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): 404 total — 30 pathogenic, 14 likely-pathogenic (top 8% of genes corpus-wide)
• GTEx eGene: eQTL in 20 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 37
• Drug target: yes — 1 curated mechanism-of-action drug; 1 molecules with ChEMBL bioactivity
• Approved drugs (ChEMBL mechanism of action): 1 — Nitisinone
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.84 (unconstrained)
• 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: 57 — 29 protein_coding, 26 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000289004

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 4: 1, TSL 5: 2

ENST00000289004, ENST00000535114, ENST00000542159, ENST00000543163, ENST00000868944, ENST00000868945, ENST00000868946, ENST00000868947, ENST00000868948, ENST00000868949, ENST00000868950, ENST00000868951, ENST00000868952, ENST00000868953, ENST00000868954, ENST00000868955, ENST00000868956, ENST00000868957, ENST00000868958, ENST00000868959, ENST00000868960, ENST00000868961, ENST00000868962, ENST00000991861, ENST00000991862, ENST00000991864, ENST00000991865, ENST00000991866, ENST00000991867, ENST00000991868, ENST00000991869, ENST00000991870, ENST00000991873, ENST00000991874, ENST00000991876, ENST00000991877, ENST00000991879, ENST00000991881, ENST00000991885, ENST00000991887, ENST00000991888, ENST00000991891, ENST00000991893, ENST00000991894, ENST00000991896, ENST00000991898, ENST00000991902, ENST00000991903, ENST00000991905, ENST00000991909, ENST00000991910, ENST00000991913, ENST00001098357, ENST00001098358, ENST00001109220, ENST00001121479, ENST00001139801

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.

Highest expression (Bgee): lobe of liver, liver, adult mammalian kidney, adult organism, kidney epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

HPD is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 20 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 22 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	3.4e-40	+0.55	12:121850296:G:A
Whole Blood	eqtl	3.8e-37	-0.45	12:121854243:G:A
Heart Left Ventricle	eqtl	1.0e-19	+0.49	12:121853479:G:A
Cells Cultured fibroblasts	eqtl	2.7e-12	+0.33	12:121859126:T:C
Artery Aorta	eqtl	2.2e-11	+0.30	12:121848794:C:T
Artery Tibial	eqtl	2.4e-09	+0.21	12:121874418:G:A
Spleen	eqtl	1.6e-08	+0.87	12:121859108:T:C
Heart Atrial Appendage	eqtl	4.5e-07	+0.26	12:121869065:A:AT
Lung	eqtl	5.4e-07	+0.25	12:121863393:A:G
Esophagus Mucosa	eqtl	2.3e-05	+0.24	12:121963595:A:G
Adrenal Gland	eqtl	1.4e-04	-0.33	12:121861230:G:T
Colon Sigmoid	eqtl	2.3e-04	+0.24	12:121872693:C:T
Adipose Subcutaneous	eqtl	1.1e-03	-0.20	12:121795589:G:C
Colon Transverse	eqtl	2.3e-03	+0.20	12:121892574:G:A
Nerve Tibial	eqtl	2.6e-03	+0.17	12:121872693:C:T
Testis	eqtl	4.1e-03	+0.29	12:121910392:AT:A
Testis	sqtl	6.9e-03	-0.33	12:122024971:C:A
Esophagus Muscularis	eqtl	2.8e-02	+0.56	12:121188562:G:C
Ovary	eqtl	2.8e-02	+0.26	12:121864714:A:G
Pituitary	sqtl	3.0e-02	-2.62	12:121089294:C:T

