PPOX

Summary

PPOX (protoporphyrinogen oxidase, HGNC:9280) is a protein-coding gene on chromosome 1q23.3, encoding Protoporphyrinogen oxidase (P50336). Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX.

This gene encodes the penultimate enzyme of heme biosynthesis, which catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. Mutations in this gene cause variegate porphyria, an autosomal dominant disorder of heme metabolism resulting from a deficiency in protoporphyrinogen oxidase, an enzyme located on the inner mitochondrial membrane. Alternatively spliced transcript variants encoding the same protein have been identified.

Source: NCBI Gene 5498 — RefSeq curated summary.

At a glance

• Gene–disease (curated): variegate porphyria (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 330 total — 40 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_001122764

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9280
Approved symbol	PPOX
Name	protoporphyrinogen oxidase
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	PPO
Ensembl gene	ENSG00000143224
Ensembl biotype	protein_coding
OMIM	600923
Entrez	5498

Gene structure

Transcript identifiers

Ensembl transcripts: 62 — 46 protein_coding, 8 retained_intron, 8 nonsense_mediated_decay

ENST00000352210, ENST00000367999, ENST00000460611, ENST00000462866, ENST00000462977, ENST00000466452, ENST00000468968, ENST00000470607, ENST00000479246, ENST00000490768, ENST00000494216, ENST00000495483, ENST00000497522, ENST00000535223, ENST00000537523, ENST00000537829, ENST00000539753, ENST00000541818, ENST00000544598, ENST00000650741, ENST00000651150, ENST00000652100, ENST00000652103, ENST00000652182, ENST00000652297, ENST00000652473, ENST00000652729, ENST00000881036, ENST00000881037, ENST00000881038, ENST00000881039, ENST00000881040, ENST00000881041, ENST00000881042, ENST00000881043, ENST00000881044, ENST00000881045, ENST00000881046, ENST00000923436, ENST00000923437, ENST00000923438, ENST00000923439, ENST00000923440, ENST00000923441, ENST00000923442, ENST00000923443, ENST00000923444, ENST00000923445, ENST00000923446, ENST00000923447, ENST00000923448, ENST00000971241, ENST00000971242, ENST00000971243, ENST00000971244, ENST00000971245, ENST00000971246, ENST00000971247, ENST00000971248, ENST00000971249, ENST00000971250, ENST00000971251

RefSeq mRNA: 10 — MANE Select: NM_001122764 NM_000309, NM_001122764, NM_001350128, NM_001350129, NM_001350130, NM_001350131, NM_001365398, NM_001365399, NM_001365400, NM_001365401

CCDS: CCDS1221

Canonical transcript exons

ENST00000367999 — 13 exons

Exon	Start	End
ENSE00001711651	161166426	161166672
ENSE00002231035	161171034	161171220
ENSE00003463790	161166840	161166934
ENSE00003521329	161167100	161167234
ENSE00003530677	161169906	161170024
ENSE00003572888	161169660	161169720
ENSE00003587863	161170907	161170949
ENSE00003609194	161167995	161168127
ENSE00003609355	161168993	161169183
ENSE00003617219	161170409	161170519
ENSE00003635722	161167371	161167486
ENSE00003641831	161168432	161168576
ENSE00003668544	161170620	161170769

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 99.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.0669 / max 119.4819, expressed in 1767 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6212	10.5236	1759
6213	0.8058	92
6214	0.4791	154
201784	0.1961	44
6215	0.0623	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.10	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.09	gold quality
epithelium of bronchus	UBERON:0002031	93.88	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.64	gold quality
bronchus	UBERON:0002185	93.53	gold quality
bronchial epithelial cell	CL:0002328	93.40	gold quality
cerebellar hemisphere	UBERON:0002245	93.28	gold quality
cerebellar cortex	UBERON:0002129	93.18	gold quality
left ovary	UBERON:0002119	93.13	gold quality
adenohypophysis	UBERON:0002196	93.08	gold quality
right ovary	UBERON:0002118	92.79	gold quality
granulocyte	CL:0000094	92.74	gold quality
endocervix	UBERON:0000458	92.54	gold quality
body of uterus	UBERON:0009853	92.34	gold quality
right adrenal gland cortex	UBERON:0035827	92.22	gold quality
right adrenal gland	UBERON:0001233	92.19	gold quality
right lobe of thyroid gland	UBERON:0001119	92.13	gold quality
metanephros cortex	UBERON:0010533	91.80	gold quality
left lobe of thyroid gland	UBERON:0001120	91.74	gold quality
pituitary gland	UBERON:0000007	91.61	gold quality
left adrenal gland cortex	UBERON:0035825	91.51	gold quality
cerebellum	UBERON:0002037	91.22	gold quality
left adrenal gland	UBERON:0001234	91.08	gold quality
tibial nerve	UBERON:0001323	91.01	gold quality
bone marrow cell	CL:0002092	90.93	gold quality
apex of heart	UBERON:0002098	90.92	gold quality
skin of abdomen	UBERON:0001416	90.91	gold quality
adrenal cortex	UBERON:0001235	90.90	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.90	gold quality
thyroid gland	UBERON:0002046	90.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-112	yes	44.25
E-ANND-3	yes	8.51

