HPD

Summary

HPD (4-hydroxyphenylpyruvate dioxygenase, HGNC:5147) is a protein-coding gene on chromosome 12q24.31, encoding 4-hydroxyphenylpyruvate dioxygenase (P32754). Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.

The protein encoded by this gene is an enzyme in the catabolic pathway of tyrosine. The encoded protein catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. Defects in this gene are a cause of tyrosinemia type 3 (TYRO3) and hawkinsinuria (HAWK). Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3242 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tyrosinemia type III (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 398 total — 30 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 23
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002150

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5147
Approved symbol	HPD
Name	4-hydroxyphenylpyruvate dioxygenase
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	4-HPPD, 4HPPD, GLOD3, HPPD
Ensembl gene	ENSG00000158104
Ensembl biotype	protein_coding
OMIM	609695
Entrez	3242

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 21 protein_coding, 2 retained_intron

ENST00000289004, ENST00000535114, ENST00000542159, ENST00000543163, ENST00000868944, ENST00000868945, ENST00000868946, ENST00000868947, ENST00000868948, ENST00000868949, ENST00000868950, ENST00000868951, ENST00000868952, ENST00000868953, ENST00000868954, ENST00000868955, ENST00000868956, ENST00000868957, ENST00000868958, ENST00000868959, ENST00000868960, ENST00000868961, ENST00000868962

RefSeq mRNA: 2 — MANE Select: NM_002150 NM_001171993, NM_002150

CCDS: CCDS53839, CCDS9224

Canonical transcript exons

ENST00000289004 — 14 exons

Exon	Start	End
ENSE00001037029	121843710	121843832
ENSE00001037035	121847052	121847214
ENSE00001037045	121856583	121856625
ENSE00001189849	121849687	121849790
ENSE00001289466	121839932	121840048
ENSE00001309044	121858821	121858859
ENSE00002260716	121839527	121839838
ENSE00003461821	121858687	121858713
ENSE00003465087	121854703	121854792
ENSE00003527133	121846862	121846933
ENSE00003538915	121856324	121856406
ENSE00003544321	121848999	121849076
ENSE00003593250	121857757	121857819
ENSE00003661574	121857328	121857432

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 99.72.

FANTOM5 (CAGE): breadth broad, TPM avg 5.0579 / max 1347.3777, expressed in 309 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133784	4.8225	246
133785	0.2030	109
133783	0.0324	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.72	gold quality
liver	UBERON:0002107	99.08	gold quality
adult mammalian kidney	UBERON:0000082	97.18	gold quality
adult organism	UBERON:0007023	97.09	gold quality
kidney epithelium	UBERON:0004819	92.53	gold quality
nephron tubule	UBERON:0001231	92.45	gold quality
renal glomerulus	UBERON:0000074	90.89	gold quality
metanephric glomerulus	UBERON:0004736	90.84	gold quality
kidney	UBERON:0002113	89.18	gold quality
cortex of kidney	UBERON:0001225	84.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.07	gold quality
thoracic aorta	UBERON:0001515	81.10	gold quality
ascending aorta	UBERON:0001496	81.09	gold quality
left uterine tube	UBERON:0001303	79.85	gold quality
metanephros cortex	UBERON:0010533	79.85	gold quality
descending thoracic aorta	UBERON:0002345	79.50	gold quality
metanephros	UBERON:0000081	79.08	gold quality
left testis	UBERON:0004533	78.87	gold quality
right testis	UBERON:0004534	78.71	gold quality
renal medulla	UBERON:0000362	77.79	gold quality
aorta	UBERON:0000947	77.34	gold quality
right adrenal gland cortex	UBERON:0035827	77.06	gold quality
left adrenal gland	UBERON:0001234	76.84	gold quality
left adrenal gland cortex	UBERON:0035825	76.75	gold quality
right adrenal gland	UBERON:0001233	76.60	gold quality
testis	UBERON:0000473	75.67	gold quality
left coronary artery	UBERON:0001626	75.61	gold quality
popliteal artery	UBERON:0002250	74.89	gold quality
tibial artery	UBERON:0007610	74.86	gold quality
adrenal cortex	UBERON:0001235	74.27	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	3370.27
E-CURD-98	yes	426.14
E-HCAD-9	yes	53.44
E-CURD-10	no	459.85
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1

miRNA regulators (miRDB)

