FECH

Summary

FECH (ferrochelatase, HGNC:3647) is a protein-coding gene on chromosome 18q21.31, encoding Ferrochelatase, mitochondrial (P22830). Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway. It is a selective cancer dependency (DepMap: 38.0% of cell lines).

The protein encoded by this gene is localized to the mitochondrion, where it catalyzes the insertion of the ferrous form of iron into protoporphyrin IX in the heme synthesis pathway. Mutations in this gene are associated with erythropoietic protoporphyria. Two transcript variants encoding different isoforms have been found for this gene. A pseudogene of this gene is found on chromosome 3.

Source: NCBI Gene 2235 — RefSeq curated summary.

At a glance

• Gene–disease (curated): protoporphyria, erythropoietic, 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 310 total — 61 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes — 34 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 38.0% of screened cell lines
• MANE Select transcript: NM_000140

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3647
Approved symbol	FECH
Name	ferrochelatase
Location	18q21.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000066926
Ensembl biotype	protein_coding
OMIM	612386
Entrez	2235

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 11 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000262093, ENST00000382873, ENST00000585494, ENST00000585699, ENST00000585747, ENST00000585878, ENST00000591977, ENST00000592111, ENST00000592699, ENST00000651787, ENST00000651812, ENST00000652755, ENST00000682485, ENST00000878110, ENST00000878111, ENST00000878112, ENST00000932840, ENST00000972075, ENST00000972076

RefSeq mRNA: 5 — MANE Select: NM_000140 NM_000140, NM_001012515, NM_001371094, NM_001371095, NM_001374778

CCDS: CCDS11964, CCDS32836, CCDS92465

Canonical transcript exons

ENST00000262093 — 11 exons

Exon	Start	End
ENSE00000000116	57544377	57550846
ENSE00000669629	57571392	57571540
ENSE00003484710	57573246	57573365
ENSE00003487393	57566447	57566581
ENSE00003492409	57562874	57562980
ENSE00003517160	57551315	57551374
ENSE00003610599	57580073	57580199
ENSE00003632198	57554260	57554424
ENSE00003686289	57554845	57554952
ENSE00003687093	57559145	57559243
ENSE00003901550	57586554	57586702

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.8111 / max 1960.0814, expressed in 1816 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172104	20.0730	1812
172102	7.5806	1687
172103	1.1574	722

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	98.84	gold quality
bone marrow	UBERON:0002371	95.12	gold quality
bone marrow cell	CL:0002092	93.64	gold quality
monocyte	CL:0000576	91.99	gold quality
mononuclear cell	CL:0000842	91.80	gold quality
muscle of leg	UBERON:0001383	91.75	gold quality
gastrocnemius	UBERON:0001388	91.68	gold quality
gluteal muscle	UBERON:0002000	91.00	gold quality
leukocyte	CL:0000738	90.97	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.42	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.22	gold quality
muscle organ	UBERON:0001630	90.11	gold quality
skeletal muscle organ	UBERON:0014892	90.11	gold quality
adrenal tissue	UBERON:0018303	89.74	gold quality
biceps brachii	UBERON:0001507	89.67	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.12	gold quality
triceps brachii	UBERON:0001509	88.65	gold quality
blood	UBERON:0000178	88.48	gold quality
calcaneal tendon	UBERON:0003701	88.24	gold quality
adult mammalian kidney	UBERON:0000082	88.09	gold quality
right adrenal gland	UBERON:0001233	88.06	gold quality
right adrenal gland cortex	UBERON:0035827	87.90	gold quality
heart left ventricle	UBERON:0002084	87.72	gold quality
skeletal muscle tissue	UBERON:0001134	87.69	gold quality
left adrenal gland	UBERON:0001234	87.57	gold quality
cardiac ventricle	UBERON:0002082	87.44	gold quality
renal medulla	UBERON:0000362	87.41	gold quality
deltoid	UBERON:0001476	87.36	silver quality
right lobe of liver	UBERON:0001114	86.64	gold quality
left adrenal gland cortex	UBERON:0035825	86.59	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	786.09
E-HCAD-4	yes	155.62
E-CURD-112	yes	80.90
E-MTAB-10042	yes	50.29
E-MTAB-9221	yes	20.54
E-CURD-122	yes	18.60
E-HCAD-9	yes	10.09
E-MTAB-9388	yes	9.62
E-HCAD-10	yes	7.52
E-MTAB-9801	yes	3.76
E-CURD-98	no	638.82
E-MTAB-9067	no	5.08
E-MTAB-9467	no	2.30
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR2, HIF1A, HNF1A, MYC, SP1

miRNA regulators (miRDB)

