HMOX2

Summary

HMOX2 (heme oxygenase 2, HGNC:5014) is a protein-coding gene on chromosome 16p13.3, encoding Heme oxygenase 2 (P30519). Catalyzes the oxidative cleavage of heme at the alpha-methene bridge carbon, released as carbon monoxide (CO), to generate biliverdin IXalpha, while releasing the central heme iron chelate as ferrous iron.

Heme oxygenase, an essential enzyme in heme catabolism, cleaves heme to form biliverdin, which is subsequently converted to bilirubin by biliverdin reductase, and carbon monoxide, a putative neurotransmitter. Heme oxygenase activity is induced by its substrate heme and by various nonheme substances. Heme oxygenase occurs as 2 isozymes, an inducible heme oxygenase-1 and a constitutive heme oxygenase-2. HMOX1 and HMOX2 belong to the heme oxygenase family. Several alternatively spliced transcript variants encoding three different isoforms have been found for this gene.

Source: NCBI Gene 3163 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 59 total — 1 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002134

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5014
Approved symbol	HMOX2
Name	heme oxygenase 2
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	HO-2
Ensembl gene	ENSG00000103415
Ensembl biotype	protein_coding
OMIM	141251
Entrez	3163

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 52 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000219700, ENST00000398595, ENST00000406590, ENST00000414777, ENST00000458134, ENST00000570445, ENST00000570622, ENST00000570646, ENST00000572812, ENST00000574466, ENST00000574594, ENST00000575051, ENST00000575120, ENST00000575129, ENST00000576827, ENST00000613539, ENST00000619528, ENST00000619913, ENST00000905894, ENST00000905895, ENST00000905896, ENST00000905897, ENST00000905898, ENST00000905899, ENST00000905900, ENST00000905901, ENST00000905902, ENST00000905903, ENST00000905904, ENST00000905905, ENST00000938913, ENST00000938914, ENST00000938915, ENST00000938916, ENST00000938917, ENST00000964450, ENST00000964451, ENST00000964452, ENST00000964453, ENST00000964454, ENST00000964455, ENST00000964456, ENST00000964457, ENST00000964458, ENST00000964459, ENST00000964460, ENST00000964461, ENST00000964462, ENST00000964463, ENST00000964464, ENST00000964465, ENST00000964466, ENST00000964467

RefSeq mRNA: 9 — MANE Select: NM_002134 NM_001127204, NM_001127205, NM_001127206, NM_001286267, NM_001286268, NM_001286269, NM_001286270, NM_001286271, NM_002134

CCDS: CCDS10517, CCDS66931, CCDS73818

Canonical transcript exons

ENST00000570646 — 6 exons

Exon	Start	End
ENSE00000667219	4509412	4509538
ENSE00000667220	4507713	4508204
ENSE00001010603	4505484	4505610
ENSE00001818091	4509629	4510347
ENSE00002677673	4476398	4476487
ENSE00003604287	4506895	4507012

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.9228 / max 545.0815, expressed in 1821 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152470	55.2957	1821
207716	0.5477	240
152471	0.0794	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	98.26	gold quality
left testis	UBERON:0004533	98.21	gold quality
prefrontal cortex	UBERON:0000451	97.78	gold quality
heart left ventricle	UBERON:0002084	97.31	gold quality
testis	UBERON:0000473	97.16	gold quality
apex of heart	UBERON:0002098	97.16	gold quality
frontal cortex	UBERON:0001870	97.05	gold quality
superior frontal gyrus	UBERON:0002661	97.02	gold quality
lower esophagus mucosa	UBERON:0035834	96.83	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.34	gold quality
right atrium auricular region	UBERON:0006631	96.32	gold quality
body of stomach	UBERON:0001161	96.19	gold quality
nucleus accumbens	UBERON:0001882	96.19	gold quality
heart	UBERON:0000948	96.12	gold quality
primary visual cortex	UBERON:0002436	96.09	gold quality
cerebral cortex	UBERON:0000956	96.05	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.05	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.99	gold quality
putamen	UBERON:0001874	95.94	gold quality
right frontal lobe	UBERON:0002810	95.94	gold quality
corpus callosum	UBERON:0002336	95.68	gold quality
caudate nucleus	UBERON:0001873	95.54	gold quality
substantia nigra	UBERON:0002038	95.48	gold quality
granulocyte	CL:0000094	95.42	gold quality
stomach	UBERON:0000945	95.41	gold quality
adult mammalian kidney	UBERON:0000082	95.33	gold quality
anterior cingulate cortex	UBERON:0009835	95.26	gold quality
esophagus mucosa	UBERON:0002469	95.22	gold quality
brain	UBERON:0000955	95.07	gold quality
Ammon’s horn	UBERON:0001954	95.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.21

