AOX1

Summary

AOX1 (aldehyde oxidase 1, HGNC:553) is a protein-coding gene on chromosome 2q33.1, encoding Aldehyde oxidase (Q06278). Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide, N-methylphthalazinium and phthalazine, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal, and vanillin.

Aldehyde oxidase produces hydrogen peroxide and, under certain conditions, can catalyze the formation of superoxide. Aldehyde oxidase is a candidate gene for amyotrophic lateral sclerosis.

Source: NCBI Gene 316 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 173 total — 1 pathogenic
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001159

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:553
Approved symbol	AOX1
Name	aldehyde oxidase 1
Location	2q33.1
Locus type	gene with protein product
Status	Approved
Aliases	AO, AOH1
Ensembl gene	ENSG00000138356
Ensembl biotype	protein_coding
OMIM	602841
Entrez	316

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 20 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000260930, ENST00000374700, ENST00000439380, ENST00000454629, ENST00000465297, ENST00000472553, ENST00000485106, ENST00000485965, ENST00000854903, ENST00000854904, ENST00000854905, ENST00000854906, ENST00000854907, ENST00000854908, ENST00000854909, ENST00000854910, ENST00000854911, ENST00000854912, ENST00000854913, ENST00000854914, ENST00000854915, ENST00000854916, ENST00000956221, ENST00000956222

RefSeq mRNA: 1 — MANE Select: NM_001159 NM_001159

CCDS: CCDS33360

Canonical transcript exons

ENST00000374700 — 35 exons

Exon	Start	End
ENSE00000803281	200609321	200609414
ENSE00000965043	200595272	200595368
ENSE00000965044	200597397	200597505
ENSE00000965045	200599620	200599746
ENSE00000965046	200602284	200602345
ENSE00000965047	200603267	200603356
ENSE00000965048	200604017	200604097
ENSE00000965049	200604696	200604840
ENSE00001075782	200586014	200586153
ENSE00001075788	200670629	200671495
ENSE00001464390	200608984	200609135
ENSE00001464391	200605536	200605628
ENSE00003469549	200659165	200659293
ENSE00003474115	200641098	200641184
ENSE00003475203	200661579	200661631
ENSE00003478245	200593146	200593203
ENSE00003486788	200620650	200620819
ENSE00003509967	200623861	200623983
ENSE00003510717	200656842	200656937
ENSE00003512697	200627353	200627449
ENSE00003513516	200659995	200660069
ENSE00003518266	200669575	200669742
ENSE00003528815	200621120	200621246
ENSE00003537361	200611384	200611493
ENSE00003541386	200615971	200616063
ENSE00003544080	200668615	200668803
ENSE00003544814	200666687	200666752
ENSE00003569603	200612609	200612793
ENSE00003614407	200662855	200662969
ENSE00003618168	200634791	200634915
ENSE00003626785	200650974	200651201
ENSE00003631997	200636911	200637044
ENSE00003658485	200638215	200638302
ENSE00003671510	200613804	200613966
ENSE00003693940	200642610	200642801

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 99.38.

FANTOM5 (CAGE): breadth broad, TPM avg 9.2910 / max 1217.8667, expressed in 863 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24556	6.7821	606
24558	1.4105	452
24555	0.4393	149
24560	0.3434	149
24559	0.2014	95
24557	0.1143	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	99.38	gold quality
right adrenal gland cortex	UBERON:0035827	99.38	gold quality
left adrenal gland cortex	UBERON:0035825	99.22	gold quality
adrenal cortex	UBERON:0001235	99.20	gold quality
left adrenal gland	UBERON:0001234	99.18	gold quality
right lobe of liver	UBERON:0001114	99.10	gold quality
adrenal gland	UBERON:0002369	98.62	gold quality
liver	UBERON:0002107	97.71	gold quality
body of pancreas	UBERON:0001150	97.39	gold quality
left uterine tube	UBERON:0001303	96.79	gold quality
germinal epithelium of ovary	UBERON:0001304	96.55	gold quality
omental fat pad	UBERON:0010414	96.17	gold quality
peritoneum	UBERON:0002358	96.13	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.88	gold quality
pancreas	UBERON:0001264	94.68	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.49	gold quality
right ovary	UBERON:0002118	94.25	gold quality
adrenal tissue	UBERON:0018303	94.19	gold quality
adipose tissue	UBERON:0001013	93.90	gold quality
nephron tubule	UBERON:0001231	93.69	gold quality
mucosa of stomach	UBERON:0001199	93.66	gold quality
adult mammalian kidney	UBERON:0000082	93.56	gold quality
left ovary	UBERON:0002119	93.42	gold quality
kidney epithelium	UBERON:0004819	92.64	gold quality
connective tissue	UBERON:0002384	92.55	gold quality
popliteal artery	UBERON:0002250	92.42	gold quality
tibial artery	UBERON:0007610	92.41	gold quality
olfactory bulb	UBERON:0002264	92.21	gold quality
parietal pleura	UBERON:0002400	92.17	gold quality
renal glomerulus	UBERON:0000074	91.70	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6142	no	74.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFE2L2, SP3, STAT1, TBXT