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

showing 100 of 291 tissues 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
coronary artery	UBERON:0001621	73.54	gold quality
right coronary artery	UBERON:0001625	73.51	gold quality
hindlimb stylopod muscle	UBERON:0004252	73.35	gold quality
adrenal gland	UBERON:0002369	72.89	gold quality
right atrium auricular region	UBERON:0006631	71.77	gold quality
right ovary	UBERON:0002118	71.49	gold quality
choroid plexus epithelium	UBERON:0003911	71.11	gold quality
left ovary	UBERON:0002119	70.67	gold quality
cardiac atrium	UBERON:0002081	69.88	gold quality
colonic epithelium	UBERON:0000397	69.33	gold quality
body of pancreas	UBERON:0001150	68.59	gold quality
gastrocnemius	UBERON:0001388	68.35	gold quality
muscle of leg	UBERON:0001383	66.91	gold quality
apex of heart	UBERON:0002098	66.74	gold quality
ovary	UBERON:0000992	65.95	gold quality
omental fat pad	UBERON:0010414	65.84	gold quality
upper lobe of left lung	UBERON:0008952	65.83	gold quality
peritoneum	UBERON:0002358	65.78	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	65.45	gold quality
right lung	UBERON:0002167	65.22	gold quality
pigmented layer of retina	UBERON:0001782	65.01	silver quality
pancreas	UBERON:0001264	64.88	gold quality
adipose tissue of abdominal region	UBERON:0007808	64.47	gold quality
ectocervix	UBERON:0012249	64.40	gold quality
heart	UBERON:0000948	64.03	gold quality
body of uterus	UBERON:0009853	64.00	gold quality
upper lobe of lung	UBERON:0008948	63.73	gold quality
monocyte	CL:0000576	63.37	gold quality
mononuclear cell	CL:0000842	63.24	gold quality
blood	UBERON:0000178	63.05	gold quality
leukocyte	CL:0000738	62.95	gold quality
spleen	UBERON:0002106	62.81	gold quality
smooth muscle tissue	UBERON:0001135	62.66	gold quality
heart left ventricle	UBERON:0002084	62.42	gold quality
muscle organ	UBERON:0001630	62.30	gold quality
fundus of stomach	UBERON:0001160	62.10	gold quality
muscle layer of sigmoid colon	UBERON:0035805	61.95	gold quality
gall bladder	UBERON:0002110	61.78	gold quality
adrenal tissue	UBERON:0018303	61.74	gold quality
cardiac ventricle	UBERON:0002082	61.68	gold quality
lower esophagus muscularis layer	UBERON:0035833	61.56	gold quality
lower esophagus	UBERON:0013473	61.51	gold quality
endometrium epithelium	UBERON:0004811	61.39	gold quality
body of stomach	UBERON:0001161	61.31	gold quality
prostate gland	UBERON:0002367	61.05	gold quality
endocervix	UBERON:0000458	60.16	gold quality
islet of Langerhans	UBERON:0000006	60.06	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	59.92	gold quality
tibial nerve	UBERON:0001323	59.16	gold quality
vagina	UBERON:0000996	59.15	gold quality
oocyte	CL:0000023	58.87	gold quality
bone marrow cell	CL:0002092	58.66	gold quality
granulocyte	CL:0000094	58.54	gold quality
stomach	UBERON:0000945	58.47	gold quality
esophagus	UBERON:0001043	58.27	gold quality
spinal cord	UBERON:0002240	58.08	gold quality
sigmoid colon	UBERON:0001159	57.96	gold quality
myometrium	UBERON:0001296	57.78	gold quality
urinary bladder	UBERON:0001255	57.74	gold quality
right lobe of thyroid gland	UBERON:0001119	57.49	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	57.34	gold quality
cerebellar vermis	UBERON:0004720	57.27	gold quality
mucosa of stomach	UBERON:0001199	57.04	gold quality
lower esophagus mucosa	UBERON:0035834	57.02	gold quality
anatomical system	UBERON:0000467	56.91	gold quality
subcutaneous adipose tissue	UBERON:0002190	56.90	gold quality
multicellular organism	UBERON:0000468	56.82	gold quality
material anatomical entity	UBERON:0000465	56.81	gold quality
adipose tissue	UBERON:0001013	56.80	gold quality
small intestine Peyer’s patch	UBERON:0003454	56.53	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