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A

miRNA regulators (miRDB)

37 targeting HMOX2, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-4536-5P	98.47	64.39	657
HSA-MIR-6873-5P	98.45	66.14	1417
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-1306-5P	97.11	64.04	755

Literature-anchored findings (GeneRIF, showing 40)

• HO-2 protein content was decreased by 17% and 5% in human trophoblast cells after 24-h exposure to 1% and 5% O(2), respectively, versus 20% O(2) but unchanged in chorionic villi (PMID:12578814)
• Low expression of HO-2 may lead to enhanced levels of free heme at the feto-maternal interface, with subsequent upregulation of adhesion molecules, allowing enhanced inflammatory cells migration to the feto-maternal interface. (PMID:14506930)
• regulation of HO expression in the human placenta is a complex process that depends, at least in part, on local glucose and oxygen concentrations. (PMID:14615405)
• HO-2 is part of the BK channel complex and enhances channel activity in normoxia (PMID:15528406)
• Catalytically inactive mutant, HO-2H45A, overexpressed in HEK293 cell lines was more sensitive to hemin as compared to control. HO-2H45A was also able to protect cells against oxidative stress injury. (PMID:16043027)
• Review summarizes function of hemoxygenase-2 as an oxygen sensor of native and recombinant large conductance, voltage- and calcium-dependent potassium BK(Ca) channels expressed in carotid body glomus cells. (PMID:16137652)
• These results suggest that HO-2 may down-regulate the expression of HO-1, thereby directing the co-ordinated expression of HO-1 and HO-2. (PMID:17064313)
• Suggest membrane potential gradient in small intestine is dependent on carbon monoxide generated by HO-2 in interstital cells of Cajal. (PMID:17510199)
• the heme regulatory motifs in HO-2 constitute a thiol/disulfide redox switch that regulates the myriad physiological functions of HO-2, including its involvement in the hypoxic response in the carotid body (PMID:17540772)
• analysis of apo- and heme-bound crystal structures of a truncated human heme oxygenase-2 (PMID:17965015)
• Our study failed to detect any association between the single nucleotide polymorphisms of the HMOX1 gene and Alzheimer’s disease (PMID:19246912)
• HO-2 may be important in controlling trophoblast invasion. (PMID:19345412)
• Enhanced oxidative stress and a decrease in the number of anti-oxidant enzymes may be associated with pre-eclampsia. (PMID:19399816)
• The thiol/disulfide switch in HO-2 responds to cellular oxidative stress and reductive conditions, representing a paradigm for how heme regulatory motifs can integrate heme homeostasis with carbon monoxide signaling and redox regulation. (PMID:19473966)
• high expression in keratinocytes prevents basal and radiation-induced gene expression of heme oxygenase 1 (PMID:19874887)
• HO-2 is important in maintaining endothelial viability and may preserve local regulation of vascular tone, thrombosis, and inflammatory responses during reductions in systemic oxygen delivery (PMID:20118244)
• These findings are consistent with the presence of a hydrogen-bonding network at the heme’s distal side within the active site of HO-2 with potentially significant differences from that observed in HO-1. (PMID:20502928)
• There was positive correlation between seminal plasma HO enzyme activity and sperm concentration, per cent of motile spermatozoa, number of motile spermatozoas ml(-1) and significant negative correlation with per cent of sperm abnormal forms. (PMID:20629646)
• HO-2, which is highly expressed in the corneal epithelium, appears to be critical for the wound healing process in the cornea. (PMID:21506105)