miRNA regulators (miRDB)

47 targeting AOX1, 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-3924	100.00	72.09	2394
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-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-4774-3P	98.90	67.82	737
HSA-MIR-6074	98.89	69.64	2187

Literature-anchored findings (GeneRIF, showing 26)

• The interaction of ABCA1 with AOX1 modulates ABCA1-linked cellular functions such as lipid efflux and phagocytosis in hepatocytes (HC), and reduced expression of AOX1 in malignant transformed HC supports the differentiation dependent upregulation of AOX1. (PMID:17992631)
• Expressed AOX1 in Escherichia coli and purified kinetically active protein. (PMID:19741035)
• characterization of AO activity in cryopreserved human hepatocytes: enzyme stability; substrate specificity; kinetics; inhibition by hydralazine (PMID:22031625)
• Human population is characterized by the presence of functionally inactive hAOX1 allelic variants as well as variants encoding enzymes with different catalytic activities. (PMID:22279051)
• The physiological role of AOX1 remains unclear, but it is known that thiopurines belong to its substrates; AOX1 contributes to azathioprine catabolism. (PMID:22495427)
• hydralazine, at a concentration of 25 to 50 muM, can be used in human hepatocyte incubations to estimate the contribution of aldehyde oxidase to the hepatic clearance of drugs and other compounds. (PMID:22522748)
• Several donors have a normal AOX1 protein level. (PMID:23857892)
• High AOX1 methylation was associated with biochemical recurrence in prostate cancer. (PMID:23918943)
• These results supported the possibility that XO/XD and AO can contribute to nitric oxide generation. (PMID:25537183)
• Data suggest that substrate specificity of AOX1 includes GDC-0834, an inhibitor of Bruton’s tyrosine kinase with potential non-steroidal anti-inflammatory agent activity; in liver cytosol, hydrolysis of GDC-0834 is primarily due to AOX1. (PMID:25845827)
• Methotrexate is poorly metabolized by human AOX1, in contrast to rabbit. (PMID:26032640)
• AOX1 SNPs exist in which the base-pair exchange of the SNP leads to loss of enzyme activity. (PMID:26842593)
• Data suggest that metabolism (and possibly pharmacokinetics) of hypnotic nitrazepam involves liver enzymes AOX1 (aldehyde oxidase 1), NAT2 (N-acetyltransferase 2), AADAC (arylacetamide deacetylase), and CYP3A4 (cytochrome P450 3A4). (PMID:28606603)
• ten novel single nucleotide polymorphisms resulting in amino acid exchanges in proximity to the FAD site of hAOX1, were characterized. (PMID:28750088)
• The SNP rs73055188 at the AOX1 locus is associated with prostate-cancer-specific survival time, and AOX1 gene expression level is correlated with biochemical recurrence of prostate cancer. (PMID:30289108)
• Non-methylation of AOX1 and IRF4 were a risk factors for breast cancer. (PMID:30293322)
• substrate selectivity of human AOX1 for the reduction of nitroaromatic drugs (PMID:30367827)
• In this study, the authors present the crystal structure of the inactive variant G1269R, revealing the first structure of a molybdenum cofactor (Moco)-free form of hAOX1. These data allowed to model, for the first time, the flexible Gate 1 that controls access to the active site. (PMID:30985987)
• Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression. (PMID:31383940)
• Study utilized a collection of computational tools with concordance analysis approaches to predict putative phenotypic effects and protein stability changes of all validated hAOX1 nonsynonymous single nucleotide polymorphisms (nsSNPs) deposited in the dbSNP. Study constitutes the first extensive analysis for the presence of nsSNPs in hAOX1. (PMID:31768259)
• This prospective study aimed to evaluate the effects of genetic polymorphisms in sulindac-related metabolizing enzyme genes including FMO3 and AOX1 on the population pharmacokinetics of sulindac in 58 pregnant women with preterm labor (PMID:31993760)
• Aldehyde oxidase 1 promoted the occurrence and development of colorectal cancer by up-regulation of expression of CD133. (PMID:32470878)
• DNA Methylation-Mediated Lowly Expressed AOX1 Promotes Cell Migration and Invasion of Prostate Cancer. (PMID:35354150)
• Aldehyde oxidase 1 activity and protein expression in human, rabbit, and pig ocular tissues. (PMID:37827455)
• Aldehyde oxidase 1 promotes gallbladder carcinogenesis through ROS-mediated activation of the Wnt/beta-catenin pathway. (PMID:38199597)
• Role of AOX1 on RXR signaling regulates osteoblastogenesis in hPDLMSCs. (PMID:39034354)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aox6	ENSDARG00000020054
mus_musculus	Aox1	ENSMUSG00000063558
rattus_norvegicus	Aox1	ENSRNOG00000015354
drosophila_melanogaster	ry	FBGN0003308
caenorhabditis_elegans		WBGENE00010083