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 23)

• Two previously undescribed mutations were identified: PPOX1423-1426-delATCT and PPOX2272insG. (PMID:12017191)
• This enzyme in its regular and mutagenized forms is targeted to mitochondria when transfected. (PMID:12556518)
• Information required for targeting to the mitochondria is contained within the first 250 amino acid residues of human PPOX. (PMID:14535846)
• Modulation of penetrance by the wild-type allele in dominantly inherited erythrohepatic and acute hepatic porphyrias was studied using PPOX. (PMID:14669009)
• Protoporphyrinogen oxidase targeting mechanism to the mitochondrion. (PMID:16621625)
• Mutation in protoporphyrinogen oxidase is associated with variegate porphyria (PMID:16947091)
• GATA-1 binding sites in exon 1 constitute key regulatory elements in differential expression of PPOX in erythroid and non-erythroid cells. (PMID:18191920)
• sequenced 27 members of a family with variegate porphyria with a T>A transversion at the intron 6 consensus splicing site in 8 patients and 4 SNPs: c.-414A>C; IVS2+121G>C; c.1188G>A and IVS12+34C>T (PMID:19229653)
• The c.851G>T and the c.1013C>G of PPOX gene were found in two and four unrelated families respectively. 1 experienced only photosensitivity, 1 only neurological symptoms and the 2 both clinical manifestations. (PMID:19656455)
• The mutation 1082-1083insC(1 base pair insertion at position 1082) in exon 10 of the PPOX gene was prevalent in the Swiss population. (PMID:19656457)
• Forty-seven variegate porphyria-causing mutations were purified by chromatography and kinetically characterized in vitro. (PMID:21048046)
• data deliver further confirmation that the South African and Dutch variegate porphyria families carrying mutation p.R59W shared a common ancestor. (PMID:21910705)
• findings emphasize the usefulness of MLPA analysis as a complement to PPOX gene sequencing analysis for comprehensive genetic diagnostics in patients with variegate prophyria (PMID:23324528)
• VP-causing mutation affect the catalytic activity of hPPO by affecting the ability of hPPO to sample the privileged conformations (PMID:23467411)
• Variegate porphyria is the result of decreased protoporphyrinogen oxidase activity. Diet supplementation with vitamins E and C restores PPOX gene expression in lymphocytes of variegate porphyria patients. (PMID:23601071)
• in the hepatic cancer tissue of two acute porphyria patients, somatic second-hit mutations result in nearly complete inactivation of PPOX and HMBS (PMID:25445397)
• GAPDH and protoporphyrinogen oxidase were shown to have higher expression in faster growing cell lines and primary tumors. Pharmacologic inhibition of GAPDH or PPOX reduced the growth of colon cancer cells in vitro (PMID:25944804)
• the regulation of PPOX gene expression can also occur through a post-transcriptional modulation of the amount of gene product and this modulation can be mediated by 5’ untranslated exon 1. (PMID:27667166)
• The genetic test showed a heterozygous mutation in the gene encoding Protoporphyrinogen Oxidase (PPOX); c.2T > A (p.Met1Lys) on chromosome 1q23, which supports the diagnosis of Variegate Porphyria (PMID:29550908)
• Mount Sinai Porphyrias Diagnostic Laboratory diagnosed 54 unrelated Variegate Porphyria individuals with 20 PPOX novel mutations. (PMID:30385147)
• Two new mutations in the PPOX gene in a patient with variegate porphyria. (PMID:32247286)
• The hydrogen bonding network involved Arg59 in human protoporphyrinogen IX oxidase is essential for enzyme activity. (PMID:33857841)
• Molecular characterization of a novel His333Arg variant of human protoporphyrinogen oxidase IX. (PMID:34968794)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppox	ENSDARG00000102167
mus_musculus	Ppox	ENSMUSG00000062729
rattus_norvegicus	Ppox	ENSRNOG00000003567
drosophila_melanogaster	Ppox	FBGN0020018
caenorhabditis_elegans	spr-5	WBGENE00005010
caenorhabditis_elegans		WBGENE00011615