• The 19G>C-HMOX1 and the -42 + 1444A>G-HMOX2 polymorphisms may be associated with the occurrence and progression of age-related macular degeneration. (PMID:21647550)
• for the first time, copy number variations in the HMOX2 gene and an association of the SNP rs2270363 with Parkinson’s disease risk. (PMID:21709601)
• Erythroid precursors were characterized by lack of significant expression of HO-1 and by progressive reduction of HO-2 during differentiation. (PMID:21765894)
• Results suggest that the c.544G>A polymorphism of the heme oxygenase-2 gene is not associated with age-related macular degeneration in this population. (PMID:21804464)
• Although the carboxy-terminal deletion mutant of HO-2 is found in the nucleus, translocation of HO-2 to the nucleus does not occur under conditions of hypoxia. (PMID:22545110)
• HO-1 and HO-2 contribute little in the pathophysiology of adenomyosis. (PMID:22559824)
• PFKFB4 and HO-2 are expressed in a coordinated manner to maintain glucose homeostasis. (PMID:22892400)
• Role of cysteine residues in heme binding to human heme oxygenase-2 elucidated by two-dimensional NMR spectroscopy. (PMID:22923613)
• increased expression of nucleated RBC, HSP90alpha and corresponding decreased expression of HO-2 in such hypoxic condition may play a protective role; to prevent cord blood RBC against stress induced damage during preeclampsia. (PMID:22935040)
• We believe that a dysfunctional HO-ferritin system leads to increased levels of proinflammatory mediators, thus contributing to the inflammation characteristic of pterygia. (PMID:23792437)
• Interactions of HO-2 with CPR and BVR, were evaluated. (PMID:25196843)
• Taken together with EPR measurements, which show the appearance of a new low-spin heme signal in reduced HO2, it appears that a cysteine residue(s) in the HRMs directly interacts with a second bound heme (PMID:25849895)
• HO-2 protein is expressed in the cytosols of skin cancer cells. (PMID:25864768)
• a weak association between HMOX2 rs1051308 polymorphisms and the risk to develop essential tremor in the Spanish population. (PMID:26091465)
• The same mechanism of heme hydroxylation to alpha-meso-hydroxyheme is employed by both isoforms HO-1 and HO-2. (PMID:26652036)
• HMOX2 contributes to high-altitude adaptation in Tibetans by functioning as a modifier in the regulation of hemoglobin metabolism. (PMID:26781569)
• The present study suggests a weak association between HMOX2 rs1051308 polymorphism and the risk to develop multiple sclerosis (MS) in Spanish Caucasian men and a trend towards association between the HMOX1 rs2071746A and MS risk. (PMID:26868429)
• HO-2 is a cellular myristate-binding protein that negatively regulates both virus replication and host inflammatory responses. (PMID:28132836)
• Our results suggest that rs1051308 is associated with risk of developing Parkinson disease in Han Chinese, and further studies involving various ethnicities are needed to validate the association. (PMID:28179208)
• The frequencies of genotype and allelic variants of ALAD rs1800435 did not differ significantly between patients with essential tremor (ET) and controls, and were not influenced by gender. Subjects carrying the ALAD rs1800435CC genotype (wild-type) and the HMOX2 rs1051308GG genotype or the HMOX2 rs1051308G allele had significantly decreased risk for ET. (PMID:28276576)
• High HMOX2 expression is associated with bladder cancer. (PMID:28320388)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmox2b	ENSDARG00000078452
danio_rerio	hmox2a	ENSDARG00000114695
mus_musculus	Hmox2	ENSMUSG00000004070
rattus_norvegicus	Hmox2	ENSRNOG00000003773
drosophila_melanogaster	Ho	FBGN0037933