182 targeting FECH, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
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-4775	99.98	75.00	6394
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 38.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Mutations in the FECH gene could not account the development of liver disease in the severe phenotype of erythropoietic protoporphyria(EPP). (PMID:11929052)
• Data indicate a significant genotype-phenotype correlation between “null allele” mutation and protoporphyrin related liver disease in erythropoietic protoporphyria. (PMID:11929053)
• Modulation of penetrance by the wild-type allele in dominantly inherited erythrohepatic and acute hepatic porphyrias was studied using FECH. (PMID:14669009)
• Mutation in ferrochelatase is associated with erythropoietic porphyria. (PMID:15046047)
• analysis of frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis (PMID:15123683)
• Identification of autosomal recessive FECH mutations in erythropoietic protoporphyria patients with higher risk of severe liver disease in the United Kingdom. (PMID:15286165)
• data for 12 ferrochelatase wild-type/EPP mutant heterodimers show that some mutations result in heterodimers with the residual activity anticipated, whereas others result in heterodimers with significantly lower activity than would be predicted (PMID:15831704)
• mutation in promoter affects binding of a transcription factor and causes erythropoietic protoporphyria phenotype (PMID:15850836)
• A common single-nucleotide polymorphism of FECH gene contributes to the genetic predisposition for erythropoietic protoporphyria. (PMID:16385445)
• Patients with erythropoietic protoporphyria usually have a mutation in 1 Ferrochelatase allele that alters enzyme structure/function, together with a polymorphism in the nonmutant allele that causes low gene expression. (PMID:16819399)
• These data suggest that the first 62 amino acids of ferrochelatase allow targeting to mitochondria but do not contain sufficient information for efficient processing of the protein. (PMID:16844398)
• Mutations and a low-expressed allele IVS3-48c (in trans to the mutation) of the ferrochelatase (FECH) gene are responsible for erythropoietic protoporphyria (EPP) which is characterized clinically by cutaneous photosensitivity. (PMID:17196862)
• Substrate is bound deep within an enclosed pocket, and the binding sites with protoporphyrin IX are mapped in detail. (PMID:17261801)
• results highlight a novel, profilin2-dependent pathway, regulating synaptic physiology, neuronal excitability, and complex behavior (PMID:17566985)
• It was found that in the H263C and H341C variants, but not the F337A variant enzymes, the side chains of N75, M76, R164, H263, F337, H341, and E343 are oriented in a fashion similar to what is found in ferrochelatase with the bound porphyrin substrate (PMID:17567154)
• large deletions of the FECH gene are an important cause of erythropoietic protoporphyria (PMID:17597821)
• mutation associated with erythropoietic protoporphyria in Chinese family (PMID:17723290)
• show that in malignant tissue a transcriptional down-regulation of FECH occurs, which causes endogenous protoporphyrin-IX accumulation (PMID:17875605)
• most cases of EPP result from the coinheritance of IVS3-48C and a mutation in the FECH gene, and also document the existence of patients with mutations in homozygosity that may present a more severe form of the disease. (PMID:17875872)
• Data shows ferrochelatase undergoes significant changes in secondary structure during the catalytic cycle. (PMID:17884090)
• a ferrochelatase mutation in a Chinese family with erythropoietic protoporphyria. (PMID:18160121)
• Report ferrochelatase functional variants resulting in erythropoietic protoporphyria in an Ashkenazi Jewish family. (PMID:18758989)
• analysis of FECH mutations in patients with seasonal palmar keratoderma in erythropoietic protoporphyria (PMID:18787536)
• The mutation analysis in the FECH gene identified different genotypes with the t/t genotype, 7 with the t/M genotype, 14 with the c/t genotype and 10 with c/M genotype from different EPP families. (PMID:19656458)
• Sequencing of the ferrochelatase gene did not show a mutation in any of the patients studied. Furthermore, the hypomorphic allele IVS3-48C was absent in all individuals. (PMID:19656459)
• analysis of skin ferrochelatase and photosensitivity in mice and man (PMID:19657351)
• ferrochelatase localizes to both the mitochondrial outer and inner membranes, and the change in the equilibrium position of the forward and reverse activities may be regulated by the phosphorylation of ferrochelatase (PMID:19691493)
• The findings show that at least in the cases of Mn, Pb, Cd, and Hg, metal “inhibition” of ferrochelatase occurs after metal insertion and results from poor or diminished product release. (PMID:19703464)
• analysis of ion selectivity and substrate inhibition in the metal ion chelation catalyzed by human ferrochelatase (PMID:19767646)
• A novel splicing FECH mutation in a Chinese erythropoietic protoporphyria family is believed to be responsible for generating the phenotypic symptoms in this family. (PMID:19888946)
• the stability of newly formed ferrochelatase protein was dramatically decreased during iron deficiency (PMID:19965627)
• A novel homoallelic missense mutation (p.Ser318Tyr) was identified in the FECH gene in erythropoietic protoporphyria and palmar keratoderma (PMID:20337824)
• More than 96% of unrelated EPP patients have ferrochelatase deficiency (MIM 177000). Inheritance of a common hypomorphic IVS3-48C FECH allele trans to a deleterious FECH mutation reduces FECH activity below a critical threshold. Review. (PMID:20850938)
• analysis of the inhibitory metal ion-binding site in ferrochelatase (PMID:20966079)
• role of IVS3-48C allele in erythropoietic protoporphyria (PMID:21132468)
• Erythropoietic protoporphyria patients and their mother revealed heterozygosity for a novel mutation (c.1052delA) in FECH gene of both children, and heterozygosity for the hypomorphic allele IVS3-48T>C in all of them. (PMID:21659066)
• function of solvent-filled channels in human ferrochelatase (PMID:22712763)
• Loss-of-function FECH and gain-of-function erythroid-specific ALAS2 mutations causing erythropoietic protoporphyria and x-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. (PMID:23364466)
• Molecular dynamic simulations provided insight into the conformational movements and function of the active site residues of human ferrochelatase. (PMID:23446439)
• Sequence analysis of the FECH gene identified a novel missense mutation in exon 4 (c.418>A, G140R) of the FECH gene, as well as the common FECH IVS3-48 polymorphism in erythropoietic protoporphyria. (PMID:23600449)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fech	ENSDARG00000003462
mus_musculus	Fech	ENSMUSG00000024588
rattus_norvegicus	Fech	ENSRNOG00000018053
drosophila_melanogaster	FeCH	FBGN0266268

Protein

Protein identifiers

Ferrochelatase, mitochondrial — P22830 (reviewed: P22830)

Alternative names: Heme synthase, Protoheme ferro-lyase

All UniProt accessions (5): P22830, A0A499FJN5, K7EJM8, K7EJX5, K7ELX4

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway.

