) is a protein-coding gene on chromosome 4q26, encoding Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4 (Q9H3R1). Essential bifunctional enzyme that catalyzes both the N-deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in heparan sulfate.

Predicted to enable deacetylase activity and heparan sulfate N-sulfotransferase activity. Predicted to be involved in heparan sulfate proteoglycan biosynthetic process and heparin proteoglycan biosynthetic process. Predicted to be located in Golgi membrane. Predicted to be active in Golgi apparatus.

Source: NCBI Gene 64579 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 107 total
• MANE Select transcript: NM_022569

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20779
Approved symbol	NDST4
Name	N-deacetylase and N-sulfotransferase 4
Location	4q26
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000138653
Ensembl biotype	protein_coding
OMIM	615039
Entrez	64579

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000264363, ENST00000504854, ENST00000514570, ENST00000613194

RefSeq mRNA: 1 — MANE Select: NM_022569 NM_022569

CCDS: CCDS3706

Canonical transcript exons

ENST00000264363 — 14 exons

Exon	Start	End
ENSE00000841882	114935206	114935334
ENSE00001121074	114845823	114845997
ENSE00001766555	114827763	114827935
ENSE00002292490	115076059	115077282
ENSE00002472984	114870768	114870950
ENSE00002511295	114848215	114848338
ENSE00002516593	114852725	114852821
ENSE00003529843	114833606	114833715
ENSE00003541002	114839378	114839548
ENSE00003543817	114937318	114937503
ENSE00003591952	114977187	114977274
ENSE00003606736	114829790	114829892
ENSE00003667195	114970430	114970584
ENSE00003892435	115113444	115113620

Expression profiles

Bgee: expression breadth broad, 65 present calls, max score 87.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.1457 / max 148.8944, expressed in 176 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53710	0.6332	99
53711	0.5125	144

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	87.87	gold quality
pons	UBERON:0000988	82.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.38	gold quality
dorsal root ganglion	UBERON:0000044	63.15	gold quality
ganglionic eminence	UBERON:0004023	62.52	gold quality
hair follicle	UBERON:0002073	62.44	gold quality
buccal mucosa cell	CL:0002336	61.24	gold quality
ventricular zone	UBERON:0003053	59.61	gold quality
adrenal tissue	UBERON:0018303	58.69	gold quality
trigeminal ganglion	UBERON:0001675	56.94	silver quality
decidua	UBERON:0002450	56.55	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	56.06	gold quality
vena cava	UBERON:0004087	55.53	gold quality
upper leg skin	UBERON:0004262	55.41	gold quality
smooth muscle tissue	UBERON:0001135	53.72	gold quality
nasal cavity epithelium	UBERON:0005384	51.54	gold quality
sperm	CL:0000019	49.85	gold quality
prefrontal cortex	UBERON:0000451	48.94	gold quality
superior vestibular nucleus	UBERON:0007227	47.88	silver quality
lateral nuclear group of thalamus	UBERON:0002736	47.41	gold quality
substantia nigra pars compacta	UBERON:0001965	47.07	silver quality
corpus callosum	UBERON:0002336	46.71	silver quality
pigmented layer of retina	UBERON:0001782	46.52	silver quality
substantia nigra pars reticulata	UBERON:0001966	45.95	gold quality
gall bladder	UBERON:0002110	45.83	silver quality
deltoid	UBERON:0001476	45.62	gold quality
medulla oblongata	UBERON:0001896	45.53	silver quality
lateral globus pallidus	UBERON:0002476	45.37	gold quality
ventral tegmental area	UBERON:0002691	45.03	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.74

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 4)

• Our results suggest that genetic variants in TYW3/CRYZ and NDST4 loci may be involved in the regulation of circulating resistin levels (PMID:22843503)
• NDST4 gene is a novel candidate tumor suppressor gene in human cancer. (PMID:23825612)
• The rs12108602 near NDST4 showed significant associations with MaxDrinks. (PMID:23953852)
• Highly-purified recombinant NDST-4 and a selective library of structurally-defined oligosaccharides were employed to determine the substrate specificity of rNDST-4. Full-length rNDST-4 lacks obvious N-deacetylase activity, and displays only N-sulfotransferase activity. NDST-4 did not show directional N-sulfotransferase activity while the N-deacetylase domain was inactive. (PMID:29158133)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndst3	ENSDARG00000041776
mus_musculus	Ndst4	ENSMUSG00000027971
rattus_norvegicus	Ndst4	ENSRNOG00000009577