Paralogs (1): XDH (ENSG00000158125)

Protein

Protein identifiers

Aldehyde oxidase — Q06278 (reviewed: Q06278)

Alternative names: Aldehyde oxidase 1, Azaheterocycle hydroxylase

All UniProt accessions (4): Q06278, C9J244, H7BXF7, H7C3Q1

UniProt curated annotations — full annotation on UniProt →

Function. Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide, N-methylphthalazinium and phthalazine, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal, and vanillin. Plays a key role in the metabolism of xenobiotics and drugs containing aromatic azaheterocyclic substituents. Participates in the bioactivation of prodrugs such as famciclovir, catalyzing the oxidation step from 6-deoxypenciclovir to penciclovir, which is a potent antiviral agent. Is probably involved in the regulation of reactive oxygen species homeostasis. May be a prominent source of superoxide generation via the one-electron reduction of molecular oxygen. May also catalyze nitric oxide (NO) production via the reduction of nitrite to NO with NADH or aldehyde as electron donor. May play a role in adipogenesis.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Tissue specificity. Abundant in liver, expressed in adipose tissue and at lower levels in lung, skeletal muscle, pancreas. In contrast to mice, no significant gender difference in AOX1 expression level (at protein level).

Activity regulation. Is very potently inhibited by raloxifene. Also inhibited by estradiol, ethinyl estradiol, hydralazine, menadione, isovanillin and thioridazine. Not inhibited by allopurinol, a xanthine dehydrogenase potent inhibitor.

Cofactor. Binds 2 [2Fe-2S] clusters per subunit. Binds 1 FAD per subunit. Binds 1 Mo-molybdopterin (Mo-MPT) cofactor per subunit.

Induction. In liver, is down-regulated by adiponectin and by the PPARA agonist, fenofibric acid.

Miscellaneous. AOX genes evolved from a xanthine oxidoreductase ancestral precursor via a series of gene duplication and suppression/deletion events. Different animal species contain a different complement of AOX genes encoding an equivalent number of AOX isoenzymes. In mammals, the two extremes are represented by certain rodents such as mice and rats, which are endowed with 4 AOX genes, and by humans, whose genome is characterized by a single active gene.

Similarity. Belongs to the xanthine dehydrogenase family.

