HINT3

Summary

HINT3 (histidine triad nucleotide binding protein 3, HGNC:18468) is a protein-coding gene on chromosome 6q22.32, encoding Adenosine 5’-monophosphoramidase HINT3 (Q9NQE9). Exhibits adenosine 5’-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5’monophosphoramidate (AMP-NH2) to yield AMP and NH2.

Histidine triad proteins, such as HINT3, are nucleotide hydrolases and transferases that act on the alpha-phosphate of ribonucleotides (Brenner, 2002 [PubMed 12119013]).

Source: NCBI Gene 135114 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 30 total — 1 pathogenic
• MANE Select transcript: NM_138571

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18468
Approved symbol	HINT3
Name	histidine triad nucleotide binding protein 3
Location	6q22.32
Locus type	gene with protein product
Status	Approved
Aliases	FLJ33126, HINT4
Ensembl gene	ENSG00000111911
Ensembl biotype	protein_coding
OMIM	609998
Entrez	135114

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000229633, ENST00000855676

RefSeq mRNA: 1 — MANE Select: NM_138571 NM_138571

CCDS: CCDS5133

Canonical transcript exons

ENST00000229633 — 5 exons

Exon	Start	End
ENSE00000762993	125972259	125972328
ENSE00000762994	125966887	125967004
ENSE00000798578	125974847	125974973
ENSE00001179627	125956770	125957178
ENSE00001446938	125977644	125980244

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.6926 / max 337.6123, expressed in 1806 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69689	19.8733	1805
69690	0.8193	522

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.07	gold quality
pons	UBERON:0000988	97.47	gold quality
vastus lateralis	UBERON:0001379	95.92	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.37	gold quality
biceps brachii	UBERON:0001507	95.30	gold quality
gastrocnemius	UBERON:0001388	95.11	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.97	gold quality
palpebral conjunctiva	UBERON:0001812	94.95	gold quality
spinal cord	UBERON:0002240	94.90	gold quality
muscle of leg	UBERON:0001383	94.76	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.54	gold quality
skeletal muscle organ	UBERON:0014892	94.50	gold quality
quadriceps femoris	UBERON:0001377	94.43	gold quality
parietal pleura	UBERON:0002400	94.22	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.57	gold quality
visceral pleura	UBERON:0002401	93.50	gold quality
tongue	UBERON:0001723	93.32	gold quality
esophagus squamous epithelium	UBERON:0006920	93.07	gold quality
cortical plate	UBERON:0005343	92.95	gold quality
body of tongue	UBERON:0011876	92.85	gold quality
amygdala	UBERON:0001876	92.70	gold quality
superior surface of tongue	UBERON:0007371	92.28	gold quality
deltoid	UBERON:0001476	92.23	gold quality
skeletal muscle tissue	UBERON:0001134	92.06	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.02	gold quality
hypothalamus	UBERON:0001898	91.75	gold quality
anterior cingulate cortex	UBERON:0009835	91.68	gold quality
embryo	UBERON:0000922	91.55	gold quality
ganglionic eminence	UBERON:0004023	91.55	gold quality
ventricular zone	UBERON:0003053	91.42	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

114 targeting HINT3, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489

Literature-anchored findings (GeneRIF, showing 2)

• Results show that significant differences in phosphoramidase activity, oligomeric state, and cellular localization suggest that Hint3s should be placed in a distinct branch of the histidine triad superfamily. (PMID:17870088)
• HINT3 suppresses AKT/mTOR signaling pathway activity during breast cancer tumorigenesis through PTEN transcriptional activation. (PMID:37203409)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	hint3	ENSDARG00000074286
mus_musculus	Hint3	ENSMUSG00000019791
rattus_norvegicus	Hint3	ENSRNOG00000014190
drosophila_melanogaster	CG15362	FBGN0031378
drosophila_melanogaster	CG34015	FBGN0054015
caenorhabditis_elegans		WBGENE00016150

Paralogs (1): APTX (ENSG00000137074)