Paralogs (1): HMOX1 (ENSG00000100292)

Protein

Protein identifiers

Heme oxygenase 2 — P30519 (reviewed: P30519)

All UniProt accessions (9): P30519, A0A087WT44, A0A1B0GXH0, I3L159, I3L1F5, I3L1Y2, I3L276, I3L463, I3L4P8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the oxidative cleavage of heme at the alpha-methene bridge carbon, released as carbon monoxide (CO), to generate biliverdin IXalpha, while releasing the central heme iron chelate as ferrous iron. Catalyzes the oxidative cleavage of heme at the alpha-methene bridge carbon, released as carbon monoxide (CO), to generate biliverdin IXalpha, while releasing the central heme iron chelate as ferrous iron.

Subcellular location. Microsome membrane. Endoplasmic reticulum membrane.

Post-translational modifications. A soluble form arises by proteolytic removal of the membrane anchor. S-nitrosylated by BLVRB.

Activity regulation. Inhibited by metalloporphyrins such as Sn- and Zn-protoporphyrins.

Similarity. Belongs to the heme oxygenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P30519-1	1	yes
P30519-2	2

RefSeq proteins (9): NP_001120676, NP_001120677, NP_001120678, NP_001273196, NP_001273197, NP_001273198, NP_001273199, NP_001273200, NP_002125* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002051	Haem_Oase	Family
IPR016053	Haem_Oase-like	Family
IPR016084	Haem_Oase-like_multi-hlx	Homologous_superfamily
IPR018207	Haem_oxygenase_CS	Conserved_site

Pfam: PF01126

Enzyme classification (BRENDA):

• EC 1.14.14.18 — heme oxygenase (biliverdin-producing) (BRENDA: 33 organisms, 138 substrates, 351 inhibitors, 37 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HEME	0.0002–0.04	15
[REDUCED CYTOCHROME P450 REDUCTASE]	0.5–21.7	6
PROTOHEME IX	0.0018–0.0164	3
NADPH	0.0061–0.023	2
[REDUCED NADPH-HEMOPROTEIN REDUCTASE]	0.0018–0.0027	2
ALPHA-MESO-OXYPROTOHEME IX	0.0036	1
CO-HEME	0.125	1
FE-HEME	0.017	1
HEMATOHEME	0.01	1
HEME B	0.0009	1
HEME C	0.029	1
HEMIN	0.01	1
PROTOHEME	0.0009	1

Catalyzed reactions (Rhea), 1 shown:

• heme b + 3 reduced [NADPH–hemoprotein reductase] + 3 O2 = biliverdin IXalpha + CO + Fe(2+) + 3 oxidized [NADPH–hemoprotein reductase] + 3 H2O + H(+) (RHEA:21764)

UniProt features (45 total): helix 13, sequence conflict 5, binding site 4, modified residue 4, turn 3, chain 2, sequence variant 2, mutagenesis site 2, repeat 2, compositionally biased region 2, initiator methionine 1, site 1, splice variant 1, topological domain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5UC9	X-RAY DIFFRACTION	1.9
5UC8	X-RAY DIFFRACTION	2
5UCA	X-RAY DIFFRACTION	2.12
2Q32	X-RAY DIFFRACTION	2.4
4WMH	X-RAY DIFFRACTION	2.5
2QPP	X-RAY DIFFRACTION	2.61
2RGZ	X-RAY DIFFRACTION	2.61

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30519-F1	81.31	0.68

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): 160 (important for catalytic activity)

Ligand- & substrate-binding residues (4): 45 (axial binding residue); 154; 199; 203

