HINT2

Summary

HINT2 (histidine triad nucleotide binding protein 2, HGNC:18344) is a protein-coding gene on chromosome 9p13.3, encoding Adenosine 5’-monophosphoramidase HINT2 (Q9BX68). 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 HINT2, are nucleotide hydrolases and transferases that act on the alpha-phosphate of ribonucleotides (Brenner, 2002 [PubMed 12119013]).

Source: NCBI Gene 84681 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 30 total
• Druggable target: yes
• MANE Select transcript: NM_032593

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18344
Approved symbol	HINT2
Name	histidine triad nucleotide binding protein 2
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000137133
Ensembl biotype	protein_coding
OMIM	609997
Entrez	84681

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding_CDS_not_defined, 5 protein_coding

ENST00000259667, ENST00000461169, ENST00000471774, ENST00000472085, ENST00000474848, ENST00000474908, ENST00000490578, ENST00000851670, ENST00000851671, ENST00000932425, ENST00000932426

RefSeq mRNA: 1 — MANE Select: NM_032593 NM_032593

CCDS: CCDS6594

Canonical transcript exons

ENST00000259667 — 5 exons

Exon	Start	End
ENSE00003496786	35812960	35813145
ENSE00003507709	35814899	35815042
ENSE00003618857	35813644	35813784
ENSE00003641004	35813445	35813549
ENSE00003682023	35813266	35813338

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 97.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.8619 / max 259.4899, expressed in 1817 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100665	18.8169	1808
100663	5.2559	1687
100664	2.7891	1487

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.78	gold quality
right lobe of liver	UBERON:0001114	97.51	gold quality
liver	UBERON:0002107	96.95	gold quality
right adrenal gland	UBERON:0001233	96.78	gold quality
right adrenal gland cortex	UBERON:0035827	96.69	gold quality
left adrenal gland cortex	UBERON:0035825	96.48	gold quality
left adrenal gland	UBERON:0001234	96.45	gold quality
adult mammalian kidney	UBERON:0000082	96.43	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.36	gold quality
heart left ventricle	UBERON:0002084	96.14	gold quality
mucosa of transverse colon	UBERON:0004991	96.07	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.93	gold quality
metanephros cortex	UBERON:0010533	95.83	gold quality
adrenal gland	UBERON:0002369	95.31	gold quality
cortex of kidney	UBERON:0001225	95.26	gold quality
heart	UBERON:0000948	95.07	gold quality
kidney	UBERON:0002113	94.94	gold quality
right atrium auricular region	UBERON:0006631	94.91	gold quality
body of pancreas	UBERON:0001150	94.83	gold quality
body of stomach	UBERON:0001161	94.83	gold quality
substantia nigra	UBERON:0002038	94.63	gold quality
putamen	UBERON:0001874	94.46	gold quality
amygdala	UBERON:0001876	94.46	gold quality
temporal lobe	UBERON:0001871	94.40	gold quality
skeletal muscle tissue	UBERON:0001134	94.33	gold quality
hypothalamus	UBERON:0001898	94.21	gold quality
right uterine tube	UBERON:0001302	94.07	gold quality
pancreas	UBERON:0001264	94.06	gold quality
fundus of stomach	UBERON:0001160	93.96	gold quality
nucleus accumbens	UBERON:0001882	93.92	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.72
E-CURD-135	no	279.06

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 10)