Subunit / interactions. Homodimer. Homotetramer. Interacts with PGRMC1; the interaction results in decreased FECH activity. Interacts with ABCB10 and SLC25A37; this interaction forms an oligomeric complex. Forms a complex with ABCB7 and ABCB10, where a dimeric FECH bridges ABCB7 and ABCB10 homodimers; this complex may be required for cellular iron homeostasis, mitochondrial function and heme biosynthesis. Interacts with ABCB7 and ABCB10.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Protoporphyria, erythropoietic, 1 (EPP1) [MIM:177000] An autosomal recessive form of porphyria with onset usually before age 10 years. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Erythropoietic protoporphyria is marked by excessive protoporphyrin in erythrocytes, plasma, liver and feces, and by widely varying photosensitive skin changes ranging from a burning or pruritic sensation to erythema, edema and wheals. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by nitric oxide (NO). The 2Fe-2S cluster could act as a NO sensor.

Cofactor. Binds 1 [2Fe-2S] cluster.

Pathway. Porphyrin-containing compound metabolism; protoheme biosynthesis; protoheme from protoporphyrin-IX: step 1/1.

Similarity. Belongs to the ferrochelatase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P22830-1	1	yes
P22830-2	2

RefSeq proteins (5): NP_000131, NP_001012533, NP_001358023, NP_001358024, NP_001361707 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001015	Ferrochelatase	Family
IPR019772	Ferrochelatase_AS	Active_site
IPR033644	Ferrochelatase_C	Domain
IPR033659	Ferrochelatase_N	Domain

Pfam: PF00762

Enzyme classification (BRENDA):

• EC 4.99.1.1 — protoporphyrin ferrochelatase (BRENDA: 0 organisms, 0 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• heme b + 2 H(+) = protoporphyrin IX + Fe(2+) (RHEA:22584)

UniProt features (85 total): sequence variant 26, helix 17, strand 11, mutagenesis site 9, binding site 7, turn 5, modified residue 4, active site 2, transit peptide 1, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
3HCN	X-RAY DIFFRACTION	1.6
2HRC	X-RAY DIFFRACTION	1.7
3AQI	X-RAY DIFFRACTION	1.7
3HCO	X-RAY DIFFRACTION	1.8
4F4D	X-RAY DIFFRACTION	1.8
1HRK	X-RAY DIFFRACTION	2
2QD4	X-RAY DIFFRACTION	2
3HCP	X-RAY DIFFRACTION	2
7CT7	X-RAY DIFFRACTION	2
7CTC	X-RAY DIFFRACTION	2
3W1W	X-RAY DIFFRACTION	2.01
4KLR	X-RAY DIFFRACTION	2.18
2PO5	X-RAY DIFFRACTION	2.2
2PO7	X-RAY DIFFRACTION	2.2
2QD1	X-RAY DIFFRACTION	2.2
2QD2	X-RAY DIFFRACTION	2.2
2QD3	X-RAY DIFFRACTION	2.2
3HCR	X-RAY DIFFRACTION	2.2
2QD5	X-RAY DIFFRACTION	2.3
2PNJ	X-RAY DIFFRACTION	2.35
4KLC	X-RAY DIFFRACTION	2.4
2HRE	X-RAY DIFFRACTION	2.5
4MK4	X-RAY DIFFRACTION	2.5
4KLA	X-RAY DIFFRACTION	2.6
4KMM	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22830-F1	87.37	0.81

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 (2): 230; 383

Ligand- & substrate-binding residues (7): 411; 115; 123; 130; 196; 403; 406

Post-translational modifications (4): 57, 138, 415, 415

Mutagenesis-validated functional residues (9):

Position	Phenotype
110	increases activity inhibition upon interaction with pgrmc1.
196	loss of activity.
360	no loss of activity.
395	no loss of activity.
403	loss of activity.
406	loss of activity.
411	loss of activity.
417	decreased activity.
417	greatly reduced activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-189451	Heme biosynthesis
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 250 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_HEMOGLOBIN_METABOLIC_PROCESS, HORIUCHI_WTAP_TARGETS_DN, GOBP_MYELOID_CELL_HOMEOSTASIS, REACTOME_METABOLISM_OF_PORPHYRINS, GOBP_ERYTHROCYTE_HOMEOSTASIS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MODULE_335, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, GOBP_PROTEIN_LIPID_COMPLEX_ASSEMBLY, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GNF2_ANK1, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY

GO Biological Process (22): generation of precursor metabolites and energy (GO:0006091), heme biosynthetic process (GO:0006783), heme A biosynthetic process (GO:0006784), heme B biosynthetic process (GO:0006785), cholesterol metabolic process (GO:0008203), response to xenobiotic stimulus (GO:0009410), response to light stimulus (GO:0009416), detection of UV (GO:0009589), response to lead ion (GO:0010288), response to insecticide (GO:0017085), erythrocyte differentiation (GO:0030218), very-low-density lipoprotein particle assembly (GO:0034379), response to ethanol (GO:0045471), obsolete protoporphyrinogen IX metabolic process (GO:0046501), response to arsenic-containing substance (GO:0046685), regulation of hemoglobin biosynthetic process (GO:0046984), response to methylmercury (GO:0051597), multicellular organismal-level iron ion homeostasis (GO:0060586), response to platinum ion (GO:0070541), cellular response to dexamethasone stimulus (GO:0071549), porphyrin-containing compound biosynthetic process (GO:0006779), response to metal ion (GO:0010038)

GO Molecular Function (13): protoporphyrin ferrochelatase activity (GO:0004325), ferrous iron binding (GO:0008198), heme binding (GO:0020037), iron-responsive element binding (GO:0030350), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), 2 iron, 2 sulfur cluster binding (GO:0051537), iron ion binding (GO:0005506), protein binding (GO:0005515), lyase activity (GO:0016829), metal ion binding (GO:0046872), tetrapyrrole binding (GO:0046906), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of porphyrins	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to chemical	3
heme biosynthetic process	2
response to metal ion	2
binding	2
metabolic process	1
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
sterol metabolic process	1
secondary alcohol metabolic process	1
response to radiation	1
response to UV	1
detection of light stimulus	1
response to toxic substance	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
plasma lipoprotein particle assembly	1
response to alcohol	1
regulation of macromolecule biosynthetic process	1
hemoglobin biosynthetic process	1
regulation of protein metabolic process	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
multicellular organismal-level chemical homeostasis	1
cellular response to glucocorticoid stimulus	1
response to dexamethasone	1
cellular response to ketone	1
lyase activity	1
iron ion binding	1
tetrapyrrole binding	1
mRNA binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
iron-sulfur cluster binding	1
transition metal ion binding	1
catalytic activity	1
cation binding	1
metal cluster binding	1
cytoplasm	1

Protein interactions and networks

STRING

2498 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FECH	ABCB10	Q9NRK6	994
FECH	SLC25A37	Q9NYZ2	985
FECH	ALAS2	P22557	979
FECH	CPOX	P36551	970
FECH	HMBS	P08396	946
FECH	FXN	Q16595	935
FECH	PPOX	P50336	933
FECH	ALAS1	P13196	902
FECH	PGRMC1	O00264	895
FECH	ACO2	Q99798	881
FECH	ALAD	P13716	879
FECH	UROS	P10746	872
FECH	UROD	P06132	867
FECH	ABCB7	O75027	862
FECH	ISCU	Q9H1K1	829

IntAct

123 interactions, top by confidence:

A	B	Type	Score
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	STRN	psi-mi:“MI:2364”(proximity)	0.880
PPP2CB	CEP43	psi-mi:“MI:0914”(association)	0.730
FECH	FECH	psi-mi:“MI:0407”(direct interaction)	0.720
FECH	FECH	psi-mi:“MI:0915”(physical association)	0.720
ABCB7	FECH	psi-mi:“MI:0914”(association)	0.710
ABCB7	FECH	psi-mi:“MI:0407”(direct interaction)	0.710
ABCB7	FECH	psi-mi:“MI:0915”(physical association)	0.710
FECH	ABCB7	psi-mi:“MI:0407”(direct interaction)	0.710
FECH	ABCB7	psi-mi:“MI:0915”(physical association)	0.710
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
FECH	PGRMC1	psi-mi:“MI:0915”(physical association)	0.700
FECH	PGRMC1	psi-mi:“MI:0414”(enzymatic reaction)	0.700
FECH	PGRMC1	psi-mi:“MI:0914”(association)	0.700
ABCB10	FECH	psi-mi:“MI:0407”(direct interaction)	0.670
PPP2R1A	PPFIA3	psi-mi:“MI:0914”(association)	0.670
NR1H3	NCOR1	psi-mi:“MI:0914”(association)	0.640
Ppp2r1a	FECH	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (204): FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), FECH (Two-hybrid), FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), FECH (Affinity Capture-MS), ATPAF2 (Affinity Capture-MS)

ESM2 similar proteins: A0A7J6F8C5, A0FKE6, A2Y3Q5, A4GNA8, A6QLU1, A7DZP8, F4JHA2, F4KAK5, O04921, O22436, O42479, O57478, O59786, P0DKG8, P11605, P15719, P16622, P17569, P22315, P22600, P22830, P35571, P39865, P39867, P39868, P42043, P42044, P42045, P43304, P52426, Q05145, Q0DIV0, Q2R1U4, Q3YA36, Q42606, Q4R755, Q5JN42, Q64521, Q69TB1, Q6AVG6