Paralogs (7): KDM1A (ENSG00000004487), MAOB (ENSG00000069535), SMOX (ENSG00000088826), IL4I1 (ENSG00000104951), PAOX (ENSG00000148832), KDM1B (ENSG00000165097), MAOA (ENSG00000189221)

Protein

Protein identifiers

Protoporphyrinogen oxidase — P50336 (reviewed: P50336)

All UniProt accessions (18): P50336, A0A1W2PNH4, A0A1W2PPA5, A0A1W2PQM0, A0A1W2PRF9, A0A494C0C8, A0A494C0D4, A0A494C0L4, A0A494C0M9, A0A494C134, A0A494C146, A0A494C1M8, D3DVG2, F5GZT7, F5H1I5, F5H825, H0YFE1, H0YFP3

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX.

Subunit / interactions. Monomer. Homodimer.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Disease relevance. Variegate porphyria (VP) [MIM:176200] A form of porphyria. 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. Variegate porphyria is an acute hepatic form characterized by partial reduction of protoporphyrinogen oxidase activity, increased photosensitivity, skin blistering and scarring of sun-exposed areas, skin hyperpigmentation, abdominal pain, and neuropsychiatric symptoms. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease. Inheritance is autosomal dominant with incomplete penetrance. The disease is caused by variants affecting the gene represented in this entry. Mutations leading to severe PPOX deficiency cause the rare homozygous variant form of VP. Missense mutations that preserve 10%-25% of wild-type activity may not cause clinically overt VP in heterozygotes. Mutations with intermediate effect on catalytic activity may cause VP, but with a low clinical penetrance. Variegate porphyria, childhood-onset (VPCO) [MIM:620483] An autosomal recessive form of variegate porphyria, a disorder of heme biosynthesis that results from diminished activity of protoporphyrinogen oxidase. VPCO is characterized by severe protoporphyrinogen oxidase deficiency, onset of photosensitization by porphyrins in early childhood, skin scarring and hyperpigmentation, and skeletal abnormalities of the hand. Additional variable features are short stature, impaired intellectual development, and seizures. VPCO patients rarely experience acute neuropsychiatric or abdominal attacks. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 FAD per subunit.

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

Similarity. Belongs to the protoporphyrinogen/coproporphyrinogen oxidase family. Protoporphyrinogen oxidase subfamily.

RefSeq proteins (10): NP_000300, NP_001116236, NP_001337057, NP_001337058, NP_001337059, NP_001337060, NP_001352327, NP_001352328, NP_001352329, NP_001352330 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002937	Amino_oxidase	Domain
IPR004572	Protoporphyrinogen_oxidase	Family
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily
IPR050464	Zeta_carotene_desat/Oxidored	Family

Pfam: PF01593

Enzyme classification (BRENDA):

• EC 1.3.3.4 — protoporphyrinogen oxidase (BRENDA: 50 organisms, 43 substrates, 644 inhibitors, 107 Km, 84 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PROTOPORPHYRINOGEN-IX	—	56
PROTOPORPHYRINOGEN IX	0.0004–0.0196	41
MESOPORPHYRINOGEN-IX	0.0005–0.09	3
COPROPORPHYRINOGEN-III	0.0053	1
HEMATOPORPHYRINOGEN-IX	0.09	1
O2	0.125	1

Catalyzed reactions (Rhea), 1 shown:

• protoporphyrinogen IX + 3 O2 = protoporphyrin IX + 3 H2O2 (RHEA:25576)