HPA expression

RNA tissue specificity: Tissue enriched

47 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	2365.4	high
Kidney	tissue	495.3	medium
Choroid plexus	tissue	242.9
Seminal vesicle	tissue	6.9	not detected
Testis	tissue	5.2	not detected
Breast	tissue	4.3	not detected
Pancreas	tissue	3.7	not detected
Adrenal gland	tissue	2.2	not detected
Adipose tissue	tissue	1.9	not detected
Vagina	tissue	1.7	not detected
Urinary bladder	tissue	1.5	not detected
Smooth muscle	tissue	1.3	not detected
Prostate	tissue	1.3	not detected
Ovary	tissue	1.2	not detected
Fallopian tube	tissue	1.2	not detected
Pituitary gland	tissue	1.1
Skeletal muscle	tissue	1.1	not detected
Heart muscle	tissue	1.0	not detected
Gallbladder	tissue	1.0	not detected
Bone marrow	tissue	0.9	not detected
Colon	tissue	0.8	not detected
Lung	tissue	0.8	not detected
Epididymis	tissue	0.7	not detected
Spleen	tissue	0.7	not detected
Locus coeruleus	tissue	0.7
Stomach 1	tissue	0.6	not detected
Esophagus	tissue	0.6	not detected
Endometrium 1	tissue	0.6	not detected
Hippocampus	tissue	0.6	not detected
Appendix	tissue	0.6	not detected
Rectum	tissue	0.5	not detected
Nucleus accumbens	tissue	0.4
Lymph node	tissue	0.3	not detected
Retina	tissue	0.3
Placenta	tissue	0.3	not detected
Thyroid gland	tissue	0.3	not detected
Small intestine	tissue	0.3	not detected
Cervix	tissue	0.2	not detected
Skin 1	tissue	0.1	not detected
Salivary gland	tissue	0.1	not detected
Parathyroid gland	tissue	0.1	not detected
Tongue	tissue	0.1
Duodenum	tissue	0.1	not detected
Thymus	tissue	0.1
Tonsil	tissue	0.1	not detected
Hippocampal formation	tissue	0.1
Septum	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — Hippocampus, CA3 (15.6), Blood vessel (10.0), Habenula (7.0), Vermis (6.4), Area postrema (3.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1

miRNA regulators (miRDB)

Targeting HPD by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

16 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 8.98e-08, LOEUF 0.845, missense Z 1.52 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000289004 — one region, missense o/e 0.87.

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:96213) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased circulating tyrosine level	2
abnormal retina morphology	1
head bobbing	1
abnormal urine homeostasis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Coccidioides posadasii str. Silveira	E9CWP5	100.0%	Diamond
Coccidioides posadasii C735 delta SOWgp	P0CW94	100.0%	Diamond
Coccidioides immitis RS	Q1E803	99.7%	Diamond
Bos taurus	Q5EA20	92.4%	Diamond
Streptomyces avermitilis MA-4680 = NBRC 14893	Q53586	92.1%	Diamond
Streptomyces coelicolor A3(2)	Q9S2F4	92.1%	Diamond
Caenorhabditis briggsae	Q60Y65	90.1%	Diamond
Xenopus tropicalis	Q5BKL0	82.8%	Diamond
Sus scrofa	Q02110	82.5%	Diamond
Daucus carota	O23920	77.2%	Diamond
Coleus scutellarioides	Q9ARF9	77.2%	Diamond
Aspergillus fumigatus Af293	Q4WHU1	76.7%	Diamond
Arabidopsis thaliana	P93836	74.5%	Diamond
Neurospora crassa OR74A	Q872T7	73.3%	Diamond
Pyricularia oryzae 70-15	Q96X22	73.3%	Diamond
Vibrio vulnificus CMCP6	O06695	69.4%	Diamond
Pseudomonas aeruginosa PAO1	Q9I576	69.4%	Diamond
Zymoseptoria tritici	O42764	67.2%	Diamond
Yarrowia lipolytica CLIB122	Q6CDR5	66.7%	Diamond
Hordeum vulgare	O48604	66.3%	Diamond
Tetrahymena thermophila	Q27203	59.1%	Diamond
Dictyostelium discoideum	Q76NV5	56.9%	Diamond
Shewanella colwelliana	P23996	44.8%	Diamond
Synechocystis sp. PCC 6803 substr. Kazusa	Q55810	38.7%	Diamond
Amycolatopsis orientalis	O52791	36.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TMEM120B	protein-coding	144404
CFAP251	protein-coding	144406
SETD1B	protein-coding	23067
LINC01089	ncRNA	338799
RHOF	protein-coding	54509
PSMD9	protein-coding	5715
TIALD	ncRNA	105370035
BCL7A	protein-coding	605
LINC02985	ncRNA	100506691
MORN3	protein-coding	283385
ORAI1	protein-coding	84876

Protein

Protein identifiers

4-hydroxyphenylpyruvate dioxygenase — P32754 (reviewed: P32754)

Alternative names: 4-hydroxyphenylpyruvic acid oxidase, N(6)-adenosine-methyltransferase HPD

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. In addition may act as a N6-methyltransferase that methylates adenosine residues at the N(6) position of some RNAs.

Subunit / interactions. Homodimer.

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

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.

Activity regulation. Inbibited by the drug 2-(2-nitro-4- trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC).