Diamond homologs: A0K4S2, A1ASJ7, A1V0U1, A2BQ06, A2BVI7, A2C0Y4, A2C7Q7, A2S570, A2Y3Q5, A3MNA4, A3ND73, A3NYY2, A3PBP9, A4JBR6, A5GDG7, A5GJF5, A5GS98, A6Q2Y9, A8F0B2, A8G3P0, A8GYD7, A9B546, A9BEE9, B0JRN7, B1JW14, B1XL79, B1YTJ5, B2J9P0, B2V955, B3CLU1, B4RD10, B5EJ44, B7K399, B7KGB9, B8GW40, B8HK77, B9M326, C0R4L0, C5BD17, C6E7U2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NFE2L2	“up-regulates quantity by expression”	FECH	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
PKR-mediated signaling	5	9.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	61
Likely pathogenic	18
Uncertain significance	90
Likely benign	68
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012439	NM_000140.5(FECH):c.175C>T (p.Gln59Ter)	Pathogenic
1069596	NM_000140.5(FECH):c.901_902del (p.Trp301fs)	Pathogenic
1370481	NM_000140.5(FECH):c.945del (p.Asp316fs)	Pathogenic
1389638	NM_000140.5(FECH):c.680G>A (p.Trp227Ter)	Pathogenic
1399753	NC_000018.9:g.(?55233659)(55240617_?)del	Pathogenic
1402376	NM_000140.5(FECH):c.843del (p.Ser281fs)	Pathogenic
1402387	NM_000140.5(FECH):c.627C>A (p.Tyr209Ter)	Pathogenic
1402419	NC_000018.10:g.57586871C>G	Pathogenic
1409435	NM_000140.5(FECH):c.1217G>A (p.Cys406Tyr)	Pathogenic
1409936	NC_000018.9:g.(?55238604)(55240617_?)del	Pathogenic
1452410	NM_000140.5(FECH):c.63_67delTCCGC (p.Pro22fs)	Pathogenic
1454603	NC_000018.9:g.(?55253766)(55254103_?)del	Pathogenic
1457371	NM_000140.5(FECH):c.463+1G>C	Pathogenic
1457748	NM_000140.5(FECH):c.253dup (p.Val85fs)	Pathogenic
1459020	NC_000018.9:g.(?55217944)(55230232_?)del	Pathogenic
1508284	NM_000140.5(FECH):c.599-2A>G	Pathogenic
1708448	NM_000140.5(FECH):c.892C>T (p.Arg298Ter)	Pathogenic
1805745	NM_000140.5(FECH):c.40del (p.Ala14fs)	Pathogenic
1918194	NM_000140.5(FECH):c.1025_1026del (p.Ile342fs)	Pathogenic
2011661	NM_000140.5(FECH):c.1077+1del	Pathogenic
2138158	NM_000140.5(FECH):c.963del (p.Leu322fs)	Pathogenic
2422454	NC_000018.9:g.(?55225777)(55226495_?)del	Pathogenic
2422455	NC_000018.9:g.(?55222057)(55225777_?)del	Pathogenic
242756	NM_000140.5(FECH):c.1231T>G (p.Cys411Gly)	Pathogenic
2500175	NM_000140.5(FECH):c.1049_1052dup (p.Glu351fs)	Pathogenic
2683631	NM_000140.5(FECH):c.215dup (p.Leu72fs)	Pathogenic
2702299	NM_000140.5(FECH):c.599-2A>C	Pathogenic
2727476	NM_000140.5(FECH):c.954dup (p.Ile319fs)	Pathogenic
2736731	NM_000140.5(FECH):c.1137+2T>G	Pathogenic
2736732	NM_000140.5(FECH):c.1078-1G>A	Pathogenic

SpliceAI

1837 predictions. Top by Δscore:

Variant	Effect	Δscore
18:57550847:C:CC	acceptor_gain	1.0000
18:57551373:CA:C	acceptor_gain	1.0000
18:57551375:C:CC	acceptor_gain	1.0000
18:57551381:C:CT	acceptor_gain	1.0000
18:57551382:A:T	acceptor_gain	1.0000
18:57551384:A:AC	acceptor_gain	1.0000
18:57554840:CTTA:C	donor_loss	1.0000
18:57554841:TTA:T	donor_loss	1.0000
18:57554844:C:CT	donor_loss	1.0000
18:57554953:C:CG	acceptor_loss	1.0000
18:57554954:T:A	acceptor_loss	1.0000
18:57562869:CTTA:C	donor_loss	1.0000
18:57562870:TTA:T	donor_loss	1.0000
18:57562871:TACCT:T	donor_loss	1.0000
18:57562981:C:CA	acceptor_loss	1.0000
18:57562981:C:CC	acceptor_gain	1.0000
18:57562982:T:A	acceptor_loss	1.0000
18:57566596:A:C	acceptor_gain	1.0000
18:57571537:CTTA:C	acceptor_gain	1.0000
18:57573244:A:AC	donor_gain	1.0000
18:57573245:C:CC	donor_gain	1.0000
18:57573245:CTT:C	donor_gain	1.0000
18:57573247:T:TA	donor_gain	1.0000
18:57586552:A:AC	donor_gain	1.0000
18:57586553:C:CC	donor_gain	1.0000
18:57586553:CG:C	donor_gain	1.0000
18:57550843:GGGC:G	acceptor_gain	0.9900
18:57550846:CCTGG:C	acceptor_loss	0.9900
18:57550847:C:CA	acceptor_loss	0.9900
18:57550848:T:C	acceptor_loss	0.9900