UniProt features (128 total): sequence variant 59, helix 23, strand 21, mutagenesis site 12, binding site 7, turn 5, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3NKS	X-RAY DIFFRACTION	1.9
4IVO	X-RAY DIFFRACTION	2.6
4IVM	X-RAY DIFFRACTION	2.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50336-F1	95.39	0.92

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (7): 9–14; 34–35; 42; 57–60; 257; 449; 454–456

Mutagenesis-validated functional residues (12):

Position	Phenotype
59	decreases enzyme activity by 75%.
59	decreases enzyme activity by 90%. strongly decreases affinity for protoporphyrinogen-ix.
74	abolishes enzyme activity. impairs protein folding and/or stability.
97	decreases enzyme activity by 89%. impairs protein folding and/or stability.
166	decreases enzyme activity by 95%.
169	decreases enzyme activity by 64%.
284	decreases enzyme activity by 87%. impairs protein folding and/or stability.
290	no effect on enzyme activity.
331	decreases enzyme activity by 50%.
334	decreases enzyme activity by 86%.
347	decreases enzyme activity by 45%.
368	decreases enzyme activity by 52%.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-189451	Heme biosynthesis

MSigDB gene sets: 0 (showing top):

GO Biological Process (7): porphyrin-containing compound biosynthetic process (GO:0006779), obsolete protoporphyrinogen IX biosynthetic process (GO:0006782), heme biosynthetic process (GO:0006783), heme A biosynthetic process (GO:0006784), heme B biosynthetic process (GO:0006785), response to xenobiotic stimulus (GO:0009410), obsolete protoporphyrinogen IX metabolic process (GO:0046501)

GO Molecular Function (3): protoporphyrinogen oxidase activity, oxygen as acceptor (GO:0004729), flavin adenine dinucleotide binding (GO:0050660), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), mitochondrial membrane (GO:0031966), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of porphyrins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
heme biosynthetic process	2
mitochondrial envelope	2
porphyrin-containing compound metabolic process	1
tetrapyrrole biosynthetic process	1
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
response to chemical	1
oxidoreductase activity, acting on the CH-CH group of donors, oxygen as acceptor	1
protoporphyrinogen oxidase activity	1
nucleotide binding	1
anion binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
organelle envelope lumen	1
mitochondrion	1
organelle membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1356 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPOX	HMBS	P08396	953
PPOX	UROD	P06132	949
PPOX	FECH	P22830	933
PPOX	CPOX	P36551	920
PPOX	UROS	P10746	859
PPOX	ALAD	P13716	859
PPOX	ALAS1	P13196	857
PPOX	ALAS2	P22557	828
PPOX	SLC6A1	P30531	826
PPOX	ABCB7	O75027	733
PPOX	ABCB10	Q9NRK6	689
PPOX	SLC25A38	Q96DW6	679
PPOX	ABCB6	Q9NP58	666
PPOX	HPD	P32754	663
PPOX	TDO2	P48775	659

IntAct

73 interactions, top by confidence:

A	B	Type	Score
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
ANTXR1	WFS1	psi-mi:“MI:0914”(association)	0.530
ZNRD2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
PPOX	Alas2	psi-mi:“MI:0914”(association)	0.350
PCDHA12	KLRG2	psi-mi:“MI:0914”(association)	0.350
ACSM5	NUDT19	psi-mi:“MI:0914”(association)	0.350
NDUFS7		psi-mi:“MI:0914”(association)	0.350
TCTN1	PPOX	psi-mi:“MI:0914”(association)	0.350
CRYBA4	APAF1	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
MAIP1	TIMM44	psi-mi:“MI:0914”(association)	0.350
ENG	IGKV2-28	psi-mi:“MI:0914”(association)	0.350
RAB5A	EIF3CL	psi-mi:“MI:0914”(association)	0.350
esxA	PGRMC1	psi-mi:“MI:0914”(association)	0.350
HTRA2	VWA8	psi-mi:“MI:0914”(association)	0.350
IMMP1L	EIF1AY	psi-mi:“MI:0914”(association)	0.350
IMMP2L	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
LIMK2	HAX1	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
RAMP2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
UQCRFS1	VWA8	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
H2AP	GNPAT	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
TRMU	IFT56	psi-mi:“MI:0914”(association)	0.350

BioGRID (96): PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS), PPOX (Affinity Capture-MS)