Post-translational modifications (4): 2, 2, 265, 282

Mutagenesis-validated functional residues (2):

Position	Phenotype
265	abolished s-nitrosylation; when associated with r-282.
282	abolished s-nitrosylation; when associated with r-265.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-189483	Heme degradation
R-HSA-6798695	Neutrophil degranulation
R-HSA-8980692	RHOA GTPase cycle
R-HSA-917937	Iron uptake and transport
R-HSA-9707564	Cytoprotection by HMOX1

MSigDB gene sets: 206 (showing top): MODULE_93, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOCC_SECRETORY_GRANULE, REACTOME_METABOLISM_OF_PORPHYRINS, MODULE_45, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MODULE_335, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_RESPONSE_TO_OXYGEN_LEVELS, GOBP_TETRAPYRROLE_METABOLIC_PROCESS, GOBP_PIGMENT_METABOLIC_PROCESS

GO Biological Process (4): response to hypoxia (GO:0001666), heme oxidation (GO:0006788), response to oxidative stress (GO:0006979), heme catabolic process (GO:0042167)

GO Molecular Function (5): heme oxygenase (decyclizing) activity (GO:0004392), heme binding (GO:0020037), metal ion binding (GO:0046872), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), specific granule membrane (GO:0035579), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Metabolism of porphyrins	1
Innate Immune System	1
RHO GTPase cycle	1
Transport of small molecules	1
Cellular response to chemical stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	2
porphyrin-containing compound catabolic process	2
heme metabolic process	2
response to decreased oxygen levels	1
pigment catabolic process	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen	1
tetrapyrrole binding	1
cation binding	1
binding	1
catalytic activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cellular anatomical structure	1
secretory granule membrane	1
specific granule	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1254 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMOX2	HARS2	P49590	924
HMOX2	BLVRA	P53004	920
HMOX2	APP	P05067	719
HMOX2	FECH	P22830	718
HMOX2	NFE2L2	Q16236	708
HMOX2	CPOX	P36551	684
HMOX2	KCNMA1	Q12791	655
HMOX2	MB	P02144	645
HMOX2	NOS3	P29474	636
HMOX2	HPX	P02790	576
HMOX2	NOS1	P29475	571
HMOX2	APLP1	P51693	548
HMOX2	HMGXB4	Q9UGU5	547
HMOX2	POR	P16435	537
HMOX2	PPOX	P50336	521

IntAct

356 interactions, top by confidence:

A	B	Type	Score
HMOX2	EBP	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	AQP6	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	FAM210B	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	RETREG3	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	TMX2	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	SGPL1	psi-mi:“MI:0915”(physical association)	0.560
ASGR2	HMOX2	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	BCL2L13	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	SAR1A	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	SLC30A8	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	FAM209A	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	SSMEM1	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	ELOVL5	psi-mi:“MI:0915”(physical association)	0.560
GET1	HMOX2	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	LAPTM5	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	ARL13B	psi-mi:“MI:0915”(physical association)	0.560
SYT1	HMOX2	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	KCNJ6	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	ELOVL4	psi-mi:“MI:0915”(physical association)	0.560
MGST3	HMOX2	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	CRB3	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (405): POTEE (Affinity Capture-MS), SYNGR1 (Affinity Capture-MS), TMEM214 (Affinity Capture-MS), ALG2 (Affinity Capture-MS), UGT8 (Affinity Capture-MS), PRAF2 (Affinity Capture-MS), GNB2 (Affinity Capture-MS), ADPGK (Affinity Capture-MS), CISD2 (Affinity Capture-MS), PTPN1 (Affinity Capture-MS), TMEM205 (Affinity Capture-MS), LMF2 (Affinity Capture-MS), HMOX2 (Proximity Label-MS), HMOX2 (Proximity Label-MS), HMOX2 (Proximity Label-MS)