AlphaMissense

2760 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:57554326:A:C	F337L	1.000
18:57554326:A:T	F337L	1.000
18:57554328:A:G	F337L	1.000
18:57554320:A:C	S339R	0.999
18:57554320:A:T	S339R	0.999
18:57554322:T:G	S339R	0.999
18:57554339:A:T	V333D	0.999
18:57554409:A:G	W310R	0.999
18:57554409:A:T	W310R	0.999
18:57554856:A:G	W301R	0.999
18:57554856:A:T	W301R	0.999
18:57562900:A:G	W227R	0.999
18:57562900:A:T	W227R	0.999
18:57562918:A:G	W221R	0.999
18:57562918:A:T	W221R	0.999
18:57562973:G:C	S202R	0.999
18:57562973:G:T	S202R	0.999
18:57562975:T:G	S202R	0.999
18:57566485:G:T	A187D	0.999
18:57566560:C:T	G162E	0.999
18:57573296:G:C	F88L	0.999
18:57573296:G:T	F88L	0.999
18:57573298:A:G	F88L	0.999
18:57554294:A:G	L348P	0.998
18:57554308:T:A	E343D	0.998
18:57554308:T:G	E343D	0.998
18:57554327:A:G	F337S	0.998
18:57554328:A:T	F337I	0.998
18:57554333:A:T	I335K	0.998
18:57554850:A:G	S303P	0.998

dbSNP variants (sampled 300 via entrez): RS1000072693 (18:57551817 G>A), RS1000135496 (18:57572285 C>T), RS1000173543 (18:57572701 G>A), RS1000269059 (18:57575559 C>T), RS1000329206 (18:57582473 G>A), RS1000465102 (18:57582217 A>G), RS1000628782 (18:57556449 G>A), RS1000716190 (18:57562828 C>T), RS1000725254 (18:57569336 C>T), RS1000745155 (18:57566095 T>A), RS1000779711 (18:57544849 G>A,C), RS1000936455 (18:57544440 C>T), RS1000966613 (18:57587197 A>T), RS1001020271 (18:57563187 G>A), RS1001037798 (18:57584561 TG>T,TGG)

Disease associations

OMIM: gene MIM:612386 | disease phenotypes: MIM:177000

GenCC curated gene-disease

Disease	Classification	Inheritance
protoporphyria, erythropoietic, 1	Definitive	Autosomal recessive
autosomal erythropoietic protoporphyria	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
protoporphyria, erythropoietic, 1	Definitive	AR

Mondo (2): protoporphyria, erythropoietic, 1 (MONDO:0008319), autosomal erythropoietic protoporphyria (MONDO:0019263)

Orphanet (1): Autosomal erythropoietic protoporphyria (Orphanet:79278)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000964	Eczematoid dermatitis
HP:0000969	Edema
HP:0000989	Pruritus
HP:0000992	Cutaneous photosensitivity
HP:0001081	Cholelithiasis
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001410	Decreased liver function
HP:0001878	Hemolytic anemia
HP:0001935	Microcytic anemia
HP:0002155	Hypertriglyceridemia
HP:0010472	Abnormal circulating porphyrin concentration
HP:0010783	Erythema
HP:0011463	Childhood onset
HP:6000697	Low tissue ferrochelatase activity

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003986_23	Migraine	6.000000e-08
GCST005993_60	Mean corpuscular hemoglobin	7.000000e-12
GCST006011_33	Mean corpuscular volume	6.000000e-09
GCST90002404_196	Red cell distribution width	2.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3879831 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

34 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 354,460 (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
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL180022	NERATINIB	4	9,404
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2105717	CABOZANTINIB	4	11,177
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL3545110	RIBOCICLIB	4	8,018
CHEMBL3989868	TUCATINIB	4	3,159
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL939	GEFITINIB	4	117,814
CHEMBL1091644	LINSITINIB	3	1,446
CHEMBL1241855	RIGOSERTIB	3	1,544
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL1079175	MK-2206	2	3,008
CHEMBL1614713	CC-401	2	389
CHEMBL1822792	MK-2461	2	686
CHEMBL1944698	ZOTIRACICLIB	2	2,915
CHEMBL2103842	VARLITINIB	2	1,703
CHEMBL3039517	RABUSERTIB	2	538
CHEMBL3120215	OSI-027	2
CHEMBL3218578	BGT-226 FREE BASE	2
CHEMBL475251	R-406	2
CHEMBL483321	CP-724714	2
CHEMBL513909	BI-2536	2
CHEMBL607707	PELITINIB	2
CHEMBL1090479	GSK-1070916	1
CHEMBL1801204	AZD-8055	1
CHEMBL2323775	MK-8033	1
CHEMBL3109738	JNJ-26483327	1

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs536560	FECH		0.00	0

Binding affinities (BindingDB)

11 measured of 29 human assays (29 total across all organisms); most potent 11 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Momelotinib	IC50	8 nM	US-9469613: (N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide
BMS-907351	IC50	9.9 nM
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide	IC50	33 nM
(Z)-but-2-enedioic acid;8-(6-methoxypyridin-3-yl)-3-methyl-1-[4-piperazin-1-yl-3-(trifluoromethyl)phenyl]imidazo[4,5-c]quinolin-2-one	IC50	41.9 nM	US-9284315: Three-ring PI3K and/or mTOR inhibitor
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	IC50	110 nM	US-9145414: 1,2,4-triazine-6-carboxamide derivative
(3R,4R)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol	KD	961 nM
ERLOTINIB HYDROCHLORIDE	KD	1200 nM
PLX-4032	EC50	1600 nM	US-9670209: Muscarinic agonists
GEFITINIB	IC50	2300 nM	US-9416123: Kinase modulators for the treatment of cancer
(E)-N-[4-(3-chloro-4-fluoro-anilino)-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)but-2-enamide	KD	3500 nM
2-methoxy-N-[(E)-3-[4-[3-methyl-4-(6-methylpyridin-3-yl)oxyanilino]quinazolin-6-yl]prop-2-enyl]acetamide	KD	110000 nM