ESM2 similar proteins: A2AI05, D3ZDK7, E1BNQ4, O55240, O70249, P21139, P24298, P25409, P50336, P51175, P56602, P97849, Q03426, Q1JPJ0, Q27979, Q2KJF7, Q3T0A0, Q3ZKN0, Q498R1, Q4JIJ2, Q5E9M9, Q5E9T8, Q5R7A2, Q5RK23, Q60714, Q60HD5, Q6AYG0, Q6NRG5, Q6P1M0, Q6P3E7, Q6PCB7, Q6PFP6, Q7TSA0, Q8BNV1, Q8BZG5, Q8C1A3, Q8CHP8, Q8IXI1, Q8JZN7, Q8QZR5

Diamond homologs: P50336, P51175, P56601, P56602, Q10062, Q60HD5, Q8BW75, A0A0A1GKA2, O24163, O32434, P0A5A8, P40012, P55826, P81383, P9WMP0, P9WMP1, Q50008, Q9AR38, Q9LRI8, Q9VW97

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	21
Uncertain significance	149
Likely benign	58
Benign	10

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070454	NM_001122764.3(PPOX):c.1280G>A (p.Trp427Ter)	Pathogenic
1072574	NM_001122764.3(PPOX):c.133del (p.Ser45fs)	Pathogenic
1072575	NM_001122764.3(PPOX):c.139C>T (p.Arg47Ter)	Pathogenic
1072576	NM_001122764.3(PPOX):c.1042dup (p.Tyr348fs)	Pathogenic
1074450	NM_001122764.3(PPOX):c.1147_1148del (p.Val383fs)	Pathogenic
1451705	NM_001122764.3(PPOX):c.808-1G>A	Pathogenic
1453380	NM_001122764.3(PPOX):c.342del	Pathogenic
1454341	NM_001122764.3(PPOX):c.384_397dup (p.Glu133delinsGlyLeuGlyTer)	Pathogenic
1454857	NC_000001.10:g.(?161137765)(161138386_?)del	Pathogenic
1457011	NM_001122764.3(PPOX):c.803G>A (p.Trp268Ter)	Pathogenic
1457796	NM_001122764.3(PPOX):c.397G>T (p.Glu133Ter)	Pathogenic
1704297	NM_001122764.3(PPOX):c.338G>C (p.Arg113Thr)	Pathogenic
2577464	NM_001122764.3(PPOX):c.506G>A (p.Gly169Glu)	Pathogenic
2577466	NM_001122764.3(PPOX):c.1043A>G (p.Tyr348Cys)	Pathogenic
2577467	NM_001122764.3(PPOX):c.413G>C (p.Arg138Pro)	Pathogenic
2577468	NM_001122764.3(PPOX):c.808G>T (p.Val270Leu)	Pathogenic
2734009	NM_001122764.3(PPOX):c.1289dup (p.Glu431fs)	Pathogenic
2971414	NM_001122764.3(PPOX):c.1325T>A (p.Leu442Ter)	Pathogenic
3611353	NM_001122764.3(PPOX):c.712C>T (p.Gln238Ter)	Pathogenic
3720253	NM_001122764.3(PPOX):c.441_442del (p.His147fs)	Pathogenic
4541809	NM_001122764.3(PPOX):c.383G>A (p.Trp128Ter)	Pathogenic
4541816	NM_001122764.3(PPOX):c.884T>C (p.Leu295Pro)	Pathogenic
523355	NM_001122764.3(PPOX):c.1353T>G (p.Tyr451Ter)	Pathogenic
643192	NM_001122764.3(PPOX):c.1092_1093del (p.Arg364fs)	Pathogenic
645203	NM_001122764.3(PPOX):c.1291+1G>C	Pathogenic
649718	NM_001122764.3(PPOX):c.78C>A (p.Cys26Ter)	Pathogenic
651549	NM_001122764.3(PPOX):c.565C>T (p.Gln189Ter)	Pathogenic
655883	NM_001122764.3(PPOX):c.2T>C (p.Met1Thr)	Pathogenic
664272	NM_001122764.3(PPOX):c.454C>T (p.Arg152Cys)	Pathogenic
664759	NM_001122764.3(PPOX):c.745dup (p.Val249fs)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3016 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:161170412:T:C	F331L	0.997
1:161170414:T:A	F331L	0.997
1:161170414:T:G	F331L	0.997
1:161169702:A:C	S284R	0.996
1:161169704:T:A	S284R	0.996
1:161169704:T:G	S284R	0.996
1:161168495:A:C	S179R	0.994
1:161168497:C:A	S179R	0.994
1:161168497:C:G	S179R	0.994
1:161168453:A:C	S165R	0.993
1:161168455:T:A	S165R	0.993
1:161168455:T:G	S165R	0.993
1:161170912:C:G	C418W	0.993
1:161169055:T:A	W227R	0.992
1:161169055:T:C	W227R	0.992
1:161170422:T:C	L334S	0.992
1:161171109:T:A	V456D	0.992
1:161171119:T:G	C459W	0.992
1:161168459:T:C	C167R	0.991
1:161168471:T:C	F171L	0.991
1:161168473:T:A	F171L	0.991
1:161168473:T:G	F171L	0.991
1:161170416:G:A	G332E	0.991
1:161168509:C:G	C183W	0.990
1:161169083:T:C	L236S	0.990
1:161170914:T:C	I419T	0.990
1:161168445:C:A	A162D	0.989
1:161169046:T:A	W224R	0.989
1:161169046:T:C	W224R	0.989
1:161169058:T:C	S228P	0.989