• Hint2 is required for an optimal steroidogenic response, possibly because of a particular signalling function exerted within the mitochondria. (PMID:18653718)
• X-ray crystal structure of human HINT2 with and without bound AMP. (PMID:23659632)
• Low HINT2 expression is associated with low response to therapy in endometrial cancer. (PMID:23682076)
• HINT2 downregulation depended on hypoxia inducible factor (HIF)-2alpha-mediated transcriptional activation of zinc finger E-box-binding homeobox 1 (ZEB1). These results suggest that HINT2 downregulation promotes HIF-2alpha expression, which induces EMT and enhances CRC cell migration and invasion. (PMID:28088787)
• Authors deduced that HINT2 triggers apoptosis in pancreatic cancer cells by regulating mitochondrial Ca(2+) influx through the mitochondrial calcium uniporter (MCU). Authors found that HINT2 can sensitize BxPC-3 and L3.6pl cells to gemcitabine-induced apoptosis and that gemcitabine up-regulates HINT2 expression. (PMID:28947137)
• Decreased electron transfer and oxidative phosphorylation capacity in the absence of HINT-2. (PMID:29913563)
• Multivariate analyses revealed that tumor size and HINT2 expression are risk factors for Hepatocellular carcinoma recurrence. HINT2 is down-regulated in Hepatocellular carcinoma, and low HINT2 expression predicts earlier tumor recurrence. HINT2 expression may serve as a prognostic indicator of recurrence in Hepatocellular carcinoma. (PMID:31770197)
• Histidine triad nucleotide-binding proteins HINT1 and HINT2 share similar substrate specificities and little affinity for the signaling dinucleotide Ap4A. (PMID:31990367)
• Biochemical, crystallographic and biophysical characterization of histidine triad nucleotide-binding protein 2 with different ligands including a non-hydrolyzable analog of Ap4A. (PMID:34329705)
• Histidine triad nucleotide-binding protein 2: From basic science to clinical implications. (PMID:37004779)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hint2	ENSDARG00000100938
mus_musculus	Hint2	ENSMUSG00000028470
rattus_norvegicus	Hint2	ENSRNOG00000015866
drosophila_melanogaster	HINT1	FBGN0031459

Paralogs (2): HINT1 (ENSG00000169567), FHIT (ENSG00000189283)

Protein

Protein identifiers

Adenosine 5’-monophosphoramidase HINT2 — Q9BX68 (reviewed: Q9BX68)

Alternative names: HINT-3, HIT-17kDa, Histidine triad nucleotide-binding protein 2, mitochondrial, PKCI-1-related HIT protein

All UniProt accessions (1): Q9BX68

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 adenosine 5’-O-p-nitrophenylphosphoramidate (AMP-pNA). Hydrolyzes fluorogenic purine nucleoside tryptamine phosphoramidates in vitro. May be involved in steroid biosynthesis. May play a role in apoptosis.

Subcellular location. Mitochondrion.

Tissue specificity. High expression in liver and pancreas. Expression is significantly down-regulated in hepatocellular carcinoma (HCC) patients.

Similarity. Belongs to the HINT family.

RefSeq proteins (1): NP_115982* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001310	Histidine_triad_HIT	Family
IPR011146	HIT-like	Domain
IPR019808	Histidine_triad_CS	Conserved_site
IPR036265	HIT-like_sf	Homologous_superfamily

Pfam: PF01230

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (25 total): strand 6, helix 5, binding site 5, modified residue 2, transit peptide 1, chain 1, mutagenesis site 1, domain 1, turn 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
4INC	X-RAY DIFFRACTION	1.19
6YPR	X-RAY DIFFRACTION	1.26
6YQD	X-RAY DIFFRACTION	1.41
5KM9	X-RAY DIFFRACTION	1.45
4INI	X-RAY DIFFRACTION	1.65
6YI0	X-RAY DIFFRACTION	1.65
5KM8	X-RAY DIFFRACTION	2
5KM5	X-RAY DIFFRACTION	2.1
6YPX	X-RAY DIFFRACTION	2.11
6YVP	X-RAY DIFFRACTION	2.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BX68-F1	85.80	0.73

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): 149 (tele-amp-histidine intermediate)

Ligand- & substrate-binding residues (5): 63; 80; 136; 142–145; 149–151

Post-translational modifications (2): 119, 139

Mutagenesis-validated functional residues (1):

Position	Phenotype
149	loss of adenosine phosphoramidase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9013405	RHOD GTPase cycle

MSigDB gene sets: 0 (showing top):

GO Biological Process (4): steroid biosynthetic process (GO:0006694), apoptotic process (GO:0006915), lipid catabolic process (GO:0016042), lipid metabolic process (GO:0006629)