16 targeting HPD, 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-6798-5P	100.00	65.77	699
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-1237-5P	95.38	62.21	451
HSA-MIR-4488	95.38	62.00	443
HSA-MIR-4697-5P	95.38	61.72	457
HSA-MIR-1228-5P	93.60	63.91	91
HSA-MIR-4649-5P	93.02	63.85	141
HSA-MIR-6729-5P	93.02	62.76	138
HSA-MIR-1268A	87.06	61.46	145
HSA-MIR-1268B	87.06	61.46	145
HSA-MIR-6784-5P	84.56	60.91	126

Literature-anchored findings (GeneRIF, showing 10)

• The IIe335Met allele is equivalent to a null mutation while the Asn241Ser allele results in a partially active enzyme with an uncoupled turnover causing elevated haykinin in urine. (PMID:17560158)
• Glutamine375 has a critical role for 4-HPPD in orientating the tail and ensuring the conformation of the terminal alpha-helix of the enzyme to maintain the integrity of the active site for biocatalysis. (PMID:23950902)
• 4-hydroxyphenylpyruvate dioxygenase gene mutation is associated with Hawkinsinuria. (PMID:26226126)
• The mutagenesis and structural simulation studies demonstrate the critical and unique role of each ligand in the function of HPPD, and which correlates with their respective co-ordination position. (PMID:26936969)
• Our findings indicate that HPD may be a useful prognostic predictor, and a potential therapeutic target for patients with breast cancer (PMID:31277952)
• this study reveals HPD as a novel regulator of LKB1-AMPK signaling-mediated HDAC10 nuclear location. (PMID:31285420)
• Role of the N-terminus in human 4-hydroxyphenylpyruvate dioxygenase activity. (PMID:31722428)
• Variant analysis of HPD genes from two families showing elevated tyrosine upon newborn screening by tandem mass spectrometry (MS/MS). (PMID:32109208)
• Tyrosine metabolic enzyme HPD is decreased and predicts unfavorable outcomes in hepatocellular carcinoma. (PMID:32891822)
• The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway. (PMID:34471290)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hpdb	ENSDARG00000044935
mus_musculus	Hpd	ENSMUSG00000029445
rattus_norvegicus	Hpd	ENSRNOG00000001338
drosophila_melanogaster	Hpd	FBGN0036992
caenorhabditis_elegans		WBGENE00001993

Paralogs (1): HPDL (ENSG00000186603)

Protein

Protein identifiers

4-hydroxyphenylpyruvate dioxygenase — P32754 (reviewed: P32754)

Alternative names: 4-hydroxyphenylpyruvic acid oxidase

All UniProt accessions (1): P32754

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Endoplasmic reticulum membrane. Golgi apparatus membrane.

Disease relevance. Tyrosinemia 3 (TYRSN3) [MIM:276710] An autosomal recessive inborn error of metabolism characterized by high levels of tyrosine in the blood, massive excretion of its derivatives into urine, seizures and mild intellectual disability. The disease is caused by variants affecting the gene represented in this entry. Hawkinsinuria (HWKS) [MIM:140350] An autosomal dominat inborn error of tyrosine metabolism characterized by failure to thrive, transient metabolic acidosis, and excretion of the unusual cyclic amino acid metabolite, hawkinsin, in the urine. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Fe cation per subunit.

Pathway. Amino-acid degradation; L-phenylalanine degradation; acetoacetate and fumarate from L-phenylalanine: step 3/6.

Similarity. Belongs to the 4HPPD family.

Isoforms (2)

UniProt ID	Names	Canonical?
P32754-1	1	yes
P32754-2	2

RefSeq proteins (2): NP_001165464, NP_002141* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004360	Glyas_Fos-R_dOase_dom	Domain
IPR005956	4OHPhenylPyrv_dOase	Family
IPR029068	Glyas_Bleomycin-R_OHBP_Dase	Homologous_superfamily
IPR037523	VOC_core	Domain
IPR041735	4OHPhenylPyrv_dOase_C	Domain
IPR041736	4OHPhenylPyrv_dOase_N	Domain

Pfam: PF00903

Enzyme classification (BRENDA):

• EC 1.13.11.27 — 4-hydroxyphenylpyruvate dioxygenase (BRENDA: 45 organisms, 27 substrates, 456 inhibitors, 87 Km, 60 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-HYDROXYPHENYLPYRUVATE	0.0017–54	71
PHENYLPYRUVATE	0.06–0.52	4
O2	0.05–0.1	3
(4-HYDROXYPHENYL)-PYRUVATE	0.027	1
2-THIENYLPYRUVATE	0.5	1
3,4-DIHYDROXYPHENYLPYRUVATE	0.05	1
3-THIENYLPYRUVATE	0.25	1
4-HYDROXYTETRAFLUOROPHENYLPYRUVATE	0.05	1
OXYGEN	0.115	1