ESM2 similar proteins: A0A0A2JB87, A1L4V7, A2Y8B9, A3AZW5, B4F8Z1, B6TPF2, B9EYZ1, E0ZS46, F4KF65, F4KFT7, I3SL57, O23052, O48722, O48782, O70252, O73688, P23711, P25362, P30519, P43242, P92983, Q0E3L5, Q0WNZ5, Q1LXE6, Q2PG53, Q38933, Q4HTS9, Q4IER0, Q4U3Y2, Q4WVD1, Q5VS72, Q69XJ4, Q6ATB4, Q6DYE4, Q7SDZ1, Q84R11, Q84ZX8, Q8H4D4, Q8S2E5, Q8S8L9

Diamond homologs: O19998, O70252, O70453, O73688, O78497, P06762, P09601, P14791, P14901, P23711, P30519, P32394, P43242, P51271, P71119, P72849, P74133, Q1XDL5, Q2PG53, Q5E9F2, Q5R7E3, Q8YVS7, I3SL57

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
HMOX2	“down-regulates activity”	HBA1
HMOX2	“down-regulates quantity”	heme	“chemical modification”
CSNK2A1	“up-regulates activity”	HMOX2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 98 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
smoothened signaling pathway	6	12.6×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	41
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3024595	GRCh37/hg19 16p13.3(chr16:2990033-4837646)x1	Pathogenic

SpliceAI

1280 predictions. Top by Δscore:

Variant	Effect	Δscore
16:4505479:TGCA:T	acceptor_loss	1.0000
16:4505480:GCA:G	acceptor_loss	1.0000
16:4505481:CAGGA:C	acceptor_loss	1.0000
16:4505482:A:AG	acceptor_gain	1.0000
16:4505482:AGG:A	acceptor_loss	1.0000
16:4505483:G:GG	acceptor_gain	1.0000
16:4505557:AGACG:A	donor_gain	1.0000
16:4506891:ACAG:A	acceptor_loss	1.0000
16:4506892:C:G	acceptor_gain	1.0000
16:4506893:A:AG	acceptor_gain	1.0000
16:4506893:AGA:A	acceptor_loss	1.0000
16:4506893:AGAAT:A	acceptor_gain	1.0000
16:4506894:G:GG	acceptor_gain	1.0000
16:4506894:GA:G	acceptor_gain	1.0000
16:4506894:GAA:G	acceptor_gain	1.0000
16:4506894:GAAT:G	acceptor_gain	1.0000
16:4506894:GAATG:G	acceptor_gain	1.0000
16:4507008:TTAAG:T	donor_loss	1.0000
16:4507009:TAAG:T	donor_loss	1.0000
16:4507011:AGG:A	donor_loss	1.0000
16:4507012:GGT:G	donor_loss	1.0000
16:4507013:G:GA	donor_loss	1.0000
16:4507711:A:AG	acceptor_gain	1.0000
16:4507712:G:GG	acceptor_gain	1.0000
16:4507712:GCT:G	acceptor_gain	1.0000
16:4508172:G:GT	donor_gain	1.0000
16:4508184:GCTTT:G	donor_gain	1.0000
16:4508188:T:G	donor_gain	1.0000
16:4508188:T:TG	donor_gain	1.0000
16:4509407:TGCA:T	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000031561 (16:4474460 C>A), RS1000051768 (16:4502770 G>A), RS1000153624 (16:4501324 C>A), RS1000161820 (16:4480035 G>A), RS1000253454 (16:4479294 C>T), RS1000308517 (16:4487031 A>G), RS1000484316 (16:4508918 C>T), RS1000540515 (16:4480976 C>T), RS1000543049 (16:4509998 C>A,G,T), RS1000759335 (16:4481365 A>G), RS1000824869 (16:4498565 A>G), RS1000884342 (16:4493769 A>C,G), RS1000915593 (16:4494167 T>C), RS1000940785 (16:4502924 C>A), RS1001035601 (16:4484091 C>T)

