Target Information

Target General Information

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Target ID

T07137 (Former ID: TTDS00314)

Target Name

Hydroxyphenylpyruvate dioxygenase (HPD)

Synonyms

HPPDase; HPD; F Alloantigen; 4HPPD

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Gene Name

HPD

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Metabolism inborn error [ICD-11: 5C50]

Function

Key enzyme in the degradation of tyrosine.

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BioChemical Class

Single donor oxidoreductase

UniProt ID

HPPD_HUMAN

EC Number

EC 1.13.11.27

Sequence

MTTYSDKGAKPERGRFLHFHSVTFWVGNAKQAASFYCSKMGFEPLAYRGLETGSREVVSH
VIKQGKIVFVLSSALNPWNKEMGDHLVKHGDGVKDIAFEVEDCDYIVQKARERGAKIMRE
PWVEQDKFGKVKFAVLQTYGDTTHTLVEKMNYIGQFLPGYEAPAFMDPLLPKLPKCSLEM
IDHIVGNQPDQEMVSASEWYLKNLQFHRFWSVDDTQVHTEYSSLRSIVVANYEESIKMPI
NEPAPGKKKSQIQEYVDYNGGAGVQHIALKTEDIITAIRHLRERGLEFLSVPSTYYKQLR
EKLKTAKIKVKENIDALEELKILVDYDEKGYLLQIFTKPVQDRPTLFLEVIQRHNHQGFG
AGNFNSLFKAFEEEQNLRGNLTNMETNGVVPGM

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3D Structure

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PDB

HIT2.0 ID

T49BJB

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Nitisinone

Drug Info

Approved

Hereditary tyrosinemia type 1

[2], [3]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

BMS-433771

Drug Info

Terminated

Respiratory syncytial virus infection

[4]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 17 Inhibitor drugs

Nitisinone

Drug Info

[1], [5]

BMS-433771

Drug Info

[4]

(4-Hydroxy-phenoxy)-acetic acid

Drug Info

[6]

2-(2-Bromo-benzoyl)-cyclohexane-1,3-dione

Drug Info

[7]

2-(2-Chloro-benzoyl)-cyclohexane-1,3-dione

Drug Info

[7]

2-(2-Iodo-benzoyl)-cyclohexane-1,3-dione

Drug Info

[7]

2-(2-Methoxy-benzoyl)-cyclohexane-1,3-dione

Drug Info

[7]

2-(2-Methyl-benzoyl)-cyclohexane-1,3-dione

Drug Info

[7]

2-(2-Nitro-benzoyl)-cyclohexane-1,3-dione

Drug Info

[7]

2-acetyl-3-hydroxycyclohex-2-enone

Drug Info

[8]

2-Acetyl-cyclohexane-1,3-dione

Drug Info

[7]

2-Cyclopropanecarbonyl-cyclohexane-1,3-dione

Drug Info

[7]

2-Propionyl-cyclohexane-1,3-dione

Drug Info

[7]

3-hydroxy-2-propionylcyclohex-2-enone

Drug Info

[8]

3-Hydroxy-4-phenyl-5H-furan-2-one

Drug Info

[6]

Acetate Ion

Drug Info

[9]

Diketonitrile

Drug Info

[5]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL)		24.528 (91/371)	1.18E-26


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Ubiquinone and other terpenoid-quinone biosynthesis	hsa00130	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy
Tyrosine metabolism	hsa00350	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Phenylalanine metabolism	hsa00360	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy

Degree	3	Degree centrality	3.22E-04	Betweenness centrality	8.09E-04
Closeness centrality	1.22E-01	Radiality	1.07E+01	Clustering coefficient	3.33E-01
Neighborhood connectivity	3.00E+00	Topological coefficient	5.33E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 4 KEGG Pathways

Ubiquinone and other terpenoid-quinone biosynthesis

Tyrosine metabolism

Phenylalanine metabolism

Metabolic pathways

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1. Expert Opin Pharmacother. 2008 May;9(7):1229-36.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6834).

REF 3

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 021232.

REF 4

Emerging drugs for respiratory syncytial virus infection. Expert Opin Emerg Drugs. 2009 Jun;14(2):207-17.

REF 5

4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target. Drug News Perspect. 2003 Oct;16(8):493-6.

REF 6

Design, synthesis, and evaluation of postulated transient intermediate and substrate analogues as inhibitors of 4-hydroxyphenylpyruvate dioxygenase. Bioorg Med Chem Lett. 2002 Jul 8;12(13):1709-13.

REF 7

SAR studies of 2-o-substituted-benzoyl- and 2-alkanoyl-cyclohexane-1,3-diones as inhibitors of 4-hydroxyphenylpyruvate dioxygenase. Bioorg Med Chem Lett. 2000 May 1;10(9):843-5.

REF 8

Enzyme inhibition potency enhancement by active site metal chelating and hydrogen bonding induced conformation-restricted cyclopropanecarbonyl deri... Bioorg Med Chem Lett. 2006 Dec 1;16(23):6024-7.

REF 9

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

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