Catalyzed reactions (Rhea), 1 shown:

• 3-(4-hydroxyphenyl)pyruvate + O2 = homogentisate + CO2 (RHEA:16189)

UniProt features (56 total): strand 18, helix 12, sequence variant 11, modified residue 5, binding site 3, domain 2, initiator methionine 1, chain 1, splice variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3ISQ	X-RAY DIFFRACTION	1.75
5EC3	X-RAY DIFFRACTION	2.1
8IM3	X-RAY DIFFRACTION	2.78
8IM2	X-RAY DIFFRACTION	2.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P32754-F1	96.00	0.93

Functional residue map

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

Ligand- & substrate-binding residues (3): 183; 266; 349

Post-translational modifications (5): 226, 250, 2, 132, 211

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8963684	Tyrosine catabolism

MSigDB gene sets: 176 (showing top): MODULE_93, GNF2_GSTM1, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, LEE_LIVER_CANCER_CIPROFIBRATE_DN, CAIRO_HEPATOBLASTOMA_CLASSES_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GNF2_LCAT, HSIAO_LIVER_SPECIFIC_GENES, MODULE_373, GNF2_HPX, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (3): L-phenylalanine catabolic process (GO:0006559), L-tyrosine catabolic process (GO:0006572), aromatic amino acid metabolic process (GO:0009072)

GO Molecular Function (6): 4-hydroxyphenylpyruvate dioxygenase activity (GO:0003868), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on single donors with incorporation of molecular oxygen (GO:0016701), dioxygenase activity (GO:0051213)

GO Cellular Component (8): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Phenylalanine and tyrosine metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
aromatic amino acid catabolic process	2
L-amino acid catabolic process	2
proteinogenic amino acid catabolic process	2
oxidoreductase activity	2
endomembrane system	2
intracellular membrane-bounded organelle	2
amino acid metabolic process	1
carboxylic acid metabolic process	1
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1730 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HPD	FAH	P16930	987
HPD	TAT	P17735	940
HPD	HGD	Q93099	757
HPD	PPOX	P50336	663
HPD	GSTZ1	O43708	641
HPD	AFP	P02771	591
HPD	HNRNPA2B1	P22626	571
HPD	ACAA1	P09110	540
HPD	UPB1	Q9UBR1	468
HPD	PAH	P00439	461
HPD	HPS1	Q92902	453
HPD	GLUL	P15104	448
HPD	ALDH18A1	P54886	407
HPD	SPTA1	P02549	400
HPD	PRCC	Q92733	394

IntAct

9 interactions, top by confidence:

A	B	Type	Score
RBMX	PTCD1	psi-mi:“MI:0914”(association)	0.530
HPD	ASPSCR1	psi-mi:“MI:0915”(physical association)	0.400
CDKN1A	HPD	psi-mi:“MI:0915”(physical association)	0.370
IKBKG	HPD	psi-mi:“MI:0915”(physical association)	0.370
HIVEP1	HPD	psi-mi:“MI:0915”(physical association)	0.370
HPD	RIDA	psi-mi:“MI:0915”(physical association)	0.370
RTN4	SCAMP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): ASPSCR1 (Affinity Capture-MS), HPD (Affinity Capture-MS), HPD (Affinity Capture-MS), ASPSCR1 (Affinity Capture-MS), TTC36 (Affinity Capture-MS), GTF2I (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), DLAT (Affinity Capture-MS), DSP (Affinity Capture-MS), PELI1 (Affinity Capture-MS), STK33 (Affinity Capture-MS), HPD (Affinity Capture-Western), HPD (Affinity Capture-Western), PELI1 (Affinity Capture-Western), STK33 (Affinity Capture-Western)

ESM2 similar proteins: A8XX92, E9CWP5, F4I1L3, O42764, O65398, O94632, O94634, P0CW94, P23996, P32754, P32755, P49429, P49915, P50107, P78820, P93836, Q00955, Q02110, Q09253, Q09751, Q0UHC4, Q10170, Q18347, Q1E803, Q22633, Q27203, Q38970, Q39366, Q3THK7, Q46I26, Q4V7C6, Q4WHU1, Q4WPV8, Q5APF2, Q5BKL0, Q5EA20, Q5RA96, Q60Y65, Q6C3P4, Q6CDR5