Paralogs (10): HS3ST1 (ENSG00000002587), NDST1 (ENSG00000070614), HS3ST2 (ENSG00000122254), HS3ST3B1 (ENSG00000125430), HS3ST3A1 (ENSG00000153976), HS3ST6 (ENSG00000162040), NDST3 (ENSG00000164100), NDST2 (ENSG00000166507), HS3ST4 (ENSG00000182601), HS3ST5 (ENSG00000249853)

Protein

Protein identifiers

Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4 — Q9H3R1 (reviewed: Q9H3R1)

Alternative names: Glucosaminyl N-deacetylase/N-sulfotransferase 4, N-heparan sulfate sulfotransferase 4

All UniProt accessions (1): Q9H3R1

UniProt curated annotations — full annotation on UniProt →

Function. Essential bifunctional enzyme that catalyzes both the N-deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in heparan sulfate. Modifies the GlcNAc-GlcA disaccharide repeating sugar backbone to make N-sulfated heparosan, a prerequisite substrate for later modifications in heparin biosynthesis. Has low deacetylase activity but high sulfotransferase activity.

Subunit / interactions. Monomer.

Subcellular location. Golgi apparatus membrane.

Pathway. Glycan metabolism; heparan sulfate biosynthesis. Glycan metabolism; heparin biosynthesis.

Miscellaneous. The presence of 4 different heparan sulfate N-deacetylase/N-sulfotransferase enzymes in mammals, as well as differences in their enzyme activity suggest that some initiate heparan sulfate modification/sulfation reactions, whereas other later on fill in or extend already modified heparan sulfate sequences.

Similarity. Belongs to the sulfotransferase 1 family. NDST subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H3R1-1	1	yes
Q9H3R1-2	2

RefSeq proteins (1): NP_072091* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000863	Sulfotransferase_dom	Domain
IPR021930	Heparan_SO4_deacetylase_dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR037359	NST/OST	Family
IPR056793	HSNSD_N	Domain

Pfam: PF00685, PF12062, PF25119

Enzyme classification (BRENDA):

• EC 2.8.2.8 — [heparan sulfate]-glucosamine N-sulfotransferase (BRENDA: 11 organisms, 86 substrates, 14 inhibitors, 13 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3’-PHOSPHOADENYLYLSULFATE	0.005–0.108	6
N-DEACETYLASE K5-POLYSACCHARIDE	0.0009–0.0224	3
N,O-DESULFOHEPARAN SULFATE TETRASACCHARIDE	2.5	1
N-DESULFOHEPARAN SULFATE	1.89	1
N-DESULFOHEPARIN	0.013	1

Catalyzed reactions (Rhea), 1 shown:

• alpha-D-glucosaminyl-heparan sulfate + 3’-phosphoadenylyl sulfate = N-sulfo-alpha-D-glucosaminyl-heparan sulfate + adenosine 3’,5’-bisphosphate + 2 H(+) (RHEA:21980)

UniProt features (20 total): glycosylation site 5, splice variant 3, binding site 3, topological domain 2, region of interest 2, chain 1, disulfide bond 1, sequence variant 1, transmembrane region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3R1-F1	91.22	0.82

Functional residue map

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

Catalytic / active sites (1): 604 (for sulfotransferase activity)

Ligand- & substrate-binding residues (3): 604–608; 702; 823–827

Disulfide bonds (1): 808–818

Glycosylation sites (5): 226, 341, 391, 657, 793

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2022928	HS-GAG biosynthesis
R-HSA-1430728	Metabolism
R-HSA-1630316	Glycosaminoglycan metabolism
R-HSA-1638091	Heparan sulfate/heparin (HS-GAG) metabolism
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives

MSigDB gene sets: 100 (showing top): GCANCTGNY_MYOD_Q6, FOXO4_01, CHX10_01, AAAYRNCTG_UNKNOWN, CAGCTG_AP4_Q5, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, YGACNNYACAR_UNKNOWN, GOBP_HEPARAN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, HEN1_01, WTGAAAT_UNKNOWN, TCF11_01, OCT1_06, TGANTCA_AP1_C, TGACATY_UNKNOWN

GO Biological Process (2): heparan sulfate proteoglycan biosynthetic process (GO:0015012), heparin proteoglycan biosynthetic process (GO:0030210)

GO Molecular Function (7): heparan sulfate N-sulfotransferase activity (GO:0015016), deacetylase activity (GO:0019213), N-acetylglucosamine deacetylase activity (GO:0050119), catalytic activity (GO:0003824), sulfotransferase activity (GO:0008146), transferase activity (GO:0016740), hydrolase activity (GO:0016787)

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

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Heparan sulfate/heparin (HS-GAG) metabolism	1
Metabolism of carbohydrates and carbohydrate derivatives	1
Glycosaminoglycan metabolism	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein O-linked glycosylation via xylose	2
catalytic activity	2
proteoglycan biosynthetic process	1
heparan sulfate proteoglycan metabolic process	1
heparin proteoglycan metabolic process	1
heparan sulfate sulfotransferase activity	1
deacylase activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
deacetylase activity	1
molecular_function	1
transferase activity, transferring sulphur-containing groups	1
Golgi apparatus	1
bounding membrane of organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

574 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDST4	HS2ST1	Q7LGA3	661
NDST4	GLCE	O94923	649
NDST4	HS6ST3	Q8IZP7	628
NDST4	HS6ST1	O60243	575
NDST4	EXTL3	O43909	565
NDST4	EXT1	Q16394	558
NDST4	EXT2	Q93063	557
NDST4	EXTL2	Q9UBQ6	542
NDST4	EXTL1	Q92935	540
NDST4	CNTNAP2	Q9UHC6	537
NDST4	ZNF385D	Q9H6B1	523
NDST4	HS6ST2	Q96MM7	518
NDST4	ATP2C2	O75185	509
NDST4	SST	P01166	508
NDST4	CHST12	Q9NRB3	497

IntAct

4 interactions, top by confidence:

A	B	Type	Score
NDST4	NPM1	psi-mi:“MI:0915”(physical association)	0.400
NDST3	PYGB	psi-mi:“MI:0914”(association)	0.350
NDST4	IGF2R	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): NDST4 (Proximity Label-MS), NDST4 (Affinity Capture-MS), FAM3C (Affinity Capture-MS), IGF2R (Affinity Capture-MS), NDST1 (Affinity Capture-MS), GNPTAB (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PUP4, A2AFS3, M0R7X9, O70472, O75882, O95803, P01134, P26012, P52799, P52848, P69849, Q02353, Q05204, Q0VCJ8, Q12841, Q13635, Q15155, Q3UHN9, Q3ZBS2, Q58D84, Q5EA46, Q5JPE7, Q5R9Y1, Q5U4X8, Q5VV63, Q5ZJB7, Q5ZMH6, Q61115, Q62356, Q62632, Q6A051, Q6GQK9, Q6GQT9, Q6P988, Q6UXG2, Q7Z5A7, Q86TD4, Q90693, Q91WE9, Q96CW9

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	98
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3355 predictions. Top by Δscore:

Variant	Effect	Δscore
4:114827931:CTAGA:C	acceptor_gain	1.0000
4:114827936:C:CC	acceptor_gain	1.0000
4:114829784:TATTA:T	donor_loss	1.0000
4:114829786:TTA:T	donor_loss	1.0000
4:114829787:TACCT:T	donor_loss	1.0000
4:114829788:A:AC	donor_gain	1.0000
4:114829789:C:CC	donor_gain	1.0000
4:114829789:CCT:C	donor_gain	1.0000
4:114829888:CAAAC:C	acceptor_gain	1.0000
4:114829890:AAC:A	acceptor_gain	1.0000
4:114829893:C:CA	acceptor_loss	1.0000
4:114829893:C:CC	acceptor_gain	1.0000
4:114833604:A:AC	donor_gain	1.0000
4:114833605:C:CC	donor_gain	1.0000
4:114845993:TATAC:T	acceptor_gain	1.0000
4:114845995:TAC:T	acceptor_gain	1.0000
4:114845995:TACC:T	acceptor_loss	1.0000
4:114845996:ACCT:A	acceptor_loss	1.0000
4:114845997:CCTGA:C	acceptor_loss	1.0000
4:114845998:C:CA	acceptor_loss	1.0000
4:114848209:TCTTA:T	donor_loss	1.0000
4:114848210:CTTA:C	donor_loss	1.0000
4:114848211:TTACC:T	donor_loss	1.0000
4:114848212:TACC:T	donor_loss	1.0000
4:114848213:A:AC	donor_gain	1.0000
4:114848213:A:C	donor_loss	1.0000
4:114848214:C:CA	donor_loss	1.0000
4:114848214:C:CC	donor_gain	1.0000
4:114848214:CCAGT:C	donor_gain	1.0000
4:114848260:T:TA	donor_gain	1.0000

AlphaMissense

5737 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:114829820:T:A	K823N	1.000
4:114829820:T:G	K823N	1.000
4:114870921:G:C	N522K	1.000
4:114870921:G:T	N522K	1.000
4:114935305:G:C	F479L	1.000
4:114935305:G:T	F479L	1.000
4:114935307:A:G	F479L	1.000
4:114937384:G:C	S447R	1.000
4:114937384:G:T	S447R	1.000
4:114937386:T:G	S447R	1.000
4:114970502:G:C	H383Q	1.000
4:114970502:G:T	H383Q	1.000
4:114827848:A:G	W863R	0.999
4:114827848:A:T	W863R	0.999
4:114829821:T:A	K823I	0.999
4:114829836:C:G	C818S	0.999
4:114829837:A:T	C818S	0.999
4:114829871:A:C	F806L	0.999
4:114829871:A:T	F806L	0.999
4:114829873:A:G	F806L	0.999
4:114839404:A:G	W754R	0.999
4:114839404:A:T	W754R	0.999
4:114839443:A:G	C741R	0.999
4:114845828:A:C	Y704D	0.999
4:114845831:A:G	W703R	0.999
4:114845831:A:T	W703R	0.999
4:114845841:C:A	R699S	0.999
4:114845841:C:G	R699S	0.999
4:114848338:C:T	G606E	0.999
4:114852729:T:A	K604N	0.999

dbSNP variants (sampled 300 via entrez): RS1000008111 (4:114949081 A>C,G), RS1000008948 (4:114895752 C>T), RS1000026403 (4:114943090 A>G), RS1000042666 (4:115022989 G>A,C), RS1000047967 (4:115018350 T>C), RS1000051722 (4:115068688 G>C), RS1000052190 (4:114865758 C>A,T), RS1000060137 (4:114858617 G>A), RS1000063694 (4:114961306 G>GT), RS1000068863 (4:115105992 A>G), RS1000069203 (4:114943462 A>C,G), RS1000081599 (4:115095866 C>A,T), RS1000081984 (4:115099797 C>A), RS1000085455 (4:114937273 T>C), RS10000924 (4:114848341 G>A,T)

Disease associations

OMIM: gene MIM:615039 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001620_3	Resistin levels	6.000000e-18
GCST002104_19	Bronchopulmonary dysplasia	1.000000e-06
GCST009215_2	Postcentral gyrus volume	3.000000e-06
GCST010796_3506	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_3507	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST011741_30	LDL cholesterol levels in HIV infection	6.000000e-07
GCST90000015_14	Parkinson’s disease motor subtype (tremor to postural instability/gait difficulty score ratio)	6.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004819	resistin measurement
EFO:0004327	electrocardiography
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0600011	Parkinson’s disease symptom measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
Phenylmercuric Acetate	affects cotreatment, increases expression	2
bisphenol A	affects cotreatment, decreases methylation	1
trichostatin A	increases expression	1
sodium arsenite	increases expression	1
mercuric bromide	affects cotreatment, increases expression	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
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	increases expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Diethylhexyl Phthalate	decreases expression	1
Silicon Dioxide	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Paclitaxel	increases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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