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.61	Kd	243	nM	ZOTIRACICLIB
6.11	Kd	783	nM	CYC-116
5.97	Kd	1069	nM	MK-2206
5.96	Kd	1089	nM	CHEMBL3688339
5.85	Kd	1419	nM	VEMURAFENIB
5.62	Kd	2415	nM	GSK-1070916
5.58	Kd	2628	nM	CABOZANTINIB
5.57	Kd	2701	nM	GSK-690693
5.55	Kd	2806	nM	LENVATINIB
5.54	Kd	2867	nM	CUDC-101
5.54	Kd	2884	nM	CHEMBL3752910
5.54	Kd	2905	nM	CHEMBL3752910
5.54	ED50	2920	nM	CHEMBL3752910
5.51	Kd	3108	nM	BGT-226 FREE BASE
5.51	Kd	3080	nM	R-406
5.47	Kd	3418	nM	MK-2461
5.46	Kd	3481	nM	CHEMBL3699142
5.42	Kd	3824	nM	RABUSERTIB
5.42	Kd	3801	nM	BI-2536
5.41	Kd	3912	nM	TUCATINIB
5.40	Kd	3974	nM	JNJ-26483327
5.38	Kd	4213	nM	LINSITINIB
5.38	Kd	4138	nM	NILOTINIB
5.30	EC50	5012	nM	VEMURAFENIB
5.25	Kd	5577	nM	RIGOSERTIB
5.22	Kd	6029	nM	NERATINIB
5.19	Kd	6501	nM	AEW-541
5.17	Kd	6682	nM	GEFITINIB
5.17	Kd	6840	nM	AXITINIB
5.16	Kd	6896	nM	AZD-8055
5.16	Kd	6905	nM	ERLOTINIB
5.13	Kd	7354	nM	CRENOLANIB
5.09	Kd	8143	nM	CHEMBL5653589
5.09	ED50	8184	nM	CHEMBL5653589

PubChem BioAssay actives

64 with measured affinity, of 276 total; 43 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
(16E)-14-methyl-20-oxa-5,7,14,27-tetrazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2(27),3,5,8,10,12(26),16,21,23-decaene	1425001: 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	0.2430	uM
4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	0.7000	uM
Gefitinib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	1.0000	uM
8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one	1425001: 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	1.0690	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425001: 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	1.0890	uM
Vemurafenib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	1.3000	uM
3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethylpyrazol-3-yl]phenyl]-1,1-dimethylurea	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	1.7000	uM
Nilotinib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	1.7000	uM
14-[[[(2R)-1,4-dioxan-2-yl]methyl-methylsulfamoyl]amino]-5-(1-methylpyrazol-4-yl)-2-oxo-7-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaene	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	2.1000	uM
3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	2.2000	uM
4-(2-methyl-3-propan-2-ylimidazol-4-yl)-N-(4-methylsulfonylphenyl)pyrimidin-2-amine	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	2.6000	uM
Cabozantinib	1425001: 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	2.6280	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	2.7000	uM
Lenvatinib	1425001: 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	2.8060	uM
7-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]oxy-N-hydroxyheptanamide	1425001: 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	2.8670	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148380: Binding affinity to human FECH incubated for 45 mins by Kinobead based pull down assay	kd	2.8840	uM
(3R,4R)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.0000	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	1425001: 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	3.0800	uM
Axitinib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.1000	uM
8-(6-methoxy-3-pyridinyl)-3-methyl-1-[4-piperazin-1-yl-3-(trifluoromethyl)phenyl]imidazo[4,5-c]quinolin-2-one	1425001: 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	3.1080	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.2000	uM
Momelotinib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.4000	uM
3-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-N-methylbenzamide	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.4000	uM
3-[3-[N-[4-[(dimethylamino)methyl]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-1H-indol-6-yl]-N-ethylprop-2-ynamide	1425001: 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	3.4810	uM
1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.8000	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	1425001: 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	3.8010	uM
1-[5-bromo-4-methyl-2-[[(2S)-morpholin-2-yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea	1425001: 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	3.8240	uM
Tucatinib	1425001: 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	3.9120	uM
5-bromo-18-methoxy-10-methyl-16-oxa-2,10,21,23-tetrazatetracyclo[15.6.2.03,8.020,24]pentacosa-1(23),3(8),4,6,17,19,21,24-octaene	1425001: 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	3.9740	uM
7-[3-(azetidin-1-ylmethyl)cyclobutyl]-5-(3-phenylmethoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	4.4000	uM
4-[4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[5,1-f][1,2,4]triazin-7-yl]cyclohexane-1-carboxylic acid	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	4.5000	uM
Neratinib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	5.1000	uM
2-[2-methoxy-5-[[(E)-2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonylmethyl]anilino]acetic acid	1425001: 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	5.5770	uM
[5-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxyphenyl]methanol	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	6.2000	uM
6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazolin-4-amine	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	6.4000	uM
7-[3-(azetidin-1-yl)cyclobutyl]-5-(3-phenylmethoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1425001: 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	6.5010	uM
Erlotinib	1425001: 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	6.9050	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148380: Binding affinity to human FECH incubated for 45 mins by Kinobead based pull down assay	kd	8.1427	uM
(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide	1425001: 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	10.5450	uM
2-methoxy-N-[(E)-3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]quinazolin-6-yl]prop-2-enyl]acetamide	1425001: 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	28.5700	uM
3-[3-(2-piperidin-1-ylethoxy)phenyl]-5-(1H-1,2,4-triazol-5-yl)-1H-indazole	1425001: 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	32.3840	uM
1-[5-(1-methylpyrazol-4-yl)-2-oxo-7-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-14-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide	1425001: 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	32.6400	uM
Pacritinib	1425001: 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	67.9140	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, decreases reaction, increases expression, affects methylation	4
Valproic Acid	affects expression, increases expression	4
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
zinc mesoporphyrin	increases chemical synthesis, increases reaction	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
bisphenol F	increases expression	1
chloroacetaldehyde	affects expression	1
tributyltin	decreases activity	1
beta-lapachone	increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
cinnamyl alcohol	increases expression	1
pyridoxal isonicotinoyl hydrazone	decreases abundance, decreases expression, decreases reaction	1
ferric chloride	decreases expression, decreases reaction, increases expression	1
tobacco tar	increases expression	1
ochratoxin A	decreases expression	1
n-hexane	increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
nickel sulfate	increases expression	1
methyl salicylate	increases expression	1
isoeugenol	increases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3877219	Binding	Stabilization of FECH in human K562 cells after 1 hr by thermal shift assay	Non-kinase targets of protein kinase inhibitors. — Nat Rev Drug Discov