Diamond homologs: E9CWP5, O06695, O23920, O42764, O48604, O52791, P0CW94, P23996, P32754, P32755, P49429, P69053, P80064, P93836, Q02110, Q18347, Q1E803, Q22633, Q27203, Q4WHU1, Q4WPV8, Q53586, Q5BKL0, Q5EA20, Q5ZT84, Q60Y65, Q6CDR5, Q6TGZ5, Q76NV5, Q872T7, Q96IR7, Q96X22, Q9ARF9, Q9I576, Q9S2F4, Q557J8, Q88JU3, Q9I6P6, Q55810, Q5XIH9

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
STK33	“down-regulates quantity by destabilization”	HPD	phosphorylation
PELI1	“down-regulates quantity by destabilization”	HPD	ubiquitination
TTC36	“up-regulates quantity by stabilization”	HPD	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	13
Uncertain significance	106
Likely benign	198
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1333313	NM_002150.3(HPD):c.463del (p.Gln155fs)	Pathogenic
1574	NM_002150.3(HPD):c.774T>G (p.Tyr258Ter)	Pathogenic
1575	NM_002150.3(HPD):c.600C>G (p.Tyr200Ter)	Pathogenic
2110723	NM_002150.3(HPD):c.184dup (p.Ile62fs)	Pathogenic
2128171	NM_002150.3(HPD):c.91C>T (p.Gln31Ter)	Pathogenic
2429187	NM_002150.3(HPD):c.248del (p.Gly83fs)	Pathogenic
2921754	NM_002150.3(HPD):c.715_724del (p.Pro239fs)	Pathogenic
2922293	NM_002150.3(HPD):c.852_853dup (p.Gly285fs)	Pathogenic
2932690	NM_002150.3(HPD):c.850_853del (p.Arg284fs)	Pathogenic
2946803	NM_002150.3(HPD):c.146del (p.Gly49fs)	Pathogenic
2948128	NM_002150.3(HPD):c.865_866del (p.Leu289fs)	Pathogenic
2950625	NM_002150.3(HPD):c.142del (p.Arg48fs)	Pathogenic
3244248	NC_000012.11:g.(?122284748)(122296729_?)del	Pathogenic
3244249	NC_000012.11:g.(?122296573)(122296729_?)del	Pathogenic
3244250	NC_000012.11:g.(?122294469)(122296729_?)del	Pathogenic
3244251	NC_000012.11:g.(?122292589)(122296729_?)del	Pathogenic
3244252	NC_000012.11:g.(?122277634)(122287716_?)del	Pathogenic
3244253	NC_000012.11:g.(?122286885)(122287716_?)del	Pathogenic
3244254	NC_000012.11:g.(?122284839)(122288809_?)del	Pathogenic
3244335	NC_000012.11:g.(?122064648)(122287716_?)del	Pathogenic
3339459	NM_002150.3(HPD):c.442dup (p.Glu148fs)	Pathogenic
3753445	NM_002150.3(HPD):c.274G>T (p.Gly92Ter)	Pathogenic
3753543	NM_002150.3(HPD):c.65_66del (p.Val22fs)	Pathogenic
3754946	NM_002150.3(HPD):c.535del (p.Glu179fs)	Pathogenic
4687140	NC_000012.11:g.(?122277432)(122296766_?)del	Pathogenic
529472	NC_000012.12:g.(?121843690)(121847234_?)del	Pathogenic
642856	NM_002150.3(HPD):c.158dup (p.Ser54fs)	Pathogenic
832353	NC_000012.12:g.(?121846842)(121849810_?)del	Pathogenic
953791	NM_002150.3(HPD):c.852_853del (p.Gly285fs)	Pathogenic
979166	NM_002150.3(HPD):c.722A>G (p.Asn241Ser)	Pathogenic

SpliceAI

1776 predictions. Top by Δscore:

Variant	Effect	Δscore
12:121839834:AAACC:A	acceptor_gain	1.0000
12:121839835:AACC:A	acceptor_gain	1.0000
12:121839836:ACC:A	acceptor_gain	1.0000
12:121839837:CC:C	acceptor_gain	1.0000
12:121839837:CCC:C	acceptor_gain	1.0000
12:121839838:CC:C	acceptor_gain	1.0000
12:121839839:C:CA	acceptor_loss	1.0000
12:121839839:C:CC	acceptor_gain	1.0000
12:121839839:C:T	acceptor_gain	1.0000
12:121839841:G:C	acceptor_gain	1.0000
12:121839846:G:T	acceptor_gain	1.0000
12:121839928:GTAC:G	donor_loss	1.0000
12:121839929:TAC:T	donor_loss	1.0000
12:121839930:A:AC	donor_gain	1.0000
12:121839931:C:A	donor_loss	1.0000
12:121839931:C:CC	donor_gain	1.0000
12:121839957:T:TA	donor_gain	1.0000
12:121840046:CTC:C	acceptor_gain	1.0000
12:121840047:TC:T	acceptor_gain	1.0000
12:121840047:TCCTA:T	acceptor_loss	1.0000
12:121840048:CC:C	acceptor_gain	1.0000
12:121840049:C:CC	acceptor_gain	1.0000
12:121840050:T:C	acceptor_loss	1.0000
12:121843675:C:A	donor_gain	1.0000
12:121843705:CTCA:C	donor_loss	1.0000
12:121843706:TCA:T	donor_loss	1.0000
12:121843708:ACC:A	donor_loss	1.0000
12:121843709:C:CG	donor_loss	1.0000
12:121843831:ATC:A	acceptor_loss	1.0000
12:121843832:TCT:T	acceptor_loss	1.0000

AlphaMissense

2602 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:121839833:A:C	F359L	0.999
12:121839833:A:T	F359L	0.999
12:121839835:A:G	F359L	0.999
12:121839995:G:C	F336L	0.998
12:121839995:G:T	F336L	0.998
12:121839997:A:G	F336L	0.998
12:121849046:G:C	H183Q	0.998
12:121849046:G:T	H183Q	0.998
12:121849047:T:G	H183P	0.998
12:121839946:G:T	R353S	0.997
12:121839962:G:C	F347L	0.997
12:121839962:G:T	F347L	0.997
12:121839964:A:G	F347L	0.997
12:121846897:G:C	H266D	0.997
12:121847135:A:G	S226P	0.997
12:121847145:G:C	S222R	0.997
12:121847145:G:T	S222R	0.997
12:121847147:T:G	S222R	0.997
12:121849034:G:C	N187K	0.997
12:121849034:G:T	N187K	0.997
12:121849048:G:C	H183D	0.997
12:121839806:G:C	F368L	0.996
12:121839806:G:T	F368L	0.996
12:121839808:A:G	F368L	0.996
12:121839818:G:C	F364L	0.996
12:121839818:G:T	F364L	0.996
12:121839820:A:G	F364L	0.996
12:121839956:T:A	E349D	0.996
12:121839956:T:G	E349D	0.996
12:121839957:T:A	E349V	0.996

dbSNP variants (sampled 300 via entrez): RS1000007751 (12:121866045 C>T), RS1000018692 (12:121864691 A>C), RS1000199445 (12:121856550 G>A), RS1000306169 (12:121851338 T>G), RS1000327894 (12:121869755 C>A), RS1000334431 (12:121851636 T>A), RS1000406525 (12:121863166 C>T), RS1000430211 (12:121889713 G>A), RS1000562671 (12:121857966 C>G,T), RS1000608591 (12:121864821 C>G), RS1000655472 (12:121846248 C>G), RS1000798490 (12:121870980 G>T), RS1000853045 (12:121845474 G>A), RS1000870964 (12:121884883 A>G), RS1000986164 (12:121885080 G>A,T)

Disease associations

OMIM: gene MIM:609695 | disease phenotypes: MIM:140350, MIM:276710, MIM:612782, MIM:615883

GenCC curated gene-disease

Disease	Classification	Inheritance
hawkinsinuria	Strong	Autosomal dominant
tyrosinemia type III	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
hawkinsinuria	Limited	AD
tyrosinemia type III	Definitive	AR

Mondo (4): hawkinsinuria (MONDO:0007700), tyrosinemia type III (MONDO:0010162), combined immunodeficiency due to ORAI1 deficiency (MONDO:0013007), myopathy, tubular aggregate, 2 (MONDO:0014383)

Orphanet (4): Hawkinsinuria (Orphanet:2118), Tyrosinemia type 3 (Orphanet:69723), Combined immunodeficiency due to CRAC channel dysfunction (Orphanet:169090), Combined immunodeficiency due to ORAI1 deficiency (Orphanet:317428)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000711	Restlessness
HP:0000821	Hypothyroidism
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001942	Metabolic acidosis
HP:0002213	Fine hair
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003161	4-Hydroxyphenylpyruvic aciduria
HP:0003231	Hypertyrosinemia
HP:0003593	Infantile onset
HP:0003607	4-hydroxyphenylacetic aciduria
HP:0003623	Neonatal onset
HP:0008070	Sparse hair
HP:0010864	Severe intellectual disability
HP:0010917	Abnormal circulating tyrosine concentration
HP:0034457	Hawkinsinuria
HP:6001004	Elevated urine hydroxyphenyllactic acid level