dbSNP variants (sampled 300 via entrez): RS1000032128 (1:161172242 T>A), RS1000092132 (1:161173729 T>C), RS1000106201 (1:161173842 C>A), RS1000230179 (1:161178493 C>G,T), RS1001087345 (1:161165892 G>A), RS1001610761 (1:161171046 A>G), RS1001703993 (1:161170696 G>A,C,T), RS1001979984 (1:161169751 A>G,T), RS1002078161 (1:161177568 C>G), RS1002159189 (1:161176223 C>T), RS1002327036 (1:161168493 T>C,G), RS1002378203 (1:161174639 A>G), RS1002430612 (1:161174873 T>TCA), RS1002547162 (1:161171440 G>A), RS1002706050 (1:161165138 C>T)

Disease associations

OMIM: gene MIM:600923 | disease phenotypes: MIM:176200, MIM:620483, MIM:176000

GenCC curated gene-disease

Disease	Classification	Inheritance
variegate porphyria	Definitive	Semidominant
variegate porphyria, childhood-onset	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
variegate porphyria	Strong	SD

Mondo (6): variegate porphyria (MONDO:0008297), variegate porphyria, childhood-onset (MONDO:0957577), cardiomyopathy (MONDO:0004994), acute intermittent porphyria (MONDO:0008294), constipation disorder (MONDO:0002203), migraine disorder (MONDO:0005277)

Orphanet (3): Variegate porphyria (Orphanet:79473), Rare cardiomyopathy (Orphanet:167848), Acute intermittent porphyria (Orphanet:79276)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0002019	Constipation

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D003248	Constipation	C23.888.821.150
D008881	Migraine Disorders	C10.228.140.546.399.750
D017118	Porphyria, Acute Intermittent	C06.552.830.150; C16.320.850.742.150; C17.800.827.742.150; C18.452.811.400.150
D046350	Porphyria, Variegate	C06.552.830.625; C16.320.850.742.625; C17.800.827.742.625; C18.452.811.400.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1926488 (SINGLE PROTEIN)

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

ChEMBL bioactivities

132 potent at pChembl≥5 of 175 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.40	Ki	40	nM	CHEMBL1926835
7.02	Ki	95.5	nM	CHEMBL2252322
7.02	Ki	95	nM	CHEMBL2252322
6.92	Ki	120.2	nM	CHEMBL2252323
6.92	Ki	120	nM	CHEMBL2252323
6.70	Ki	199.5	nM	CHEMBL2252320
6.70	Ki	200	nM	CHEMBL2252320
6.70	Ki	200	nM	CHEMBL1926845
6.60	Ki	251.2	nM	CHEMBL1926967
6.60	Ki	250	nM	CHEMBL1926967
6.52	Ki	302	nM	CHEMBL2252321
6.52	Ki	300	nM	CHEMBL2252321
6.50	Ki	320	nM	CHEMBL1926960
6.49	Ki	323.6	nM	CHEMBL1926960
6.48	Ki	331.1	nM	CHEMBL1926963
6.48	Ki	330	nM	CHEMBL1926963
6.47	Ki	340	nM	CHEMBL1926837
6.44	Ki	360	nM	CHEMBL1926961
6.28	Ki	524.8	nM	CHEMBL2252326
6.28	Ki	530	nM	CHEMBL2252326
6.17	Ki	676.1	nM	CHEMBL2252319
6.17	Ki	670	nM	CHEMBL2252319
6.16	Ki	700	nM	CHEMBL1926863
6.16	Ki	700	nM	CHEMBL1926961
6.16	Ki	691.8	nM	CHEMBL2252347
6.16	Ki	690	nM	CHEMBL2252347
6.15	Ki	708	nM	CHEMBL1926863
6.15	Ki	708	nM	CHEMBL1926961
6.14	Ki	724.4	nM	CHEMBL2230219
6.14	Ki	720	nM	SULFENTRAZONE
6.14	Ki	720	nM	CHEMBL2230219
6.14	Ki	724.4	nM	SULFENTRAZONE
6.14	Ki	720	nM	CHEMBL1926857
6.11	Ki	776.2	nM	CHEMBL2252325
6.11	Ki	780	nM	CHEMBL2252325
6.08	Ki	831.8	nM	CHEMBL2230215
6.08	Ki	840	nM	CHEMBL2230215
6.01	Ki	977.2	nM	CHEMBL2230211
6.01	Ki	980	nM	CHEMBL2230211
6.00	Ki	1000	nM	CHEMBL1926964
6.00	Ki	1010	nM	CHEMBL1926964
5.99	Ki	1023	nM	CHEMBL2252331
5.99	Ki	1023	nM	CHEMBL2252328
5.99	Ki	1030	nM	CHEMBL2252331
5.99	Ki	1030	nM	CHEMBL2252328
5.97	Ki	1072	nM	CHEMBL2230214
5.97	Ki	1070	nM	CHEMBL2230214
5.97	Ki	1070	nM	CHEMBL1926964
5.93	Ki	1175	nM	CHEMBL1926862
5.93	Ki	1170	nM	CHEMBL1926862