Cofactor. Binds 1 Fe(2+) 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)

• 3-(4-hydroxyphenyl)pyruvate + O2 = homogentisate + CO2 (RHEA:16189)
• an adenosine in mRNA + S-adenosyl-L-methionine = an N(6)-methyladenosine in mRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:55584)

UniProt features (61 total): strand 18, helix 13, sequence variant 11, modified residue 5, mutagenesis site 4, binding site 3, domain 2, initiator methionine 1, chain 1, splice variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
3ISQ	Crystal structure of human 4-Hydroxyphenylpyruvate dioxygenase	X-RAY DIFFRACTION	1.75
5EC3	Structural insight into the catalyitc mechanism of human 4-Hydroxyphenylpyruvate …	X-RAY DIFFRACTION	2.1
8IM3	Crystal structure of human HPPD complexed with compound a10	X-RAY DIFFRACTION	2.78
8IM2	Crystal structure of human HPPD complexed with NTBC	X-RAY DIFFRACTION	2.81

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of amino acid metabolism

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear speckles

Antibody reliability (HPA): IH enhanced · IF uncertain

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)

Position	Role
183	Fe(2+)
266	Fe(2+)
349	Fe(2+)

Post-translational modifications (5)

Type	Positions
Phosphoserine	226, 250, 211
N-acetylthreonine	2
N6-succinyllysine	132

Mutagenesis-validated functional residues (4)

Position	Phenotype
251	abolishes 4-hydroxyphenylpyruvate dioxygenase activity.
265	abolishes 4-hydroxyphenylpyruvate dioxygenase activity.
334	reduces 4-hydroxyphenylpyruvate dioxygenase activity. 33-fold decrease in catalytic efficiency.
363	reduces 4-hydroxyphenylpyruvate dioxygenase activity. decreases in substrate affinity.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-8963684	Tyrosine catabolism	curated
R-HSA-1430728	Metabolism	—
R-HSA-71291	Metabolism of amino acids and derivatives	—
R-HSA-8963691	Phenylalanine and tyrosine metabolism	—

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 (7): 4-hydroxyphenylpyruvate dioxygenase activity (GO:0003868), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on single donors with incorporation of molecular oxygen (GO:0016701), dioxygenase activity (GO:0051213)

GO Cellular Component (5): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Phenylalanine and tyrosine metabolism	1
Metabolism	1
Metabolism of amino acids and derivatives	1

GO top-level categories

21 GO namespaces:

Category	Terms
amino acid catabolic process	2
aromatic amino acid catabolic process	2
proteinogenic amino acid catabolic process	2
oxidoreductase activity	2
cellular anatomical structure	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
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
cytoplasm	1
extracellular vesicle	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 15 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
L-tyrosine catabolic process	BP	direct assay
extracellular exosome	CC	high-throughput assay
4-hydroxyphenylpyruvate dioxygenase activity	MF	direct assay
protein homodimerization activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,378 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HPD	FAH	P16930	984
HPD	TAT	P17735	940
HPD	HGD	Q93099	813
HPD	GSTZ1	O43708	626
HPD	AFP	P02771	585
HPD	GLOD5	A6NK44	568
HPD	PPOX	P50336	567
HPD	HNRNPA2B1	P22626	565
HPD	PAH	P00439	552
HPD	UPB1	Q9UBR1	512
HPD	IDUA	P35475	426
HPD	ACAA1	P09110	397
HPD	MCEE	Q96PE7	374
HPD	ALB	P02768	373
HPD	CYCS	P00001	371

IntAct

Human interaction partners of HPD in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
ASPSCR1	physical association	0.400	1
CDKN1A	physical association	0.370	1
HIVEP1	physical association	0.370	1
IKBKG	physical association	0.370	1
RIDA	physical association	0.370	1

BioGRID (28 interactions; top human partners by supporting records): PELI1 (Affinity Capture-MS; 3 records), RBMX (Affinity Capture-MS; 3 records), STK33 (Affinity Capture-MS; 3 records), ASPSCR1 (Affinity Capture-MS; 2 records), TTC36 (Affinity Capture-MS; 2 records), ARFGEF2 (Affinity Capture-MS), BAG2 (Affinity Capture-MS), CDKN1A (Two-hybrid), DLAT (Affinity Capture-MS), DSP (Affinity Capture-MS), GTF2I (Affinity Capture-MS), HIVEP1 (Two-hybrid), HRSP12 (Two-hybrid), IKBKG (Two-hybrid), MMGT1 (Affinity Capture-MS)