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001073_1	Urinary metabolites	1.000000e-46
GCST001762_413	Obesity-related traits	3.000000e-06
GCST003119_18	Urinary metabolites	7.000000e-78
GCST003119_8	Urinary metabolites	2.000000e-80
GCST009733_159	Urinary metabolite levels in chronic kidney disease	3.000000e-11
GCST010242_386	HDL cholesterol levels	4.000000e-10
GCST012020_524	Serum metabolite levels	2.000000e-11
GCST012021_65	Serum metabolite levels	2.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0003940	physical activity
EFO:0005116	urinary metabolite measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C535845	Hawkinsinuria (supp.)
C557826	Immune dysfunction with T-cell inactivation due to calcium entry defect 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1861 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,497 (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
CHEMBL1337	NITISINONE	4	1,497

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 1.-.-.- Oxidoreductases

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

Ligand	Action	Affinity	Parameter
nitisinone	Inhibition	7.4	pIC50

ChEMBL bioactivities

113 potent at pChembl≥5 of 113 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	Ki	10	nM	CHEMBL3342603
7.96	Ki	11	nM	CHEMBL3343183
7.89	Ki	13	nM	CHEMBL3342605
7.85	Ki	14	nM	CHEMBL3342604
7.82	Ki	15	nM	CHEMBL3342432
7.75	Ki	18	nM	CHEMBL3342610
7.72	Ki	19	nM	CHEMBL3342431
7.70	Ki	20	nM	CHEMBL3342602
7.68	IC50	21	nM	CHEMBL3408320
7.66	Ki	22	nM	CHEMBL3342609
7.66	Ki	22	nM	CHEMBL3342598
7.66	IC50	22	nM	CHEMBL3408314
7.66	IC50	22	nM	CHEMBL3408319
7.62	Ki	24	nM	CHEMBL3342599
7.60	Ki	25	nM	CHEMBL3343184
7.60	Ki	25	nM	CHEMBL3342611
7.51	Ki	31	nM	CHEMBL3342607
7.50	Ki	32	nM	CHEMBL3342614
7.47	Ki	34	nM	CHEMBL3342608
7.47	Ki	34	nM	CHEMBL3342606
7.43	Ki	37	nM	NITISINONE
7.42	Ki	38	nM	CHEMBL3342601
7.41	IC50	39	nM	CHEMBL3408324
7.40	Ki	40	nM	CHEMBL3343182
7.40	IC50	40	nM	CHEMBL3408325
7.33	IC50	47	nM	CHEMBL4533679
7.24	Ki	58	nM	CHEMBL3342600
7.23	Ki	59	nM	CHEMBL3343187
7.23	IC50	59	nM	CHEMBL3408157
7.22	Ki	60	nM	CHEMBL3342612
7.21	IC50	61	nM	CHEMBL3408313
7.20	IC50	63	nM	CHEMBL4526579
7.19	IC50	64	nM	CHEMBL3408321
7.17	IC50	68	nM	CHEMBL3408156
7.17	IC50	68	nM	CHEMBL4564855
7.17	IC50	68	nM	CHEMBL4582009
7.16	IC50	70	nM	CHEMBL4571726
7.16	IC50	70	nM	CHEMBL4540372
7.13	Ki	74	nM	CHEMBL3342416
7.11	IC50	77	nM	CHEMBL3408326
7.10	Ki	79	nM	CHEMBL3342415
7.09	Ki	81	nM	CHEMBL3342426
7.07	Ki	86	nM	CHEMBL3342412
7.07	IC50	85	nM	CHEMBL4567229
7.06	Ki	87	nM	CHEMBL3342428
7.05	Ki	90	nM	CHEMBL3343186
7.05	Ki	90	nM	CHEMBL3342419
7.04	IC50	91	nM	CHEMBL4554387
7.03	Ki	93	nM	CHEMBL3342418
7.02	IC50	95	nM	CHEMBL4564283

