Target Information
Target General Information | Top | |||||
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Target ID |
T75890
(Former ID: TTDR01187)
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Target Name |
Dihydrothymine dehydrogenase (DPYD)
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Synonyms |
Dihydrouracil dehydrogenase; Dihydropyrimidine dehydrogenase [NADP(+)]; Dihydropyrimidine dehydrogenase; DPD; DHPDHase
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Gene Name |
DPYD
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
Catalyzes the reduction of uracil and thymine. Also involved the degradation of the chemotherapeutic drug 5-fluorouracil. Involved in pyrimidine base degradation.
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BioChemical Class |
CH/CH donor oxidoreductase
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UniProt ID | ||||||
EC Number |
EC 1.3.1.2
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Sequence |
MAPVLSKDSADIESILALNPRTQTHATLCSTSAKKLDKKHWKRNPDKNCFNCEKLENNFD
DIKHTTLGERGALREAMRCLKCADAPCQKSCPTNLDIKSFITSIANKNYYGAAKMIFSDN PLGLTCGMVCPTSDLCVGGCNLYATEEGPINIGGLQQFATEVFKAMSIPQIRNPSLPPPE KMSEAYSAKIALFGAGPASISCASFLARLGYSDITIFEKQEYVGGLSTSEIPQFRLPYDV VNFEIELMKDLGVKIICGKSLSVNEMTLSTLKEKGYKAAFIGIGLPEPNKDAIFQGLTQD QGFYTSKDFLPLVAKGSKAGMCACHSPLPSIRGVVIVLGAGDTAFDCATSALRCGARRVF IVFRKGFVNIRAVPEEMELAKEEKCEFLPFLSPRKVIVKGGRIVAMQFVRTEQDETGKWN EDEDQMVHLKADVVISAFGSVLSDPKVKEALSPIKFNRWGLPEVDPETMQTSEAWVFAGG DVVGLANTTVESVNDGKQASWYIHKYVQSQYGASVSAKPELPLFYTPIDLVDISVEMAGL KFINPFGLASATPATSTSMIRRAFEAGWGFALTKTFSLDKDIVTNVSPRIIRGTTSGPMY GPGQSSFLNIELISEKTAAYWCQSVTELKADFPDNIVIASIMCSYNKNDWTELAKKSEDS GADALELNLSCPHGMGERGMGLACGQDPELVRNICRWVRQAVQIPFFAKLTPNVTDIVSI ARAAKEGGANGVTATNTVSGLMGLKSDGTPWPAVGIAKRTTYGGVSGTAIRPIALRAVTS IARALPGFPILATGGIDSAESGLQFLHSGASVLQVCSAIQNQDFTVIEDYCTGLKALLYL KSIEELQDWDGQSPATVSHQKGKPVPRIAELMDKKLPSFGPYLEQRKKIIAENKIRLKEQ NVAFSPLKRNCFIPKRPIPTIKDVIGKALQYLGTFGELSNVEQVVAMIDEEMCINCGKCY MTCNDSGYQAIQFDPETHLPTITDTCTGCTLCLSVCPIVDCIKMVSRTTPYEPKRGVPLS VNPVC Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
ADReCS ID | BADD_A01329 ; BADD_A01462 ; BADD_A02149 ; BADD_A03065 ; BADD_A04623 ; BADD_A05061 ; BADD_A06316 ; BADD_A06627 |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
1 | Fluorouracil | Drug Info | Approved | Solid tumour/cancer | [2] | |
Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | Eniluracil | Drug Info | Phase 2 | Hyperlipidaemia | [3] | |
2 | RO-09-4889 | Drug Info | Phase 1 | Solid tumour/cancer | [4] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | FL-386 | Drug Info | Discontinued in Phase 2 | Hyperlipidaemia | [5] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 5 Inhibitor drugs | + | ||||
1 | Fluorouracil | Drug Info | [1] | |||
2 | (5s)-5-Iododihydro-2,4(1h,3h)-Pyrimidinedione | Drug Info | [8] | |||
3 | 5-Iodouracil | Drug Info | [8] | |||
4 | 6-Carboxymethyluracil | Drug Info | [8] | |||
5 | Flavin-Adenine Dinucleotide | Drug Info | [8] | |||
Modulator | [+] 3 Modulator drugs | + | ||||
1 | Eniluracil | Drug Info | [3] | |||
2 | RO-09-4889 | Drug Info | [4], [6] | |||
3 | FL-386 | Drug Info | [6], [7] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Different Human System Profiles of Target | Top |
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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
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There is no similarity protein (E value < 0.005) for this target
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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.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Pyrimidine metabolism | hsa00240 | Affiliated Target |
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Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
beta-Alanine metabolism | hsa00410 | Affiliated Target |
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Class: Metabolism => Metabolism of other amino acids | Pathway Hierarchy | ||
Pantothenate and CoA biosynthesis | hsa00770 | Affiliated Target |
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Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy | ||
Drug metabolism - other enzymes | hsa00983 | Affiliated Target |
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Class: Metabolism => Xenobiotics biodegradation and metabolism | Pathway Hierarchy |
Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 4.09E-04 |
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Closeness centrality | 1.52E-01 | Radiality | 1.20E+01 | Clustering coefficient | 4.64E-01 |
Neighborhood connectivity | 8.13E+00 | Topological coefficient | 2.71E-01 | Eccentricity | 13 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"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 Regulators | Top | |||||
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Target-regulating microRNAs |
Target Affiliated Biological Pathways | Top | |||||
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BioCyc | [+] 3 BioCyc Pathways | + | ||||
1 | Pyrimidine ribonucleosides degradation | |||||
2 | Thymine degradation | |||||
3 | Uracil degradation | |||||
KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
1 | Pyrimidine metabolism | |||||
2 | beta-Alanine metabolism | |||||
3 | Pantothenate and CoA biosynthesis | |||||
4 | Drug metabolism - other enzymes | |||||
5 | Metabolic pathways | |||||
Panther Pathway | [+] 1 Panther Pathways | + | ||||
1 | Pyrimidine Metabolism | |||||
Pathwhiz Pathway | [+] 2 Pathwhiz Pathways | + | ||||
1 | Beta-Alanine Metabolism | |||||
2 | Pyrimidine Metabolism | |||||
WikiPathways | [+] 2 WikiPathways | + | ||||
1 | Metabolism of nucleotides | |||||
2 | Fluoropyrimidine Activity |
References | Top | |||||
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REF 1 | Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells. Eur J Cancer. 2002 Jun;38(9):1271-7. | |||||
REF 2 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. | |||||
REF 3 | Eniluracil: an irreversible inhibitor of dihydropyrimidine dehydrogenase. Expert Opin Investig Drugs. 2000 Jul;9(7):1635-49. | |||||
REF 4 | Single ascending dose tolerability, pharmacokinetic-pharmacodynamic study of dihydropyrimidine dehydrogenase inhibitor Ro 09-4889. Clin Cancer Res. 2004 Apr 1;10(7):2327-35. | |||||
REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002285) | |||||
REF 6 | Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res. 2012 Jan;40(Database issue):D1128-36. | |||||
REF 7 | Effects of FL-386 on faecal lipid excretion in humans. J Int Med Res. 1993 Sep-Oct;21(5):225-33. | |||||
REF 8 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. |
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