GO Molecular Function (5): nucleotide binding (GO:0000166), hydrolase activity (GO:0016787), adenosine 5’-monophosphoramidase activity (GO:0043530), catalytic activity (GO:0003824), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
steroid metabolic process	1
lipid biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
lipid metabolic process	1
catabolic process	1
primary metabolic process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
molecular_function	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1474 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HINT2	HINT3	Q9NQE9	658
HINT2	SPAG8	Q99932	461
HINT2	APTX	Q7Z2E3	460
HINT2	RPP25L	Q8N5L8	372
HINT2	LSM7	Q9UK45	354
HINT2	NAA38	Q9BRA0	329
HINT2	HNRNPCL2	B2RXH8	316
HINT2	YTHDF1	Q9BYJ9	316
HINT2	PRR12	Q9ULL5	314
HINT2	NUDT2	P50583	308
HINT2	ANGPTL8	Q6UXH0	305
HINT2	NANS	Q9NR45	303
HINT2	GALT	P07902	299
HINT2	KARS1	Q15046	299
HINT2	YTHDF2	Q9Y5A9	288

IntAct

24 interactions, top by confidence:

A	B	Type	Score
HINT2	HINT2	psi-mi:“MI:0407”(direct interaction)	0.440
HINT2	CFTR	psi-mi:“MI:0915”(physical association)	0.370
CFTR	HINT2	psi-mi:“MI:0915”(physical association)	0.370
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
SH2D3C	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
HINT2	CST4	psi-mi:“MI:0914”(association)	0.350
HINT2	DBT	psi-mi:“MI:0914”(association)	0.350
CTAG2	LAMB2	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
GNLY	GTPBP10	psi-mi:“MI:0914”(association)	0.350
HINT2	PAEP	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
MRFAP1		psi-mi:“MI:0914”(association)	0.350
OSBPL11	DNM1L	psi-mi:“MI:0914”(association)	0.350
AURKAIP1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
	VWA8	psi-mi:“MI:2364”(proximity)	0.270
HSPD1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
MGST3	VWA8	psi-mi:“MI:2364”(proximity)	0.270
PDK1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
TRMT61B	VWA8	psi-mi:“MI:2364”(proximity)	0.270
IMMP2L	MRPL45	psi-mi:“MI:2364”(proximity)	0.270
PARL	HAX1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (393): HINT2 (Affinity Capture-RNA), HINT2 (Affinity Capture-MS), HINT2 (Affinity Capture-MS), HINT2 (Proximity Label-MS), HINT2 (Proximity Label-MS), HINT2 (Proximity Label-MS), HINT2 (Proximity Label-MS), HINT2 (Proximity Label-MS), HINT2 (Co-fractionation), NENF (Co-fractionation), HINT2 (Co-fractionation), HINT2 (Co-fractionation), HINT2 (Co-fractionation), HINT2 (Co-fractionation), HINT2 (Co-fractionation)

ESM2 similar proteins: A0A0U2WCB2, A6NK44, A6QLI6, A8XX92, A9NNH7, B9FK36, O42764, P05165, P07997, P08680, P0DTA4, P13196, P13446, P14882, P16635, P22557, P43090, P54889, Q19842, Q28CR0, Q2KIZ3, Q2QMG2, Q42523, Q42777, Q4KLB0, Q4WHU1, Q502D1, Q553V2, Q5I0C3, Q5R557, Q5R7K1, Q5R9R9, Q612F5, Q63147, Q6CDR5, Q6JQN1, Q759G5, Q872T7, Q8K370, Q91ZA3

Diamond homologs: C4LYI2, O07513, O07817, O66536, O76463, O84390, O94586, P0A5B6, P0ACE7, P0ACE8, P0ACE9, P26724, P32083, P32084, P42855, P42856, P44956, P47378, P49773, P49774, P49776, P53795, P57438, P62958, P62959, P64382, P64383, P70349, P73481, P75504, P80912, P94252, P95937, P9WML2, P9WML3, Q04344, Q1KZG4, Q23921, Q28BZ2, 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	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

659 predictions. Top by Δscore:

Variant	Effect	Δscore
9:35813339:C:CC	acceptor_gain	1.0000
9:35813439:TCCCA:T	donor_loss	1.0000
9:35813440:CCCAC:C	donor_loss	1.0000
9:35813441:CCACC:C	donor_loss	1.0000
9:35813442:CA:C	donor_loss	1.0000
9:35813443:A:AT	donor_loss	1.0000
9:35813444:C:G	donor_loss	1.0000
9:35813548:CA:C	acceptor_gain	1.0000
9:35813550:C:CC	acceptor_gain	1.0000
9:35813638:CCCCA:C	donor_loss	1.0000
9:35813639:CCCA:C	donor_loss	1.0000
9:35813640:CCACC:C	donor_loss	1.0000
9:35813641:CACCT:C	donor_loss	1.0000
9:35813642:ACC:A	donor_loss	1.0000
9:35813643:C:CA	donor_loss	1.0000
9:35813643:CCTG:C	donor_gain	1.0000
9:35813146:C:CC	acceptor_gain	0.9900
9:35813335:GAAG:G	acceptor_gain	0.9900
9:35813337:AG:A	acceptor_gain	0.9900
9:35813341:A:C	acceptor_gain	0.9900
9:35813440:C:A	donor_gain	0.9900
9:35813444:CCTG:C	donor_gain	0.9900
9:35813545:AGACA:A	acceptor_gain	0.9900
9:35813546:GACA:G	acceptor_gain	0.9900
9:35813644:C:G	donor_loss	0.9900
9:35813651:T:TA	donor_gain	0.9900
9:35814983:C:A	donor_gain	0.9900
9:35813334:AGAAG:A	acceptor_gain	0.9800
9:35813336:AAG:A	acceptor_gain	0.9800
9:35813547:ACAC:A	acceptor_loss	0.9800

AlphaMissense

1028 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:35813117:T:A	Q143H	0.996
9:35813117:T:G	Q143H	0.996
9:35813313:G:T	A118D	0.996
9:35813500:A:T	V91D	0.996
9:35813698:G:C	F56L	0.996
9:35813698:G:T	F56L	0.996
9:35813700:A:G	F56L	0.996
9:35813068:A:G	W160R	0.995
9:35813068:A:T	W160R	0.995
9:35813101:G:C	H149D	0.995
9:35813138:G:C	N136K	0.995
9:35813138:G:T	N136K	0.995
9:35813095:G:C	H151D	0.994
9:35813539:A:G	F78S	0.994
9:35813690:A:G	I59T	0.994
9:35813093:A:C	H151Q	0.993
9:35813093:A:T	H151Q	0.993
9:35813095:G:T	H151N	0.993
9:35813508:G:C	H88Q	0.993
9:35813508:G:T	H88Q	0.993
9:35813510:G:C	H88D	0.993
9:35813532:A:C	D80E	0.993
9:35813532:A:T	D80E	0.993
9:35813091:A:T	V152E	0.992
9:35813099:G:C	H149Q	0.992
9:35813099:G:T	H149Q	0.992
9:35813101:G:T	H149N	0.992
9:35813066:C:A	W160C	0.991
9:35813066:C:G	W160C	0.991
9:35813085:C:T	G154E	0.991

dbSNP variants (sampled 300 via entrez): RS1001285126 (9:35812685 C>G,T), RS1001508162 (9:35816446 T>G), RS1001567843 (9:35813021 CAG>C), RS1002579286 (9:35815413 G>A,C), RS1003512502 (9:35813967 G>A,C), RS1003686426 (9:35817137 T>C), RS1003747524 (9:35816799 G>A,C), RS1004149595 (9:35814145 A>G), RS1004592059 (9:35812874 G>A,T), RS1005712630 (9:35816818 G>A), RS1006156232 (9:35817156 A>G), RS1006750698 (9:35815671 G>A,C), RS1006867489 (9:35816072 CT>C), RS1007130482 (9:35815467 G>C), RS1007690202 (9:35814428 G>A)

Disease associations

OMIM: gene MIM:609997 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_52	Brain morphology (MOSTest)	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724647 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects expression, affects cotreatment, increases expression	3
Valproic Acid	affects cotreatment, increases expression, affects expression	3
Benzo(a)pyrene	increases expression, affects expression	2
Cyclosporine	decreases expression, increases expression	2
GSK-J4	decreases expression	1
tetrahydropalmatine	decreases expression	1
perfluorooctanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
jinfukang	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, 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	increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Diuron	decreases expression	1
Doxorubicin	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Ozone	increases abundance, affects expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tunicamycin	increases expression	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5659917	Binding	Inhibition of human recombinant PKCi at 15 nM in presence of ATP by radiometric assay relative to control	A Potent and Selective ULK1 Inhibitor Suppresses Autophagy and Sensitizes Cancer Cells to Nutrient Stress. — iScience

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2YP	Abcam HEK293T HINT2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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