RefSeq proteins (1): NP_001150* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000674	Ald_Oxase/Xan_DH_a/b	Domain
IPR001041	2Fe-2S_ferredoxin-type	Domain
IPR002346	Mopterin_DH_FAD-bd	Domain
IPR002888	2Fe-2S-bd	Domain
IPR005107	CO_DH_flav_C	Domain
IPR006058	2Fe2S_fd_BS	Binding_site
IPR008274	AldOxase/xan_DH_MoCoBD1	Domain
IPR012675	Beta-grasp_dom_sf	Homologous_superfamily
IPR014313	Aldehyde_oxidase	Family
IPR016166	FAD-bd_PCMH	Domain
IPR016167	FAD-bd_PCMH_sub1	Homologous_superfamily
IPR016169	FAD-bd_PCMH_sub2	Homologous_superfamily
IPR016208	Ald_Oxase/xanthine_DH-like	Family
IPR022407	OxRdtase_Mopterin_BS	Binding_site
IPR036010	2Fe-2S_ferredoxin-like_sf	Homologous_superfamily
IPR036318	FAD-bd_PCMH-like_sf	Homologous_superfamily
IPR036683	CO_DH_flav_C_dom_sf	Homologous_superfamily
IPR036856	Ald_Oxase/Xan_DH_a/b_sf	Homologous_superfamily
IPR036884	2Fe-2S-bd_dom_sf	Homologous_superfamily
IPR037165	AldOxase/xan_DH_Mopterin-bd_sf	Homologous_superfamily
IPR046867	AldOxase/xan_DH_MoCoBD2	Domain

Pfam: PF00111, PF00941, PF01315, PF01799, PF02738, PF03450, PF20256

Enzyme classification (BRENDA):

• EC 1.2.3.1 — aldehyde oxidase (BRENDA: 54 organisms, 471 substrates, 271 inhibitors, 460 Km, 207 kcat entries)

Substrate kinetics (BRENDA)

115 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BENZALDEHYDE	0.0006–7.13	49
PHTHALAZINE	0.0011–1.264	26
PHENANTHRIDINE	0.0019–0.385	24
ACETALDEHYDE	0.0025–52.9	16
SALICYLALDEHYDE	0.0035–5.2	16
N-METHYLNICOTINAMIDE	0.08–7	13
(+)-4-(4-CYANOANILINO)-5,6-DIHYDRO-7-HYDROXY-7H-	0.0109–0.131	12
(S)-RS-8359	0.0027–0.173	10
PENTANAL	0.0134–5.566	10
VANILLIN	0.0023–6	9
2-HYDROXYPYRIMIDINE	0.0044–14.7	8
PROPIONALDEHYDE	0.0028–1.634	8
FORMALDEHYDE	3.6–35.9	7
N1-METHYLNICOTINAMIDE	0.0094–0.1285	7
ZEBULARINE	0.0073–0.102	7

Catalyzed reactions (Rhea), 2 shown:

• an aldehyde + O2 + H2O = a carboxylate + H2O2 + H(+) (RHEA:16829)
• retinal + O2 + H2O = retinoate + H2O2 + H(+) (RHEA:56736)

UniProt features (171 total): strand 59, helix 57, binding site 21, turn 11, sequence conflict 10, sequence variant 6, domain 2, mutagenesis site 2, chain 1, modified residue 1, active site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4UHW	X-RAY DIFFRACTION	2.6
7OPN	X-RAY DIFFRACTION	2.6
4UHX	X-RAY DIFFRACTION	2.7
7ORC	X-RAY DIFFRACTION	2.7
8EMT	ELECTRON MICROSCOPY	2.92
6Q6Q	X-RAY DIFFRACTION	3.1
5EPG	X-RAY DIFFRACTION	3.39

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06278-F1	95.13	0.93

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): 1270 (proton acceptor; for azaheterocycle hydroxylase activity)

Ligand- & substrate-binding residues (21): 117; 149; 151; 151; 264–271; 345; 354; 358; 367; 411; 806–807; 1047 …

Post-translational modifications (1): 1068

Mutagenesis-validated functional residues (2):

Position	Phenotype
44	disrupts protein stability.
1269	no effect on dimerization. loss of oxidase activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-964975	Vitamin B6 activation to pyridoxal phosphate
R-HSA-1430728	Metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors

MSigDB gene sets: 171 (showing top): MODULE_93, ELVIDGE_HYPOXIA_DN, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, BROWNE_HCMV_INFECTION_48HR_DN, CAIRO_HEPATOBLASTOMA_CLASSES_DN, HOWLIN_PUBERTAL_MAMMARY_GLAND, KOYAMA_SEMA3B_TARGETS_UP, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_CDC25_UP, GROSS_HYPOXIA_VIA_ELK3_UP, GROSS_HYPOXIA_VIA_ELK3_ONLY_DN, DELYS_THYROID_CANCER_DN, HSIAO_LIVER_SPECIFIC_GENES

GO Biological Process (2): lipid metabolic process (GO:0006629), xenobiotic metabolic process (GO:0006805)

GO Molecular Function (12): aldehyde oxidase activity (GO:0004031), iron ion binding (GO:0005506), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), molybdopterin cofactor binding (GO:0043546), flavin adenine dinucleotide binding (GO:0050660), NAD binding (GO:0051287), 2 iron, 2 sulfur cluster binding (GO:0051537), FAD binding (GO:0071949), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (6): cytosol (GO:0005829), microtubule cytoskeleton (GO:0015630), nuclear body (GO:0016604), intercellular bridge (GO:0045171), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
primary metabolic process	1
metabolic process	1
cellular response to xenobiotic stimulus	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors, oxygen as acceptor	1
transition metal ion binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
nucleotide binding	1
anion binding	1
adenyl nucleotide binding	1
iron-sulfur cluster binding	1
flavin adenine dinucleotide binding	1
catalytic activity	1
cation binding	1
metal cluster binding	1
cytoplasm	1
cytoskeleton	1
nucleoplasm	1
intracellular membraneless organelle	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1618 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AOX1	MOCOS	Q96EN8	969
AOX1	SUOX	P51687	966
AOX1	MOCS1	Q9NZB8	961
AOX1	MOCS2	O96007	945
AOX1	GPHN	Q9NQX3	837
AOX1	MAOB	P27338	688
AOX1	ALS2	Q96Q42	658
AOX1	ALDH2	P05091	650
AOX1	ACOX1	Q15067	650
AOX1	CCDC181	Q5TID7	625
AOX1	CYP2C9	P11712	611
AOX1	ADCY10	Q96PN6	601
AOX1	CYP2B6	P20813	597
AOX1	MMUT	P22033	589
AOX1	INMT	O95050	587

IntAct

8 interactions, top by confidence:

A	B	Type	Score
AOX1	AOX1	psi-mi:“MI:0407”(direct interaction)	0.560
AOX1	CRKL	psi-mi:“MI:0915”(physical association)	0.370
GK	AOX1	psi-mi:“MI:0915”(physical association)	0.370
RBL1	AOX1	psi-mi:“MI:0915”(physical association)	0.370
RCHY1	AOX1	psi-mi:“MI:0915”(physical association)	0.370
TEX101	NDUFA4	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): AOX1 (Two-hybrid), AOX1 (Two-hybrid), AOX1 (Affinity Capture-MS), AOX1 (Affinity Capture-MS), AOX1 (Affinity Capture-MS), AOX1 (Two-hybrid), AOX1 (Affinity Capture-MS), RBL1 (Two-hybrid), CRKL (Two-hybrid), GK (Two-hybrid), RCHY1 (Two-hybrid)

ESM2 similar proteins: A0A1U8QNG8, B9FK36, C4NYZ3, F4JLI5, G3X982, H9TB17, H9TB18, H9TB19, O23887, O23888, O54754, P08793, P10351, P14882, P22811, P22985, P47989, P47990, P48034, P80456, P80457, P91711, Q00519, Q06278, Q12553, Q38970, Q3TYQ9, Q54FB7, Q5FB27, Q5I0C3, Q5QE78, Q5QE79, Q5QE80, Q5SGK3, Q69R21, Q6AUV1, Q6Z351, Q7G191, Q7G192, Q7G193