Protein

Protein identifiers

Adenosine 5’-monophosphoramidase HINT3 — Q9NQE9 (reviewed: Q9NQE9)

Alternative names: Histidine triad nucleotide-binding protein 3

All UniProt accessions (1): Q9NQE9

UniProt curated annotations — full annotation on UniProt →

Function. Exhibits adenosine 5’-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5’monophosphoramidate (AMP-NH2) to yield AMP and NH2. Hydrolyzes lysyl-AMP (AMP-N-epsilon-(N-alpha-acetyl lysine methyl ester)) generated by lysine tRNA ligase. Hydrolyzes 3-indolepropionic acyl-adenylate and fluorogenic purine nucleoside tryptamine phosphoramidates in vitro.

Subunit / interactions. Forms dimers to octamers and even larger oligomer. Interacts with CALM1.

Subcellular location. Cytoplasm. Nucleus.

Similarity. Belongs to the HINT family.

RefSeq proteins (1): NP_612638* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011146	HIT-like	Domain
IPR036265	HIT-like_sf	Homologous_superfamily

Pfam: PF11969

Catalyzed reactions (Rhea), 1 shown:

• adenosine 5’-phosphoramidate + H2O = NH4(+) + AMP (RHEA:67916)

UniProt features (12 total): binding site 2, initiator methionine 1, chain 1, sequence variant 1, mutagenesis site 1, domain 1, region of interest 1, short sequence motif 1, compositionally biased region 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQE9-F1	86.44	0.76

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): 145 (tele-amp-histidine intermediate)

Ligand- & substrate-binding residues (2): 76–77; 145–147

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (1):

Position	Phenotype
145	abolishes adenosine 5’-monophosphoramidase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 108 (showing top): TERAMOTO_OPN_TARGETS_CLUSTER_4, GARCIA_TARGETS_OF_FLI1_AND_DAX1_DN, BASAKI_YBX1_TARGETS_DN, FISCHER_DREAM_TARGETS, SENESE_HDAC3_TARGETS_DN, MODULE_69, GEORGES_TARGETS_OF_MIR192_AND_MIR215, chr6q22, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_CARBON_NITROGEN_BUT_NOT_PEPTIDE_BONDS_IN_LINEAR_AMIDES, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_CARBON_NITROGEN_BUT_NOT_PEPTIDE_BONDS, WHITFIELD_CELL_CYCLE_G2, JOHNSTONE_PARVB_TARGETS_3_UP, BRUINS_UVC_RESPONSE_LATE, WAKABAYASHI_ADIPOGENESIS_PPARG_BOUND_8D, WAMUNYOKOLI_OVARIAN_CANCER_GRADES_1_2_UP

GO Biological Process (0):

GO Molecular Function (5): nucleotide binding (GO:0000166), identical protein binding (GO:0042802), adenosine 5’-monophosphoramidase activity (GO:0043530), catalytic activity (GO:0003824), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
nucleoside phosphate binding	1
heterocyclic compound binding	1
protein binding	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
molecular_function	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

759 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HINT3	HINT2	Q9BX68	658
HINT3	HINT1	P49773	612
HINT3	GALT	P07902	531
HINT3	KARS1	Q15046	520
HINT3	SUCLG1	P53597	515
HINT3	ACBD5	Q5T8D3	483
HINT3	ASCC3	Q8N3C0	452
HINT3	MTG2	Q9H4K7	410
HINT3	ZWINT	O95229	373
HINT3	FAM20C	Q8IXL6	352
HINT3	MSL1	Q68DK7	343
HINT3	DCPS	Q96C86	333
HINT3	CYP26B1	Q9NR63	293
HINT3	COL8A2	P25067	293
HINT3	APTX	Q7Z2E3	290

IntAct

24 interactions, top by confidence:

A	B	Type	Score
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
PEX19	FAM20B	psi-mi:“MI:0914”(association)	0.530
FBXO15	CPA6	psi-mi:“MI:0914”(association)	0.530
PEX19	MYO1D	psi-mi:“MI:0914”(association)	0.530
FBXO15	HSPD1	psi-mi:“MI:0914”(association)	0.350
NMES1	NDUFS8	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
PTPMT1	TIMM44	psi-mi:“MI:0914”(association)	0.350
COQ9	ACOT7	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
CALML3	MYO1C	psi-mi:“MI:0914”(association)	0.350
HINT3	DHRS3	psi-mi:“MI:0914”(association)	0.350
NIP7	RPLP0	psi-mi:“MI:0914”(association)	0.350
HINT3	HRAS	psi-mi:“MI:0914”(association)	0.350
CALM1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
VCP	FAM171A2	psi-mi:“MI:0914”(association)	0.350
FCGR3B	FCGR3A	psi-mi:“MI:0914”(association)	0.350
HINT3	NUCB2	psi-mi:“MI:0914”(association)	0.350

BioGRID (34): HINT3 (Affinity Capture-MS), HINT3 (Affinity Capture-MS), HINT3 (Synthetic Growth Defect), HINT3 (Reconstituted Complex), HINT3 (Affinity Capture-MS), HINT3 (Affinity Capture-MS), HINT3 (Affinity Capture-MS), HINT3 (Affinity Capture-MS), HINT3 (Affinity Capture-MS), DHRS3 (Affinity Capture-MS), GCC2 (Affinity Capture-MS), FBXO7 (Affinity Capture-MS), NUCB1 (Affinity Capture-MS), HINT3 (Affinity Capture-MS), HINT3 (Affinity Capture-MS)

ESM2 similar proteins: D3ZV31, E1BGQ2, O35465, P0C0T1, P0CL18, P41214, P50747, P61797, P61798, P61799, P61800, P61801, Q13572, Q14CH1, Q2TBA3, Q3B7U9, Q496Y0, Q497B8, Q58CR3, Q5R9L4, Q5RA63, Q69ZK0, Q6GR37, Q6NYU2, Q6PFY8, Q7T287, Q7TQC5, Q7YRZ1, Q7YRZ2, Q7Z2E3, Q7Z6J4, Q8BKW4, Q8BNV1, Q8BYN3, Q8HXH0, Q8K2I9, Q8K4H4, Q8N371, Q8NFZ0, Q8TCU6

Diamond homologs: C4LYI2, F4K1R2, O07513, O07817, O66536, O84390, O94586, P0A5B6, P0ACE7, P0ACE8, P0ACE9, P26724, P32083, P32084, P42855, P42856, P44956, P47378, P49773, P49774, P53795, P57438, P62958, P62959, P64382, P64383, P70349, P73481, P75504, P80912, P94252, P95937, P9WML0, P9WML1, P9WML2, P9WML3, Q04344, Q23921, Q2YDJ4, Q58276

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	1
Likely pathogenic	0
Uncertain significance	26
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
442817	GRCh37/hg19 6q22.31-23.2(chr6:122612641-131564463)x1	Pathogenic

SpliceAI

827 predictions. Top by Δscore:

Variant	Effect	Δscore
6:125966883:TTA:T	acceptor_loss	1.0000
6:125966884:TA:T	acceptor_loss	1.0000
6:125966885:A:AG	acceptor_gain	1.0000
6:125966885:AG:A	acceptor_loss	1.0000
6:125966886:G:GT	acceptor_gain	1.0000
6:125966886:GA:G	acceptor_gain	1.0000
6:125966886:GAA:G	acceptor_gain	1.0000
6:125966886:GAAT:G	acceptor_gain	1.0000
6:125966986:A:T	donor_gain	1.0000
6:125967003:GG:G	donor_gain	1.0000
6:125967004:GG:G	donor_gain	1.0000
6:125967005:G:GG	donor_gain	1.0000
6:125967005:GTA:G	donor_loss	1.0000
6:125967006:T:G	donor_loss	1.0000
6:125972253:TTACA:T	acceptor_loss	1.0000
6:125972254:TACA:T	acceptor_loss	1.0000
6:125972255:ACAG:A	acceptor_loss	1.0000
6:125972256:CAGTT:C	acceptor_loss	1.0000
6:125972257:A:AC	acceptor_loss	1.0000
6:125972257:A:AG	acceptor_gain	1.0000
6:125972257:AGTT:A	acceptor_gain	1.0000
6:125972258:G:GT	acceptor_gain	1.0000
6:125972258:GT:G	acceptor_gain	1.0000
6:125972258:GTT:G	acceptor_gain	1.0000
6:125972258:GTTG:G	acceptor_gain	1.0000
6:125972258:GTTGA:G	acceptor_gain	1.0000
6:125974974:G:GG	donor_gain	1.0000
6:125966039:G:T	donor_gain	0.9900
6:125966884:TAGAA:T	acceptor_gain	0.9900
6:125966885:AGAAT:A	acceptor_gain	0.9900

AlphaMissense

1198 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:125974854:T:C	F133L	0.999
6:125974855:T:C	F133S	0.999
6:125974856:T:A	F133L	0.999
6:125974856:T:G	F133L	0.999
6:125974965:T:C	F170L	0.999
6:125974967:T:A	F170L	0.999
6:125974967:T:G	F170L	0.999
6:125957125:T:C	F50L	0.998
6:125957127:C:A	F50L	0.998
6:125957127:C:G	F50L	0.998
6:125974857:C:G	H134D	0.998
6:125974898:T:A	H147Q	0.998
6:125974898:T:G	H147Q	0.998
6:125974900:T:A	V148D	0.998
6:125966906:T:C	F74S	0.997
6:125966935:C:G	H84D	0.997
6:125966942:T:C	L86P	0.997
6:125972259:T:A	V107D	0.997
6:125974886:C:A	H143Q	0.997
6:125974886:C:G	H143Q	0.997
6:125974890:C:G	H145D	0.997
6:125974894:T:C	L146P	0.997
6:125974896:C:A	H147N	0.997
6:125974896:C:G	H147D	0.997
6:125974966:T:C	F170S	0.997
6:125966902:T:C	C73R	0.996
6:125966913:T:A	D76E	0.996
6:125966913:T:G	D76E	0.996
6:125966937:T:A	H84Q	0.996
6:125966937:T:G	H84Q	0.996

dbSNP variants (sampled 300 via entrez): RS1000001503 (6:125955576 A>T), RS1000058867 (6:125976534 G>T), RS1000080182 (6:125957704 C>T), RS1000094350 (6:125978367 A>G), RS1000305483 (6:125964759 C>G), RS1000404650 (6:125958313 G>C), RS1000469756 (6:125964798 C>T), RS1000544452 (6:125978625 G>A), RS1000871319 (6:125970166 G>A), RS1000899403 (6:125963158 A>T), RS1000905821 (6:125964405 C>T), RS1000921937 (6:125970676 C>T), RS1000923357 (6:125972615 G>T), RS1001152614 (6:125976970 C>T), RS1001198126 (6:125958745 A>G)

Disease associations

OMIM: gene MIM:609998 | 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
GCST006661_299	Male-pattern baldness	6.000000e-10
GCST90020025_1086	Waist-to-hip ratio adjusted for BMI	2.000000e-13
GCST90020026_130	Hip index	3.000000e-08
GCST90020026_139	Hip index	6.000000e-11
GCST90020027_1112	Waist-hip index	2.000000e-14

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	3
bisphenol A	affects expression, decreases expression	2
trichostatin A	decreases expression, affects cotreatment	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	increases expression	1
kojic acid	increases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
zinc chromate	increases abundance, increases expression	1
nickel sulfate	increases expression	1
cupric oxide	increases expression	1
resorcinol	decreases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
corosolic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Clorgyline	increases expression	1

Clinical trials (associated diseases)

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