SIGNOR signaling

3 signaling 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

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ HPD homodimer	1	HPD

Disease & clinical

Genetic variants

Variant evidence for HPD: 404 ClinVar records (44 pathogenic / likely pathogenic); 8 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	14
Uncertain significance	107
Likely benign	203
Benign	20

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 44 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1573	NM_002150.3(HPD):c.479A>G (p.Tyr160Cys)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
642856	NM_002150.3(HPD):c.158dup (p.Ser54fs)	Pathogenic	criteria provided, single submitter	1
953791	NM_002150.3(HPD):c.852_853del (p.Gly285fs)	Pathogenic	criteria provided, single submitter	1
1333313	NM_002150.3(HPD):c.463del (p.Gln155fs)	Pathogenic	criteria provided, single submitter	1
2110723	NM_002150.3(HPD):c.184dup (p.Ile62fs)	Pathogenic	criteria provided, single submitter	1
2128171	NM_002150.3(HPD):c.91C>T (p.Gln31Ter)	Pathogenic	criteria provided, single submitter	1
2921754	NM_002150.3(HPD):c.715_724del (p.Pro239fs)	Pathogenic	criteria provided, single submitter	1
2922293	NM_002150.3(HPD):c.852_853dup (p.Gly285fs)	Pathogenic	criteria provided, single submitter	1
2932690	NM_002150.3(HPD):c.850_853del (p.Arg284fs)	Pathogenic	criteria provided, single submitter	1
2946803	NM_002150.3(HPD):c.146del (p.Gly49fs)	Pathogenic	criteria provided, single submitter	1
2948128	NM_002150.3(HPD):c.865_866del (p.Leu289fs)	Pathogenic	criteria provided, single submitter	1
2950625	NM_002150.3(HPD):c.142del (p.Arg48fs)	Pathogenic	criteria provided, single submitter	1
3339459	NM_002150.3(HPD):c.442dup (p.Glu148fs)	Pathogenic	criteria provided, single submitter	1
3753445	NM_002150.3(HPD):c.274G>T (p.Gly92Ter)	Pathogenic	criteria provided, single submitter	1
3753543	NM_002150.3(HPD):c.65_66del (p.Val22fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore HPD’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 979):

Position(s)	Effect	Δscore	Sites
12:121839839–121839841	acceptor_gain	1.0000	2
12:121839839–121839840	acceptor_loss	1.0000	4
12:121839846	acceptor_gain	1.0000
12:121839930–121839931	donor_loss	1.0000	4
12:121840049–121840050	acceptor_loss	1.0000	5
12:121843675	donor_gain	1.0000
12:121843708–121843709	donor_loss	1.0000	5
12:121843833–121843834	acceptor_loss	1.0000	6
12:121846860–121846861	donor_loss	1.0000	5
12:121846934–121846935	acceptor_loss	1.0000	5

AlphaMissense

1,097 missense substitutions predicted likely pathogenic (of 2,602 scored), across 271 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M193	9	0.858	0.973
H183	8	0.994	0.998
H266	8	0.994	0.997
D325	8	0.986	0.994
D182	8	0.985	0.993
F336	8	0.981	0.998
F359	8	0.977	0.999
F368	8	0.971	0.996
F347	8	0.964	0.997
F364	8	0.958	0.996
H144	8	0.939	0.986
F206	8	0.931	0.989
D91	8	0.928	0.980
N187	8	0.925	0.997
D327	8	0.914	0.975
N363	8	0.914	0.995
D342	8	0.911	0.976
D213	8	0.906	0.973
F288	8	0.905	0.985
N241	8	0.904	0.996

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Liver Hepatocellular Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Glioblastoma Multiforme (validation)	unfavorable	5.43e-08
Uterine Corpus Endometrial Carcinoma (TCGA)	unfavorable	0.000425

Disease associations

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

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
hawkinsinuria	Strong	Autosomal dominant	3
tyrosinemia type III	Strong	Autosomal recessive	4

ClinGen Gene-Disease Validity

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

2 validity classifications:

Disease	Classification	Inheritance
hawkinsinuria	Limited	AD
tyrosinemia type III	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (9 panels, 8 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

9 panels:

Panel	Rating
DDG2P	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Paediatric disorders	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green
Fetal anomalies	amber