Diamond homologs: A0A1U8QNG8, C4NYZ3, D7REY5, F4JLI5, G3X982, H9TB17, H9TB18, H9TB19, O32143, O33818, O54754, O87682, P08793, P10351, P19915, P19921, P22811, P22985, P47989, P47990, P48034, P77165, P80456, P80457, P91711, Q00519, Q06278, Q0QLF1, Q0QLF3, Q12553, Q3TYQ9, Q46801, Q4J6M5, Q51697, Q54FB7, Q59128, Q5FB27, Q5QE78, Q5QE79, Q5QE80

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	116
Likely benign	16
Benign	9

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
147739	GRCh38/hg38 2q33.1(chr2:200346708-201156417)x1	Pathogenic

SpliceAI

4723 predictions. Top by Δscore:

Variant	Effect	Δscore
2:200586150:CAAGG:C	donor_loss	1.0000
2:200586151:AAGG:A	donor_loss	1.0000
2:200586152:AGGT:A	donor_loss	1.0000
2:200586153:GGTG:G	donor_loss	1.0000
2:200586154:G:GA	donor_loss	1.0000
2:200586155:T:G	donor_loss	1.0000
2:200597388:A:AG	acceptor_gain	1.0000
2:200597388:ATTCT:A	acceptor_gain	1.0000
2:200597389:T:G	acceptor_gain	1.0000
2:200597392:T:TA	acceptor_gain	1.0000
2:200597441:AT:A	acceptor_gain	1.0000
2:200597442:T:TA	acceptor_gain	1.0000
2:200599728:T:G	donor_gain	1.0000
2:200599744:GTG:G	donor_gain	1.0000
2:200599746:GGTA:G	donor_loss	1.0000
2:200599748:T:G	donor_loss	1.0000
2:200602346:G:GG	donor_gain	1.0000
2:200603349:G:GT	donor_gain	1.0000
2:200604012:TTTA:T	acceptor_loss	1.0000
2:200604013:TTAGA:T	acceptor_gain	1.0000
2:200604014:TAGA:T	acceptor_gain	1.0000
2:200604015:A:AG	acceptor_gain	1.0000
2:200604016:G:GA	acceptor_gain	1.0000
2:200604016:GA:G	acceptor_gain	1.0000
2:200604016:GAC:G	acceptor_gain	1.0000
2:200604016:GACA:G	acceptor_gain	1.0000
2:200604016:GACAA:G	acceptor_gain	1.0000
2:200604093:TAATG:T	donor_gain	1.0000
2:200604094:AATG:A	donor_gain	1.0000
2:200604095:ATG:A	donor_gain	1.0000

AlphaMissense

8820 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:200599656:T:C	F116L	0.996
2:200599658:C:A	F116L	0.996
2:200599658:C:G	F116L	0.996
2:200599659:T:C	C117R	0.995
2:200599661:C:G	C117W	0.995
2:200597453:T:A	V86D	0.994
2:200620728:G:T	G595W	0.994
2:200599660:G:A	C117Y	0.993
2:200636983:T:C	F807L	0.992
2:200636985:T:A	F807L	0.992
2:200636985:T:G	F807L	0.992
2:200599650:T:A	C114S	0.991
2:200599650:T:C	C114R	0.991
2:200599651:G:C	C114S	0.991
2:200599654:G:A	G115D	0.990
2:200599668:G:T	G120W	0.990
2:200656855:T:A	V1030D	0.990
2:200595291:G:C	K41N	0.989
2:200595291:G:T	K41N	0.989
2:200595322:T:C	C52R	0.989
2:200620729:G:T	G595V	0.989
2:200660003:T:G	C1103W	0.989
2:200593196:G:C	R32S	0.988
2:200593196:G:T	R32S	0.988
2:200599659:T:A	C117S	0.988
2:200599660:G:C	C117S	0.988
2:200620729:G:A	G595E	0.988
2:200656914:G:T	G1050W	0.988
2:200666731:T:A	N1196K	0.988
2:200666731:T:G	N1196K	0.988

dbSNP variants (sampled 300 via entrez): RS1000045742 (2:200672795 G>A), RS1000061218 (2:200613869 G>A,T), RS1000108642 (2:200591290 A>G), RS1000116028 (2:200674104 A>C), RS1000124586 (2:200605152 C>T), RS1000179887 (2:200637911 A>G), RS1000190918 (2:200632690 G>A), RS1000240309 (2:200645012 T>A,G), RS1000247616 (2:200639145 G>A,C), RS1000247768 (2:200655052 G>C), RS1000280605 (2:200598004 G>A,C,T), RS1000299855 (2:200638839 A>C), RS1000317308 (2:200585229 A>G), RS1000408885 (2:200606970 T>C), RS1000461581 (2:200636091 G>A)