PubChem BioAssay actives

113 with measured affinity, of 117 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
3-(3-chlorophenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0100	uM
3-(2-bromo-4-methylphenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0110	uM
2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-3-(3-methylphenyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0130	uM
3-(3-bromophenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0140	uM
3-(2-fluorophenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0150	uM
3-(4-bromophenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0180	uM
2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-3-phenylquinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0190	uM
3-(3-fluorophenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0200	uM
1,3-diethyl-5-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)benzimidazol-2-one	1197161: Inhibition of human recombinant His-tagged HPPD expressed in Escherichia coli BL21(DE3) by UV/visible plate reader analysis	ic50	0.0210	uM
3-(2-chlorophenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0220	uM
3-(4-chlorophenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0220	uM
3-ethyl-1-methyl-5-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)benzimidazol-2-one	1197161: Inhibition of human recombinant His-tagged HPPD expressed in Escherichia coli BL21(DE3) by UV/visible plate reader analysis	ic50	0.0220	uM
1-ethyl-5-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-3-propylbenzimidazol-2-one	1197161: Inhibition of human recombinant His-tagged HPPD expressed in Escherichia coli BL21(DE3) by UV/visible plate reader analysis	ic50	0.0220	uM
3-(2-bromophenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0240	uM
2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-3-(4-methylphenyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0250	uM
3-(3,4-dichlorophenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0250	uM
2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-3-[3-(trifluoromethoxy)phenyl]quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0310	uM
3-(4-chloro-2-methylphenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0320	uM
3-(3-methoxyphenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0340	uM
3-(4-fluorophenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0340	uM
Nitisinone	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0370	uM
3-(2-methoxyphenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0380	uM
3-ethyl-5-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-1-propylbenzimidazol-2-one	1197161: Inhibition of human recombinant His-tagged HPPD expressed in Escherichia coli BL21(DE3) by UV/visible plate reader analysis	ic50	0.0390	uM
3-(4-fluoro-2-methylphenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0400	uM
5-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-1,3-dipropylbenzimidazol-2-one	1197161: Inhibition of human recombinant His-tagged HPPD expressed in Escherichia coli BL21(DE3) by UV/visible plate reader analysis	ic50	0.0400	uM
2-[[3-[(4-bromophenyl)methoxy]-2-nitrophenyl]-hydroxymethylidene]cyclohexane-1,3-dione	1638282: Inhibition of human recombinant HPPD expressed in Escherichia coli BL21 (DE3) assessed as effect on maleylacetoacetate formation incubated for 10 mins by human HGD coupled enzyme assay	ic50	0.0470	uM
2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-3-(2-methylphenyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0580	uM
3-(2,4-dimethylphenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0590	uM
1-methyl-5-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-3-propylbenzimidazol-2-one	1197161: Inhibition of human recombinant His-tagged HPPD expressed in Escherichia coli BL21(DE3) by UV/visible plate reader analysis	ic50	0.0590	uM
3-(4-methoxyphenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0600	uM
1-methyl-5-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-3-propan-2-ylbenzimidazol-2-one	1197161: Inhibition of human recombinant His-tagged HPPD expressed in Escherichia coli BL21(DE3) by UV/visible plate reader analysis	ic50	0.0610	uM
2-[[3-[(2,4-dichlorophenyl)methoxy]-2-nitrophenyl]-hydroxymethylidene]cyclohexane-1,3-dione	1638282: Inhibition of human recombinant HPPD expressed in Escherichia coli BL21 (DE3) assessed as effect on maleylacetoacetate formation incubated for 10 mins by human HGD coupled enzyme assay	ic50	0.0630	uM
1-ethyl-5-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-3-propan-2-ylbenzimidazol-2-one	1197161: Inhibition of human recombinant His-tagged HPPD expressed in Escherichia coli BL21(DE3) by UV/visible plate reader analysis	ic50	0.0640	uM
3-[2-nitro-4-(trifluoromethyl)benzoyl]hexane-2,4-dione	1197161: Inhibition of human recombinant His-tagged HPPD expressed in Escherichia coli BL21(DE3) by UV/visible plate reader analysis	ic50	0.0680	uM
