Target Information
| Target General Information | Top | |||||
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| Target ID |
T60366
(Former ID: TTDS00313)
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| Target Name |
Ornithine decarboxylase (ODC1)
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| Synonyms |
ODC
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| Gene Name |
ODC1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | African trypanosomiasis [ICD-11: 1F51] | |||||
| Function |
Polyamines are essential for cell proliferation and are implicated in cellular processes, ranging from DNA replication to apoptosis. Catalyzes the first and rate-limiting step of polyamine biosynthesis that converts ornithine into putrescine, which is the precursor for the polyamines, spermidine and spermine.
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| BioChemical Class |
Carbon-carbon lyase
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| UniProt ID | ||||||
| EC Number |
EC 4.1.1.17
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| Sequence |
MNNFGNEEFDCHFLDEGFTAKDILDQKINEVSSSDDKDAFYVADLGDILKKHLRWLKALP
RVTPFYAVKCNDSKAIVKTLAATGTGFDCASKTEIQLVQSLGVPPERIIYANPCKQVSQI KYAANNGVQMMTFDSEVELMKVARAHPKAKLVLRIATDDSKAVCRLSVKFGATLRTSRLL LERAKELNIDVVGVSFHVGSGCTDPETFVQAISDARCVFDMGAEVGFSMYLLDIGGGFPG SEDVKLKFEEITGVINPALDKYFPSDSGVRIIAEPGRYYVASAFTLAVNIIAKKIVLKEQ TGSDDEDESSEQTFMYYVNDGVYGSFNCILYDHAHVKPLLQKRPKPDEKYYSSSIWGPTC DGLDRIVERCDLPEMHVGDWMLFENMGAYTVAAASTFNGFQRPTIYYVMSGPAWQLMQQF QNPDFPPEVEEQDASTLPVSCAWESGMKRHRAACASASINV Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| ADReCS ID | BADD_A01759 ; BADD_A02053 ; BADD_A05554 | |||||
| HIT2.0 ID | T02WMA | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Eflornithine | Drug Info | Approved | African trypanosomiasis | [2], [3] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | Putrescine | Drug Info | Discontinued in Phase 2 | Burn and burn infection | [4], [5] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 18 Inhibitor drugs | + | ||||
| 1 | Eflornithine | Drug Info | [1], [6] | |||
| 2 | Putrescine | Drug Info | [6] | |||
| 3 | (2R,5R)-delta-methyl-alpha-acetylenic putrescine | Drug Info | [1] | |||
| 4 | 1-Amino-3-(aminoxy)-2-propanol Dihydrochloride | Drug Info | [7] | |||
| 5 | 3-(Aminooxy)propan-1-amine hydrochloride | Drug Info | [7] | |||
| 6 | 3-methoxy-4-hydroxylonchocarpin | Drug Info | [8] | |||
| 7 | 4-hydroxylonchocarpin | Drug Info | [8] | |||
| 8 | Alpha-monofluoromethyl-3,4-dehydroornithine | Drug Info | [1] | |||
| 9 | Alpha-monofluoromethyl-3,4-dehydroornithine ethyl ester | Drug Info | [1] | |||
| 10 | Alpha-monofluoromethyl-3,4-dehydroornithine methyl ester | Drug Info | [1] | |||
| 11 | AMXT-1501 | Drug Info | [9] | |||
| 12 | APA | Drug Info | [10], [11] | |||
| 13 | G418 | Drug Info | [6] | |||
| 14 | LONCHOCARPUSONE | Drug Info | [8] | |||
| 15 | N'-Pyridoxyl-Lysine-5'-Monophosphate | Drug Info | [6] | |||
| 16 | N-Pyridoxyl-Glycine-5-Monophosphate | Drug Info | [6] | |||
| 17 | Pyridoxine-5'-Phosphate | Drug Info | [6] | |||
| 18 | ZAPOTIN | Drug Info | [12] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Pyridoxal phosphate | Ligand Info | |||||
| Structure Description | Structure of an intellectual disability-associated ornithine decarboxylase variant G84R in complex with PLP | PDB:7U6U | ||||
| Method | X-ray diffraction | Resolution | 1.85 Å | Mutation | Yes | [13] |
| PDB Sequence |
EEFDCHFLDE
16 GFTAKDILDQ26 KINEVSSSDD36 KDAFYVADLG46 DILKKHLRWL56 KALPRVTPFY 66 AVKCNDSKAI76 VKTLAATRTG86 FDCASKTEIQ96 LVQSLGVPPE106 RIIYANPCKQ 116 VSQIKYAANN126 GVQMMTFDSE136 VELMKVARAH146 PKAKLVLRIA156 TDDSKAVCRL 166 SVKFGATLRT176 SRLLLERAKE186 LNIDVVGVSF196 HVGSGCTDPE206 TFVQAISDAR 216 CVFDMGAEVG226 FSMYLLDIGG236 GFPGSEDVKL246 KFEEITGVIN256 PALDKYFPSD 266 SGVRIIAEPG276 RYYVASAFTL286 AVNIIAKKIV296 LEQTFMYYVN319 DGVYGSFNCI 329 LYDHAHVKPL339 LQKRPKPDEK349 YYSSSIWGPT359 CDGLDRIVER369 CDLPEMHVGD 379 WMLFENMGAY389 TVAAASTFNG399 FQRPTIYYVM409 SGPAWQLMQQ419 FQN |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: APA | Ligand Info | |||||