PubChem BioAssay actives

132 with measured affinity, of 208 total; 50 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
ethyl [5-(5-tert-butyl-2-oxo-1,3,4-thiadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanylformate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	0.0400	uM
2-(4-chloro-2-fluoro-5-propoxyphenyl)-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	0.0950	uM
2-(4-chloro-2-fluoro-5-prop-2-enoxyphenyl)-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	0.1200	uM
2-(4-chloro-5-ethoxy-2-fluorophenyl)-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	0.1995	uM
ethyl [5-(5-tert-butyl-2-oxo-1,3,4-thiadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanylformate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	0.2000	uM
ethyl 3-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]propanoate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	0.2500	uM
2-(2,4-dichloro-5-propoxyphenyl)-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	0.3000	uM
ethyl 3-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]propanoate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	0.3200	uM
ethyl [5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanylformate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	0.3300	uM
ethyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-thiadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]acetate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	0.3400	uM
ethyl 4-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]butanoate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	0.3600	uM
2-[4-chloro-5-[(3-chlorophenyl)methoxy]-2-fluorophenyl]-3-hydroxy-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	0.5248	uM
2-(2,4-dichloro-5-ethoxyphenyl)-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	0.6700	uM
2-(4-chloro-2-fluoro-5-propan-2-yloxyphenyl)-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	0.6900	uM
propyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	0.7000	uM
methyl [5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanylformate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	0.7200	uM
ethyl [5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanylformate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	0.7200	uM
N-[2,4-dichloro-5-[4-(difluoromethyl)-3-methyl-5-oxo-1,2,4-triazol-1-yl]phenyl]methanesulfonamide	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	0.7200	uM
2-[4-chloro-2-fluoro-5-[(3-fluorophenyl)methoxy]phenyl]-3-hydroxy-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	0.7762	uM
tert-butyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	0.8318	uM
propyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	0.9772	uM
ethyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	1.0000	uM
2-[4-chloro-5-[(3-chlorophenyl)methoxy]-2-fluorophenyl]-3-methoxy-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	1.0233	uM
2-(4-chloro-2-fluoro-5-prop-2-enoxyphenyl)-3-hydroxy-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	1.0233	uM
methyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	1.0700	uM
propan-2-yl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	1.1700	uM
propan-2-yl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-thiadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]acetate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	1.2600	uM
ethyl 3-[[5-(5-tert-butyl-2-oxo-1,3,4-thiadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]propanoate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	1.2800	uM
propyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-thiadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]acetate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	1.3100	uM
ethyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]-2-methylpropanoate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	1.3490	uM
ethyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]propanoate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	1.4125	uM
ethyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]-2-methylpropanoate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	1.5400	uM
ethyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	1.5800	uM
ethyl 2-[[6-bromo-5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-1,3-benzothiazol-2-yl]sulfanyl]-2-methylpropanoate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	1.5800	uM
tert-butyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	1.5849	uM
ethyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]propanoate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	1.6900	uM
ethyl 3-[[6-bromo-5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-1,3-benzothiazol-2-yl]sulfanyl]propanoate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	1.6900	uM
5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid	633804: Inhibition of human PPO expressed in Escherichia coli BL21(DE3) by continuous fluorometric method	ki	1.7100	uM
5-tert-butyl-3-(6-fluoro-2-prop-2-ynylsulfanyl-1,3-benzothiazol-5-yl)-1,3,4-oxadiazol-2-one	633802: Inhibition of human PPO by capillary electrophoresis method	ki	1.9200	uM
ethyl 4-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]butanoate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	2.0200	uM
propan-2-yl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	2.1700	uM
5-tert-butyl-3-(2,4-dichloro-5-propan-2-yloxyphenyl)-1,3,4-oxadiazol-2-one	633802: Inhibition of human PPO by capillary electrophoresis method	ki	2.9300	uM
methyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-thiadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]acetate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	3.0500	uM
5-tert-butyl-3-(6-chloro-2-prop-2-enylsulfanyl-1,3-benzothiazol-5-yl)-1,3,4-oxadiazol-2-one	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	3.0903	uM
propyl 2-[[6-bromo-5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	3.0903	uM
ethyl 2-[2-chloro-5-(1,3-dioxo-3a,4,5,6,7,7a-hexahydroisoindol-2-yl)-4-fluorophenoxy]propanoate	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	3.3000	uM
ethyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-thiadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]-2-methylpropanoate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	3.4600	uM
methyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-oxadiazol-3-yl)-6-fluoro-1,3-benzothiazol-2-yl]sulfanyl]acetate	1081027: Inhibition of Homo sapiens (human) recombinant protoporphyrinogen oxidase expressed in Escherichia coli JM109 assessed as oxidation of protoporphyrinogen IX substrate by UV-visible spectrophotometry	ki	3.9811	uM
2-(4-chloro-2-fluoro-5-methoxyphenyl)-3-methoxy-4,5,6,7-tetrahydro-3H-isoindol-1-one	1091968: Inhibition of Homo sapiens (human) protoporphyrinogen oxidase	ki	4.4668	uM
ethyl 2-[[5-(5-tert-butyl-2-oxo-1,3,4-thiadiazol-3-yl)-6-chloro-1,3-benzothiazol-2-yl]sulfanyl]acetate	633802: Inhibition of human PPO by capillary electrophoresis method	ki	5.8200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	6
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases expression	1
nobiletin	decreases reaction, increases expression	1
sodium arsenate	decreases reaction, increases expression	1
sodium arsenite	decreases expression	1
acifluorfen	decreases activity	1
cupric chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Air Pollutants	increases expression, increases abundance	1
Atrazine	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Doxorubicin	increases expression	1
Estradiol	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1929737	Binding	Inhibition of human PPO by capillary electrophoresis method	Quantitative structure-activity relationships of 1,3,4-thiadiazol-2(3H)-ones and 1,3,4-oxadiazol-2(3H)-ones as human protoporphyrinogen oxidase inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1PY	Abcam K-562 PPOX KO	Cancer cell line	Female
CVCL_D2LK	Abcam Raji PPOX KO	Cancer cell line	Male
CVCL_TF53	HAP1 PPOX (-)	Cancer cell line	Male
CVCL_WQ35	Abcam Jurkat PPOX KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT03338816	PHASE3	COMPLETED	ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT02922413	PHASE2	TERMINATED	Panhematin for Prevention of Acute Attacks of Porphyria
NCT05854784	PHASE2	COMPLETED	Study to Evaluate the Safety and Efficacy of Afamelanotide in Patients With Variegate Porphyria (VP)