Disease associations

OMIM: gene MIM:141251 | 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
GCST006956_6	Erectile dysfunction	2.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2546 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,741 (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
CHEMBL2103882	TIVANTINIB	3	2,741

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Haem oxygenase

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

Ligand	Action	Affinity	Parameter
compound 1 [PMID: 16821802]	Inhibition	3.52	pIC50

ChEMBL bioactivities

9 potent at pChembl≥5 of 10 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.70	Kd	20.04	nM	CHEMBL5653589
7.70	ED50	20.04	nM	CHEMBL5653589
6.92	Kd	119	nM	TIVANTINIB
6.92	Kd	119	nM	CHEMBL5613267
6.34	IC50	460	nM	CHEMBL4166126
5.66	IC50	2200	nM	CHEMBL482686
5.39	Kd	4085	nM	CHEMBL3752910
5.39	ED50	4085	nM	CHEMBL3752910
5.12	IC50	7640	nM	CHEMBL4214264

PubChem BioAssay actives

7 with measured affinity, of 275 total; 7 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148522: Binding affinity to human HMOX2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0200	uM
(3R,4R)-3-(1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-3-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione	1425018: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.1190	uM
N-[3-[2-(1-phenylbenzimidazol-2-yl)ethyl]phenyl]pyrazine-2-carboxamide	2127387: Binding affinity to avi-tagged HO-2 (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.1190	uM
1-imidazol-1-yl-4,4-diphenylbutan-2-one	1633152: Inhibition of HO-2 (unknown origin)	ic50	0.4600	uM
1-[4-(3-bromophenoxy)butyl]imidazole	1633152: Inhibition of HO-2 (unknown origin)	ic50	2.2000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148522: Binding affinity to human HMOX2 incubated for 45 mins by Kinobead based pull down assay	kd	4.0847	uM
1-[4-[6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one	1716423: Covalent binding affinity to HMOX2 at Cys282 residue in human NCI-H358 cells assessed as reduction of log2 H/L ratio for tryptic peptide GALEGSSCPFR incubated for 4 hrs followed by cell lysis and subsequently labelled with light thiol probe N-((S)-18-iodo-11-isopropyl-10,13,17-trioxo-3,6-dioxa-9,12,16-triazaoctadecyl)-6-((4R,5S)-5-methyl-2-oxoimidazolidin-4-yl)hexanamide and heavy thiol probe 4 for 1 hr under dark conditions followed by tryptic digestion for overnight and measured by discovery ABPP based nano LC-MS/MS analysis	ic50	7.6400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, increases expression	6
bisphenol A	affects expression, affects cotreatment, increases expression	2
sodium arsenite	decreases expression, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
Vehicle Emissions	increases expression	2
Hydrogen Peroxide	decreases response to substance, affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
tert-Butylhydroperoxide	decreases response to substance, decreases expression, increases methylation	2
Nanotubes, Carbon	increases expression, decreases expression	2
Particulate Matter	increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
titanium dioxide	increases expression	1
trichostatin A	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pinosylvin	increases expression	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
chromium histidinate	increases expression	1
abexinostat	decreases expression, increases reaction	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2415821	Binding	Inhibition of HO-1 (unknown origin) expressed in human imatinib mesylate-resistant LAMA-84 cells assessed as bilirubin formation at 10 uM after 24 hrs relative to control	Evaluation of novel aryloxyalkyl derivatives of imidazole and 1,2,4-triazole as heme oxygenase-1 (HO-1) inhibitors and their antitumor properties. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1N6	Abcam K-562 HMOX2 KO	Cancer cell line	Female
CVCL_D2JR	Abcam Raji HMOX2 KO	Cancer cell line	Male
CVCL_SR58	HAP1 HMOX2 (-) 1	Cancer cell line	Male
CVCL_UQ72	Abcam Jurkat HMOX2 KO	Cancer cell line	Male
CVCL_XP59	HAP1 HMOX2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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