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

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

HPO phenotypes

37 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000501	Glaucoma
HP:0000613	Photophobia
HP:0000711	Restlessness
HP:0000729	Autistic behavior
HP:0000821	Hypothyroidism
HP:0001097	Keratoconjunctivitis sicca
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001328	Specific learning disability
HP:0001337	Tremor
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:0003637	Reduced circulating 4-Hydroxyphenylpyruvate dioxygenase activity
HP:0007018	Attention deficit hyperactivity disorder
HP:0007879	Allergic conjunctivitis
HP:0008070	Sparse hair
HP:0010864	Severe intellectual disability
HP:0010917	Abnormal circulating tyrosine concentration
HP:0012758	Neurodevelopmental delay
HP:0034457	Hawkinsinuria
HP:6000479	Elevated urine N-acetyltyrosine level
HP:6000598	Elevated urinary succinylacetone level
HP:6001004	Elevated urine hydroxyphenyllactic acid level

GWAS associations

8 associations:

Study	Trait	p-value
GCST003119_8	Urinary metabolites	2e-80
GCST003119_18	Urinary metabolites	7e-78
GCST001073_1	Urinary metabolites	1e-46
GCST012020_247	Serum metabolite levels	2e-11
GCST012021_65	Serum metabolite levels	2e-11
GCST009733_52	Urinary metabolite levels in chronic kidney disease	3e-11
GCST010242_285	HDL cholesterol levels	4e-10
GCST001762_413	Obesity-related traits	3e-6

EFO canonical traits (from GWAS)

4 canonical traits:

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 disease descriptors:

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)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the HPD protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
NITISINONE	Small molecule	4

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,528 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1337	NITISINONE	4	1,528

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Oxidoreductases

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

Ligand	Action	Affinity	Parameter
nitisinone	Inhibition	7.4	pIC50

Binding affinities (BindingDB)

113 measured of 113 human assays (113 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL3342603	KI	10 nM
CHEMBL3343183	KI	11 nM
CHEMBL3342605	KI	13 nM
CHEMBL3342604	KI	14 nM
CHEMBL3342432	KI	15 nM
CHEMBL3342610	KI	18 nM
CHEMBL3342431	KI	19 nM
CHEMBL3342602	KI	20 nM
CHEMBL3408320	IC50	21 nM
CHEMBL3342598	KI	22 nM
CHEMBL3342609	KI	22 nM
CHEMBL3408314	IC50	22 nM
CHEMBL3408319	IC50	22 nM
CHEMBL3342599	KI	24 nM
CHEMBL3343184	KI	25 nM
CHEMBL3342611	KI	25 nM
CHEMBL3342607	KI	31 nM
CHEMBL3342614	KI	32 nM
CHEMBL3342606	KI	34 nM
CHEMBL3342608	KI	34 nM
2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione	KI	37 nM
CHEMBL3342601	KI	38 nM
CHEMBL3408324	IC50	39 nM
CHEMBL3343182	KI	40 nM
CHEMBL3408325	IC50	40 nM
CHEMBL4533679	IC50	47 nM
CHEMBL3342600	KI	58 nM
CHEMBL3343187	KI	59 nM
CHEMBL3408157	IC50	59 nM
CHEMBL3342612	KI	60 nM
CHEMBL3408313	IC50	61 nM
CHEMBL4526579	IC50	63 nM
CHEMBL3408321	IC50	64 nM
CHEMBL3408156	IC50	68 nM
CHEMBL4564855	IC50	68 nM
CHEMBL4582009	IC50	68 nM
CHEMBL4540372	IC50	70 nM
CHEMBL4571726	IC50	70 nM
CHEMBL3342416	KI	74 nM
CHEMBL3408326	IC50	77 nM
CHEMBL3342415	KI	79 nM
CHEMBL3342426	KI	81 nM
CHEMBL4567229	IC50	85 nM
CHEMBL3342412	KI	86 nM
CHEMBL3342428	KI	87 nM
CHEMBL3342419	KI	90 nM
CHEMBL3343186	KI	90 nM
CHEMBL4554387	IC50	91 nM
CHEMBL3342418	KI	93 nM
CHEMBL4564283	IC50	95 nM

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	increases methylation, affects expression, decreases expression, increases expression	4
Cyclosporine	decreases expression, increases 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 expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Cisplatin	increases expression	1
Succimer	affects cotreatment, decreases expression	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)

Via MONDO — disease-level, not drug-specific.

2 trials:

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for HPD across ~30M SureChEMBL compounds — explore on Sugi Predict.