| Structure Description | A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 3-aminooxy-1-aminopropane | PDB:2OO0 | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [14] |
| PDB Sequence |
AGENLYFQSL
0 MNNFGNEEFD10 CHFLDEGFTA20 KDILDQKINE30 VSSSDDKDAF40 YVADLGDILK 50 KHLRWLKALP60 RVTPFYAVKC70 NDSKAIVKTL80 AATGTGFDCA90 SKTEIQLVQS 100 LGVPPERIIY110 ANPCKQVSQI120 KYAANNGVQM130 MTFDSEVELM140 KVARAHPKAK 150 LVLRIATDDS160 KAVCRLSVKF170 GATLRTSRLL180 LERAKELNID190 VVGVSFHVGS 200 GCTDPETFVQ210 AISDARCVFD220 MGAEVGFSMY230 LLDIGGGFPG240 SEDVKLKFEE 250 ITGVINPALD260 KYFPSDSGVR270 IIAEPGRYYV280 ASAFTLAVNI290 IAKKIVLEQT 313 FMYYVNDGVY323 GSFNCILYDH333 AHVKPLLQKR343 PKPDEKYYSS353 SIWGPTCDGL 363 DRIVERCDLP373 EMHVGDWMLF383 ENMGAYTVAA393 ASTFNGFQRP403 TIYYVMSGPA 413 WQLMQQFQN
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| 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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| Arginine and proline metabolism | hsa00330 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Glutathione metabolism | hsa00480 | Affiliated Target |
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| Class: Metabolism => Metabolism of other amino acids | Pathway Hierarchy | ||
| Degree | 11 | Degree centrality | 1.18E-03 | Betweenness centrality | 9.76E-04 |
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| Closeness centrality | 1.77E-01 | Radiality | 1.29E+01 | Clustering coefficient | 1.09E-01 |
| Neighborhood connectivity | 5.09E+00 | Topological coefficient | 1.61E-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 Transcription Factors | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) |
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| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 1 BioCyc Pathways | + | ||||
| 1 | Putrescine biosynthesis I | |||||
| NetPath Pathway | [+] 3 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| 2 | IL2 Signaling Pathway | |||||
| 3 | TGF_beta_Receptor Signaling Pathway | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Ornithine degradation | |||||
| 2 | CCKR signaling map ST | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Spermidine and Spermine Biosynthesis | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Validated targets of C-MYC transcriptional activation | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Plasmodium falciparum and Plasmodium berghei: effects of ornithine decarboxylase inhibitors on erythrocytic schizogony. Exp Parasitol. 1987 Oct;64(2):237-43. | |||||
| 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: 5176). | |||||
| REF 3 | Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40. | |||||
| REF 4 | 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: 2388). | |||||
| 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 800013366) | |||||
| REF 6 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 7 | Selective delivery of 2-hydroxy APA to Trypanosoma brucei using the melamine motif. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4364-6. | |||||
| REF 8 | New bioactive flavonoids and stilbenes in cub resin insecticide. J Nat Prod. 1999 Feb;62(2):205-10. | |||||
| REF 9 | 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. (Target id: 1276). | |||||
| REF 10 | 2-substituted 3-(aminooxy)propanamines as inhibitors of ornithine decarboxylase: synthesis and biological activity. J Med Chem. 1992 Apr 17;35(8):1339-44. | |||||
| REF 11 | Antileishmanial effect of 3-aminooxy-1-aminopropane is due to polyamine depletion. Antimicrob Agents Chemother. 2007 Feb;51(2):528-34. | |||||
| REF 12 | Synthesis and cancer chemopreventive activity of zapotin, a natural product from Casimiroa edulis. J Med Chem. 2007 Jan 25;50(2):350-5. | |||||
| REF 13 | Structure and Enzymatic Activity of an Intellectual Disability-Associated Ornithine Decarboxylase Variant, G84R. ACS Omega. 2022 Sep 13;7(38):34665-34675. | |||||
| REF 14 | A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane. Biochem J. 2007 Jul 15;405(2):261-8. | |||||
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