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1MI	Abcam K-562 FECH KO	Cancer cell line	Female
CVCL_D2J3	Abcam Raji FECH KO	Cancer cell line	Male
CVCL_GS68	GM05008	Finite cell line	Female
CVCL_UQ50	Abcam Jurkat FECH KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004940	PHASE3	COMPLETED	Phase III Study of L-Cysteine in Patients With Erythropoietic Protoporphyria
NCT00979745	PHASE3	COMPLETED	Phase III Confirmatory Study in Erythropoietic Protoporphyria (EPP)
NCT01605136	PHASE3	COMPLETED	Phase III Confirmatory Study in Erythropoietic Protoporphyria
NCT04053270	PHASE3	COMPLETED	Multicentre Phase III Erythropoietic Protoporphyria Study
NCT04402489	PHASE3	COMPLETED	Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Erythropoietic Protoporphyria or X-Linked Protoporphyria
NCT04578496	PHASE3	COMPLETED	A Safety Extension Study in Patients With Erythropoietic Protoporphyria (EPP)
NCT05005975	PHASE3	RECRUITING	Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP)
NCT06144840	PHASE3	ACTIVE_NOT_RECRUITING	INcreased Sun Exposure Without Pain In Research Participants With EPP or XLP
NCT06910358	PHASE3	ACTIVE_NOT_RECRUITING	Study of Bitopertin in Participants With EPP or XLP (APOLLO)
NCT01097044	PHASE2	COMPLETED	Phase II Confirmatory Study in Erythropoietic Protoporphyria (EPP)
NCT03520036	PHASE2	COMPLETED	Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Erythropoietic Protoporphyria
NCT05020184	PHASE2	COMPLETED	Effect of Oral Cimetidine in the Protoporphyrias
NCT05308472	PHASE2	COMPLETED	Study of Bitopertin to Evaluate the Safety, Tolerability, Efficacy, and PPIX Concentrations in Participants With EPP
NCT06971900	PHASE2	ENROLLING_BY_INVITATION	GATEWAY: A Phase 2a Study of PORT-77 in Adults With Erythropoietic Protoporphyria
NCT01422915	PHASE2/PHASE3	COMPLETED	Sorbent Therapy of the Cutaneous Porphyrias
NCT05883748	PHASE2/PHASE3	ENROLLING_BY_INVITATION	HELIOS: Open-Label, Long-Term Extension Study to Investigate the Safety, Tolerability, and Efficacy of DISC-1459 (Bitopertin) in Participants With EPP or XLP
NCT06388642	PHASE1/PHASE2	COMPLETED	Pharmacokinetics of Afamelanotide in Erythropoietic Protoporphyria Patients
NCT00004831	Not specified	COMPLETED	Study of Cysteine Hydrochloride for Erythropoietic Protoporphyria
NCT00206869	Not specified	UNKNOWN	Does Exercise and Heat Increase the Lightsensibility in Patients With Erythropoietic Protoporphyria
NCT01550705	Not specified	TERMINATED	Effect of Isoniazid on Protoporphyrin Levels in Erythropoietic Protoporphyria
NCT01688895	Not specified	COMPLETED	Erythropoietic Protoporphyrias: Studies of the Natural History, Genotype-Phenotype Correlations, and Psychosocial Impact
NCT01880983	Not specified	COMPLETED	Mitoferrin-1 Expression in Erythropoietic Protoporphyria (Porphyria Rare Disease Clinical Research Consortium (RDCRC))
NCT02979249	Not specified	COMPLETED	Oral Iron for Erythropoietic Protoporphyrias
NCT03682731	Not specified	COMPLETED	Light Exposure Patterns and Symptoms Among Patients With Erythropoietic Protoporphyria
NCT05572125	Not specified	COMPLETED	Iron Therapy in Erythropoietic Protoporphyria
NCT05780840	Not specified	UNKNOWN	Protection Against Visible Light by Dihydroxyacetone in Erythropoietic Protoporphyria
NCT07567131	Not specified	RECRUITING	Observational Study of Adults and Adolescents With Erythropoietic Protoporphyria (EPP) and X-linked Porphyria (XLP)
NCT07603401	Not specified	TEMPORARILY_NOT_AVAILABLE	Expanded Access Program of Bitopertin For Participants With EPP or XLP