2-[[3-[(3,5-dimethylphenyl)methoxy]-2-nitrophenyl]-hydroxymethylidene]cyclohexane-1,3-dione	1638282: Inhibition of human recombinant HPPD expressed in Escherichia coli BL21 (DE3) assessed as effect on maleylacetoacetate formation incubated for 10 mins by human HGD coupled enzyme assay	ic50	0.0680	uM
2-[[3-[(4-bromo-2-fluorophenyl)methoxy]-2-nitrophenyl]-hydroxymethylidene]cyclohexane-1,3-dione	1638282: Inhibition of human recombinant HPPD expressed in Escherichia coli BL21 (DE3) assessed as effect on maleylacetoacetate formation incubated for 10 mins by human HGD coupled enzyme assay	ic50	0.0680	uM
2-[hydroxy-[3-[(4-methylphenyl)methoxy]-2-nitrophenyl]methylidene]cyclohexane-1,3-dione	1638282: Inhibition of human recombinant HPPD expressed in Escherichia coli BL21 (DE3) assessed as effect on maleylacetoacetate formation incubated for 10 mins by human HGD coupled enzyme assay	ic50	0.0700	uM
2-[hydroxy-[2-nitro-3-[(4-propan-2-ylphenyl)methoxy]phenyl]methylidene]cyclohexane-1,3-dione	1638282: Inhibition of human recombinant HPPD expressed in Escherichia coli BL21 (DE3) assessed as effect on maleylacetoacetate formation incubated for 10 mins by human HGD coupled enzyme assay	ic50	0.0700	uM
6-(2,5-dimethyl-3-oxo-1H-pyrazole-4-carbonyl)-2-methyl-3-(3-methylphenyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0740	uM
3-tert-butyl-5-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)-1-propylbenzimidazol-2-one	1197161: Inhibition of human recombinant His-tagged HPPD expressed in Escherichia coli BL21(DE3) by UV/visible plate reader analysis	ic50	0.0770	uM
6-(2,5-dimethyl-3-oxo-1H-pyrazole-4-carbonyl)-3-(2-fluorophenyl)-2-methylquinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0790	uM
6-(2,5-dimethyl-3-oxo-1H-pyrazole-4-carbonyl)-3-(2-fluoro-4-methylphenyl)-2-methylquinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0810	uM
2-[hydroxy-[2-nitro-4-(trifluoromethyl)phenyl]methylidene]cyclohexane-1,3-dione	1638282: Inhibition of human recombinant HPPD expressed in Escherichia coli BL21 (DE3) assessed as effect on maleylacetoacetate formation incubated for 10 mins by human HGD coupled enzyme assay	ic50	0.0850	uM
3-(2-chlorophenyl)-6-(2,5-dimethyl-3-oxo-1H-pyrazole-4-carbonyl)-2-methylquinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0860	uM
3-(2-bromo-4-methylphenyl)-6-(2,5-dimethyl-3-oxo-1H-pyrazole-4-carbonyl)-2-methylquinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0870	uM
6-(2,5-dimethyl-3-oxo-1H-pyrazole-4-carbonyl)-3-(3-fluorophenyl)-2-methylquinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0900	uM
3-(2-chloro-4-methylphenyl)-2-methyl-6-(2-methyl-3-oxo-1H-pyrazole-4-carbonyl)quinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0900	uM
2-[[3-[(4-bromophenyl)methoxy]phenyl]-hydroxymethylidene]cyclohexane-1,3-dione	1638282: Inhibition of human recombinant HPPD expressed in Escherichia coli BL21 (DE3) assessed as effect on maleylacetoacetate formation incubated for 10 mins by human HGD coupled enzyme assay	ic50	0.0910	uM
3-(3-bromophenyl)-6-(2,5-dimethyl-3-oxo-1H-pyrazole-4-carbonyl)-2-methylquinazolin-4-one	1162498: Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	ki	0.0930	uM
2-[[3-[(2,4-difluorophenyl)methoxy]-2-nitrophenyl]-hydroxymethylidene]cyclohexane-1,3-dione	1638282: Inhibition of human recombinant HPPD expressed in Escherichia coli BL21 (DE3) assessed as effect on maleylacetoacetate formation incubated for 10 mins by human HGD coupled enzyme assay	ic50	0.0950	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, decreases expression, increases expression, increases methylation	4
Cyclosporine	increases expression, decreases expression	4
sodium arsenite	decreases expression, increases expression, increases methylation	3
Acetaminophen	decreases expression	2
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
bisphenol A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
tamibarotene	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	increases expression	1
Succimer	decreases expression, affects cotreatment	1
Dimethylnitrosamine	increases expression	1
Estradiol	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Methapyrilene	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Tretinoin	increases expression	1
Valproic Acid	decreases expression	1
Aflatoxin B1	affects expression	1
Cadmium Chloride	increases abundance, increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3388490	Binding	Inhibition of purified His6-tagged recombinant human HPPD assessed as inhibition of maleylacetoacetate formation after 30 mins by UV/visible spectrophotometry	Pyrazolone-quinazolone hybrids: a novel class of human 4-hydroxyphenylpyruvate dioxygenase inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F1P2	HyCyte HCT 116 KO-hHPD	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04196959	Not specified	COMPLETED	Evaluation of TYR Sphere
NCT06298292	Not specified	NOT_YET_RECRUITING	Acceptability/Tolerance of Protein Substitutes in Tablet Form for the Dietary Management of Rare Aminoacidopathies