Disease associations

OMIM: gene MIM:602841 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): primary ovarian failure (MONDO:0005387)

Orphanet (1): NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001428_6	Intelligence	6.000000e-08
GCST003815_46	Late-onset Alzheimer’s disease	8.000000e-06
GCST008156_110	Hip circumference adjusted for BMI	2.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:1001870	late-onset Alzheimers disease
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3257 (SINGLE PROTEIN), CHEMBL4106157 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,257,782 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL135	ESTRADIOL	4	123,080
CHEMBL1521	ZALEPLON	4	9,958
CHEMBL219916	DOMPERIDONE	4	18,305
CHEMBL276832	HYDRALAZINE	4	23,794
CHEMBL411	DIETHYLSTILBESTROL	4	353,912
CHEMBL42	CLOZAPINE	4	37,581
CHEMBL43	AMSACRINE	4	82,326
CHEMBL532	ERYTHROMYCIN	4	141,173
CHEMBL567	PERPHENAZINE	4	21,883
CHEMBL590	MENADIONE	4	21,034
CHEMBL691	ETHINYL ESTRADIOL	4	40,543
CHEMBL71	CHLORPROMAZINE	4	45,827
CHEMBL7568	QUINACRINE	4	20,112
CHEMBL81	RALOXIFENE	4	78,049
CHEMBL83	TAMOXIFEN	4	171,635
CHEMBL102970	PYRIDOXAL	3	24,358
CHEMBL44	GENISTEIN	2	44,212

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10931910	Metabolism/PK	3	XK469
rs3731722	Dosage	3	allopurinol;febuxostat	Gout
rs55754655	Efficacy	3	azathioprine	Inflammatory Bowel Diseases
rs75995567	Dosage	3	allopurinol;febuxostat	Gout

PharmGKB variants

8 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10931910	AOX1	3	1.75	1	XK469
rs55754655	AOX1	3	2.50	1	azathioprine
rs11678615	AOX1		0.00	0
rs3731722	AOX1	3	2.25	1	allopurinol;febuxostat
rs75995567	AOX1	3	1.75	1	allopurinol;febuxostat
rs149229670	AOX1		0.00	0
rs143692548	AOX1		0.00	0
rs112951726	AOX1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 1.2.3.1 Aldehyde oxidase

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
raloxifene	Inhibition	7.35	pIC50

ChEMBL bioactivities

34 potent at pChembl≥5 of 42 total, top 31 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.06	Ki	0.87	nM	RALOXIFENE
9.05	Ki	0.9	nM	RALOXIFENE
8.64	Ki	2.3	nM	RALOXIFENE
8.52	IC50	3	nM	RALOXIFENE
8.30	IC50	5	nM	GENISTEIN
8.30	IC50	5	nM	ESTRADIOL
8.30	IC50	5	nM	ETHINYL ESTRADIOL
8.24	IC50	5.7	nM	RALOXIFENE
8.10	IC50	8	nM	RALOXIFENE
7.48	IC50	33	nM	PERPHENAZINE
7.40	IC50	40	nM	CHEMBL56149
7.35	IC50	44.5	nM	RALOXIFENE
7.10	IC50	80	nM	ESTRADIOL
6.70	IC50	200	nM	MENADIONE
6.47	IC50	340	nM	GENISTEIN
6.37	Ki	430	nM	ETHINYL ESTRADIOL
6.34	IC50	460	nM	DIETHYLSTILBESTROL
6.33	Ki	470	nM	MENADIONE
6.24	IC50	570	nM	ETHINYL ESTRADIOL
6.24	IC50	570	nM	CHLORPROMAZINE
6.21	Ki	620	nM	CHLORPROMAZINE
6.06	Ki	870	nM	ESTRADIOL
5.92	Ki	1200	nM	DOMPERIDONE
5.82	Ki	1500	nM	MENADIONE
5.64	Ki	2300	nM	CHLORPROMAZINE
5.50	IC50	3200	nM	AMSACRINE
5.48	IC50	3300	nM	QUINACRINE
5.44	Ki	3600	nM	ETHINYL ESTRADIOL
5.41	IC50	3930	nM	HYDRALAZINE
5.36	Ki	4400	nM	ESTRADIOL
5.29	Ki	5100	nM	CLOZAPINE

PubChem BioAssay actives

34 with measured affinity, of 413 total; 13 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Raloxifene	1210790: Uncompetitive inhibition of human liver cytosolic aldehyde oxidase using phthalazine as substrate assessed as enzyme-substrate complex by Lineweaver-Burk plot analysis	ki	0.0009	uM
Genistein	1930376: Inhibition of human liver AOX using phthalazine as substrate incubated for 2.5 mins by HPLC-MS analysis	ic50	0.0050	uM
Estradiol	1930376: Inhibition of human liver AOX using phthalazine as substrate incubated for 2.5 mins by HPLC-MS analysis	ic50	0.0050	uM
ethinyl estradiol	1930376: Inhibition of human liver AOX using phthalazine as substrate incubated for 2.5 mins by HPLC-MS analysis	ic50	0.0050	uM
Perphenazine	547838: Inhibition of human aldehyde oxidase	ic50	0.0330	uM
N-[2-(dimethylamino)ethyl]-7-hydroxyacridine-4-carboxamide	547838: Inhibition of human aldehyde oxidase	ic50	0.0400	uM
Menadione	547838: Inhibition of human aldehyde oxidase	ic50	0.2000	uM
Diethylstilbestrol	547838: Inhibition of human aldehyde oxidase	ic50	0.4600	uM
Chlorpromazine	547838: Inhibition of human aldehyde oxidase	ic50	0.5700	uM
Domperidone	1210791: Competitive inhibition of human liver cytosolic aldehyde oxidase using DACA as substrate assessed as free enzyme by Lineweaver-Burk plot analysis	ki	1.2000	uM
N-[4-(acridin-9-ylamino)-3-methoxyphenyl]methanesulfonamide	547838: Inhibition of human aldehyde oxidase	ic50	3.2000	uM
4-N-(6-chloro-2-methoxyacridin-9-yl)-1-N,1-N-diethylpentane-1,4-diamine	547838: Inhibition of human aldehyde oxidase	ic50	3.3000	uM
Clozapine	1210791: Competitive inhibition of human liver cytosolic aldehyde oxidase using DACA as substrate assessed as free enzyme by Lineweaver-Burk plot analysis	ki	5.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression, increases expression	7
Benzo(a)pyrene	increases expression, increases mutagenesis, decreases expression, decreases methylation	5
Cyclosporine	increases expression, affects cotreatment, decreases expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Methotrexate	affects metabolic processing, decreases expression, increases expression	3
Silicon Dioxide	decreases expression, increases expression	3
Valproic Acid	decreases expression, decreases methylation	3
methylmercuric chloride	decreases expression, increases expression	2
bisphenol A	affects cotreatment, increases methylation, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
zoniporide	affects metabolic processing, increases hydrolysis, increases metabolic processing, decreases reaction	2
Panobinostat	affects cotreatment, decreases expression	2
Aerosols	decreases expression, increases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Progesterone	increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
bufotalin	increases expression	1
propionaldehyde	increases expression	1
trichostatin A	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
3,4-dichloroaniline	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	affects cotreatment, increases expression	1

ChEMBL screening assays

155 unique, capped per target: 142 admet, 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1640074	ADMET	Activity of aldehyde oxidase in human liver cytosol	Aldehyde oxidase: an enzyme of emerging importance in drug discovery. — J Med Chem
CHEMBL4420028	Binding	Inhibition of aldehyde oxidase in human liver cytosolic fraction using methyl-nicotinamide substrate incubated for 120 mins by HPLC analysis	Therapeutic agent for nonalcoholic fatty liver disease

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7K4	Ubigene A-549 AOX1 KO	Cancer cell line	Male
CVCL_D9XJ	Ubigene HeLa AOX1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists